Anemia

The calcium channel blocker amlodipine, added to iron chelation therapy, significantly reduced excess myocardial iron concentration in patients with thalassemia major, compared with chelation alone, according to results from a randomized trial.

The findings (Blood. 2016;128[12]:1555-61) suggest that amlodipine, a cheap, widely available drug with a well-established safety profile, may serve as an adjunct to standard treatment for people with thalassemia major and cardiac siderosis. Cardiovascular disease caused by excess myocardial iron remains a major cause of morbidity and mortality in thalassemia major.

Juliano L. Fernandes, MD, PhD, of the Jose Michel Kalaf Research Institute in Campinas, Brazil, led the study, which randomized 62 patients already receiving chelation treatment for thalassemia major to 1 year of chelation plus placebo (n = 31) or chelation plus 5 mg daily amlodipine (n = 31).

Patients in each arm were subdivided into two subgroups: those whose baseline myocardial iron concentration was within normal thresholds, and those with excess myocardial iron concentration as measured by magnetic resonance imaging (above 0.59 mg/g dry weight or with a cardiac T2* below 35 milliseconds).

In the amlodipine arm, patients with excess cardiac iron at baseline (n = 15) saw significant reductions in myocardial iron concentrations at 1 year, compared with those randomized to placebo (n = 15). The former had a median reduction of –0.26 mg/g (95% confidence interval, –1.02 to –0.01) while the placebo group saw an increase of 0.01 mg/g (95% CI, 20.13 to 20.23; P = .02).

The investigators acknowledged that some of the findings were limited by the study’s short observation period.

Patients without excess myocardial iron concentration at baseline did not see significant changes associated with amlodipine. While Dr. Fernandes and his colleagues could not conclude that the drug prevented excess cardiac iron from accumulating, “our data cannot rule out the possibility that extended use of amlodipine might prevent myocardial iron accumulation with a longer observation period.”

Secondary endpoints of the study included measurements of iron storage in the liver and of serum ferritin, neither of which appeared to be affected by amlodipine treatment, which the investigators said was consistent with the drug’s known mechanism of action. No serious adverse effects were reported related to amlodipine treatment.

Dr. Fernandes and his colleagues also did not find improvements in left ventricular ejection fraction associated with amlodipine use at 12 months. This may be due, they wrote in their analysis, to a “relatively low prevalence of reduced ejection fraction or severe myocardial siderosis upon trial enrollment, limiting the power of the study to assess these outcomes.”

The government of Brazil and the Sultan Bin Khalifa Translational Research Scholarship sponsored the study. Dr. Fernandes reported receiving fees from Novartis and Sanofi. The remaining 12 authors disclosed no conflicts of interest.

The calcium channel blocker amlodipine, added to iron chelation therapy, significantly reduced excess myocardial iron concentration in patients with thalassemia major, compared with chelation alone, according to results from a randomized trial.

The findings (Blood. 2016;128[12]:1555-61) suggest that amlodipine, a cheap, widely available drug with a well-established safety profile, may serve as an adjunct to standard treatment for people with thalassemia major and cardiac siderosis. Cardiovascular disease caused by excess myocardial iron remains a major cause of morbidity and mortality in thalassemia major.

Juliano L. Fernandes, MD, PhD, of the Jose Michel Kalaf Research Institute in Campinas, Brazil, led the study, which randomized 62 patients already receiving chelation treatment for thalassemia major to 1 year of chelation plus placebo (n = 31) or chelation plus 5 mg daily amlodipine (n = 31).

Patients in each arm were subdivided into two subgroups: those whose baseline myocardial iron concentration was within normal thresholds, and those with excess myocardial iron concentration as measured by magnetic resonance imaging (above 0.59 mg/g dry weight or with a cardiac T2* below 35 milliseconds).

In the amlodipine arm, patients with excess cardiac iron at baseline (n = 15) saw significant reductions in myocardial iron concentrations at 1 year, compared with those randomized to placebo (n = 15). The former had a median reduction of –0.26 mg/g (95% confidence interval, –1.02 to –0.01) while the placebo group saw an increase of 0.01 mg/g (95% CI, 20.13 to 20.23; P = .02).

The investigators acknowledged that some of the findings were limited by the study’s short observation period.

Patients without excess myocardial iron concentration at baseline did not see significant changes associated with amlodipine. While Dr. Fernandes and his colleagues could not conclude that the drug prevented excess cardiac iron from accumulating, “our data cannot rule out the possibility that extended use of amlodipine might prevent myocardial iron accumulation with a longer observation period.”

Secondary endpoints of the study included measurements of iron storage in the liver and of serum ferritin, neither of which appeared to be affected by amlodipine treatment, which the investigators said was consistent with the drug’s known mechanism of action. No serious adverse effects were reported related to amlodipine treatment.

Dr. Fernandes and his colleagues also did not find improvements in left ventricular ejection fraction associated with amlodipine use at 12 months. This may be due, they wrote in their analysis, to a “relatively low prevalence of reduced ejection fraction or severe myocardial siderosis upon trial enrollment, limiting the power of the study to assess these outcomes.”

The government of Brazil and the Sultan Bin Khalifa Translational Research Scholarship sponsored the study. Dr. Fernandes reported receiving fees from Novartis and Sanofi. The remaining 12 authors disclosed no conflicts of interest.

The calcium channel blocker amlodipine, added to iron chelation therapy, significantly reduced excess myocardial iron concentration in patients with thalassemia major, compared with chelation alone, according to results from a randomized trial.

The findings (Blood. 2016;128[12]:1555-61) suggest that amlodipine, a cheap, widely available drug with a well-established safety profile, may serve as an adjunct to standard treatment for people with thalassemia major and cardiac siderosis. Cardiovascular disease caused by excess myocardial iron remains a major cause of morbidity and mortality in thalassemia major.

Juliano L. Fernandes, MD, PhD, of the Jose Michel Kalaf Research Institute in Campinas, Brazil, led the study, which randomized 62 patients already receiving chelation treatment for thalassemia major to 1 year of chelation plus placebo (n = 31) or chelation plus 5 mg daily amlodipine (n = 31).

Patients in each arm were subdivided into two subgroups: those whose baseline myocardial iron concentration was within normal thresholds, and those with excess myocardial iron concentration as measured by magnetic resonance imaging (above 0.59 mg/g dry weight or with a cardiac T2* below 35 milliseconds).

In the amlodipine arm, patients with excess cardiac iron at baseline (n = 15) saw significant reductions in myocardial iron concentrations at 1 year, compared with those randomized to placebo (n = 15). The former had a median reduction of –0.26 mg/g (95% confidence interval, –1.02 to –0.01) while the placebo group saw an increase of 0.01 mg/g (95% CI, 20.13 to 20.23; P = .02).

The investigators acknowledged that some of the findings were limited by the study’s short observation period.

Patients without excess myocardial iron concentration at baseline did not see significant changes associated with amlodipine. While Dr. Fernandes and his colleagues could not conclude that the drug prevented excess cardiac iron from accumulating, “our data cannot rule out the possibility that extended use of amlodipine might prevent myocardial iron accumulation with a longer observation period.”

Secondary endpoints of the study included measurements of iron storage in the liver and of serum ferritin, neither of which appeared to be affected by amlodipine treatment, which the investigators said was consistent with the drug’s known mechanism of action. No serious adverse effects were reported related to amlodipine treatment.

Dr. Fernandes and his colleagues also did not find improvements in left ventricular ejection fraction associated with amlodipine use at 12 months. This may be due, they wrote in their analysis, to a “relatively low prevalence of reduced ejection fraction or severe myocardial siderosis upon trial enrollment, limiting the power of the study to assess these outcomes.”

The government of Brazil and the Sultan Bin Khalifa Translational Research Scholarship sponsored the study. Dr. Fernandes reported receiving fees from Novartis and Sanofi. The remaining 12 authors disclosed no conflicts of interest.

A sickled red blood cell

alongside a normal one

Image by Betty Pace

A case series published in Blood indicates that some patients with mildly symptomatic sickle cell disease (SCD) can live long lives if they

comply with treatment recommendations and lead a healthy lifestyle.

The paper includes details on 4 women with milder forms of SCD who survived beyond age 80.

“For those with mild forms of SCD, these women show that lifestyle modifications may improve disease outcomes,” said author Samir K. Ballas, MD, of Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

Three of the women described in this case series were treated at the Sickle Cell Center of Thomas Jefferson University, and 1 was treated in Brazil’s Instituto de Hematologia Arthur de Siqueira Cavalcanti in Rio de Janeiro.

The women had different ancestries—2 African-American, 1 Italian-American, and 1 African-Brazilian—and different diagnoses—2 with hemoglobin SC disease and 2 with sickle cell anemia. But all 4 women had what Dr Ballas called “desirable” disease states.

“These women never had a stroke, never had recurrent acute chest syndrome, had a relatively high fetal hemoglobin count, and had infrequent painful crises,” Dr Ballas said. “Patients like this usually—but not always—experience relatively mild SCD, and they live longer with better quality of life.”

In addition, all of the women took steps to maintain and improve their health and had long-term family support. Dr Ballas said these factors likely contributed to the women’s long lives and high quality of life.

“All of the women were non-smokers who consumed little to no alcohol and maintained a normal body mass index,” he said. “This was coupled with a strong compliance to their treatment regimens and excellent family support at home.”

Family support was defined as having a spouse or child who provided attentive, ongoing care. And all of the women had at least 1 such caregiver.

Treatment compliance was based on observations by healthcare providers, including study authors. According to these observations, all of the women showed “excellent” adherence when it came to medication intake, appointments, and referrals.

As the women had relatively mild disease states, none of them were qualified to receive treatment with hydroxyurea. Instead, they received hydration, vaccination (including annual flu shots), and blood transfusion and analgesics as needed.

Even with their mild disease states and healthy lifestyles, these women did not live crisis-free lives. Each experienced disease-related complications necessitating medical attention.

The women had 0 to 3 vaso-occlusive crises per year. Two women required frequent transfusions (and had iron overload), and 2 required occasional transfusions. One woman had 2 episodes of acute chest syndrome, and the second episode led to her death.

Ultimately, 3 of the women died. One died of acute chest syndrome and septicemia at age 82, and another died of cardiac complications at age 86. For a third woman, the cause of death, at age 82, was unknown. The fourth woman remains alive at age 82.

As the median life expectancy of women with SCD in the US is 47, Dr Ballas and his colleagues said these 4 women may “provide a blueprint of how to live a long life despite having a serious medical condition like SCD.”

“I would often come out to the waiting room and find these ladies talking with other SCD patients, and I could tell that they gave others hope, that just because they have SCD does not mean that they are doomed to die by their 40s . . . ,” Dr Ballas said. “[I]f they take care of themselves and live closely with those who can help keep them well, that there is hope for them to lead long, full lives.”

A sickled red blood cell

alongside a normal one

Image by Betty Pace

A case series published in Blood indicates that some patients with mildly symptomatic sickle cell disease (SCD) can live long lives if they

comply with treatment recommendations and lead a healthy lifestyle.

The paper includes details on 4 women with milder forms of SCD who survived beyond age 80.

“For those with mild forms of SCD, these women show that lifestyle modifications may improve disease outcomes,” said author Samir K. Ballas, MD, of Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

Three of the women described in this case series were treated at the Sickle Cell Center of Thomas Jefferson University, and 1 was treated in Brazil’s Instituto de Hematologia Arthur de Siqueira Cavalcanti in Rio de Janeiro.

The women had different ancestries—2 African-American, 1 Italian-American, and 1 African-Brazilian—and different diagnoses—2 with hemoglobin SC disease and 2 with sickle cell anemia. But all 4 women had what Dr Ballas called “desirable” disease states.

“These women never had a stroke, never had recurrent acute chest syndrome, had a relatively high fetal hemoglobin count, and had infrequent painful crises,” Dr Ballas said. “Patients like this usually—but not always—experience relatively mild SCD, and they live longer with better quality of life.”

In addition, all of the women took steps to maintain and improve their health and had long-term family support. Dr Ballas said these factors likely contributed to the women’s long lives and high quality of life.

“All of the women were non-smokers who consumed little to no alcohol and maintained a normal body mass index,” he said. “This was coupled with a strong compliance to their treatment regimens and excellent family support at home.”

Family support was defined as having a spouse or child who provided attentive, ongoing care. And all of the women had at least 1 such caregiver.

Treatment compliance was based on observations by healthcare providers, including study authors. According to these observations, all of the women showed “excellent” adherence when it came to medication intake, appointments, and referrals.

As the women had relatively mild disease states, none of them were qualified to receive treatment with hydroxyurea. Instead, they received hydration, vaccination (including annual flu shots), and blood transfusion and analgesics as needed.

Even with their mild disease states and healthy lifestyles, these women did not live crisis-free lives. Each experienced disease-related complications necessitating medical attention.

The women had 0 to 3 vaso-occlusive crises per year. Two women required frequent transfusions (and had iron overload), and 2 required occasional transfusions. One woman had 2 episodes of acute chest syndrome, and the second episode led to her death.

Ultimately, 3 of the women died. One died of acute chest syndrome and septicemia at age 82, and another died of cardiac complications at age 86. For a third woman, the cause of death, at age 82, was unknown. The fourth woman remains alive at age 82.

As the median life expectancy of women with SCD in the US is 47, Dr Ballas and his colleagues said these 4 women may “provide a blueprint of how to live a long life despite having a serious medical condition like SCD.”

“I would often come out to the waiting room and find these ladies talking with other SCD patients, and I could tell that they gave others hope, that just because they have SCD does not mean that they are doomed to die by their 40s . . . ,” Dr Ballas said. “[I]f they take care of themselves and live closely with those who can help keep them well, that there is hope for them to lead long, full lives.”

A sickled red blood cell

alongside a normal one

Image by Betty Pace

A case series published in Blood indicates that some patients with mildly symptomatic sickle cell disease (SCD) can live long lives if they

comply with treatment recommendations and lead a healthy lifestyle.

The paper includes details on 4 women with milder forms of SCD who survived beyond age 80.

“For those with mild forms of SCD, these women show that lifestyle modifications may improve disease outcomes,” said author Samir K. Ballas, MD, of Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

Three of the women described in this case series were treated at the Sickle Cell Center of Thomas Jefferson University, and 1 was treated in Brazil’s Instituto de Hematologia Arthur de Siqueira Cavalcanti in Rio de Janeiro.

The women had different ancestries—2 African-American, 1 Italian-American, and 1 African-Brazilian—and different diagnoses—2 with hemoglobin SC disease and 2 with sickle cell anemia. But all 4 women had what Dr Ballas called “desirable” disease states.

“These women never had a stroke, never had recurrent acute chest syndrome, had a relatively high fetal hemoglobin count, and had infrequent painful crises,” Dr Ballas said. “Patients like this usually—but not always—experience relatively mild SCD, and they live longer with better quality of life.”

In addition, all of the women took steps to maintain and improve their health and had long-term family support. Dr Ballas said these factors likely contributed to the women’s long lives and high quality of life.

“All of the women were non-smokers who consumed little to no alcohol and maintained a normal body mass index,” he said. “This was coupled with a strong compliance to their treatment regimens and excellent family support at home.”

Family support was defined as having a spouse or child who provided attentive, ongoing care. And all of the women had at least 1 such caregiver.

Treatment compliance was based on observations by healthcare providers, including study authors. According to these observations, all of the women showed “excellent” adherence when it came to medication intake, appointments, and referrals.

As the women had relatively mild disease states, none of them were qualified to receive treatment with hydroxyurea. Instead, they received hydration, vaccination (including annual flu shots), and blood transfusion and analgesics as needed.

Even with their mild disease states and healthy lifestyles, these women did not live crisis-free lives. Each experienced disease-related complications necessitating medical attention.

The women had 0 to 3 vaso-occlusive crises per year. Two women required frequent transfusions (and had iron overload), and 2 required occasional transfusions. One woman had 2 episodes of acute chest syndrome, and the second episode led to her death.

Ultimately, 3 of the women died. One died of acute chest syndrome and septicemia at age 82, and another died of cardiac complications at age 86. For a third woman, the cause of death, at age 82, was unknown. The fourth woman remains alive at age 82.

As the median life expectancy of women with SCD in the US is 47, Dr Ballas and his colleagues said these 4 women may “provide a blueprint of how to live a long life despite having a serious medical condition like SCD.”

“I would often come out to the waiting room and find these ladies talking with other SCD patients, and I could tell that they gave others hope, that just because they have SCD does not mean that they are doomed to die by their 40s . . . ,” Dr Ballas said. “[I]f they take care of themselves and live closely with those who can help keep them well, that there is hope for them to lead long, full lives.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Flora Peyvandi, MD, PhD

Photo courtesy of ASH

THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.

Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.

These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.

Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.

According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.

Previous results from TITAN

TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.

The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.

These and other results from TITAN were published in NEJM earlier this year.

Post-hoc analyses

Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.

The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.

There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.

There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.

There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.

Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.

When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.

When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.

“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.

“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”

“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.

Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.

The team described this work in Nature Communications.

Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.

With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.

This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.

The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.

“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.

“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”

The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.

Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.

The team described this work in Nature Communications.

Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.

With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.

This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.

The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.

“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.

“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”

The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.

Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.

The team described this work in Nature Communications.

Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.

With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.

This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.

The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.

“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.

“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”

The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Stem cells for transplant

Photo by Chad McNeeley

An investigational gene therapy known as LentiGlobin BB305 has been accepted into the European Medicines Agency’s (EMA’s) Priority Medicines (PRIME) program as a treatment for patients with transfusion-dependent beta-thalassemia (TDT).

LentiGlobin BB305 is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are then returned to the patient via transplant.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs. The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate potential to benefit patients with unmet medical need through early clinical or nonclinical data.

Bluebird bio, the company developing LentiGlobin BB305, is also participating in the EMA’s Adaptive Pathways pilot program.

Like PRIME, the Adaptive Pathways program aims to expedite patient access to therapies with the potential to treat serious conditions with unmet need. It uses the existing European Union (EU) regulatory framework for medicines, including conditional approval.

“PRIME designation will allow bluebird bio to further improve our communication with European regulators as we continue to refine our evidence generation plan in the context of adaptive biomedical innovation,” said David Davidson, MD, chief medical officer of bluebird bio.

“Overall, we believe this will enable us to accelerate development of LentiGlobin drug product for patients with transfusion-dependent beta-thalassemia, a life-shortening disease with significant unmet medical need.”

“Earlier this year, we completed enrollment in the Northstar (HGB-204) global clinical study of LentiGlobin drug product in patients with TDT, which, along with the supporting HGB-205 study, will form the basis of our eventual application for conditional approval in the EU under the Adaptive Pathways pilot program.”

Doctor using a smartphone

Photo by Daniel Sone

HEIDELBERG, GERMANY—Scientists have developed a smartphone application called HemaApp that can be used to measure hemoglobin levels and screen for anemia non-invasively.

HemaApp uses illumination sources from a smartphone, in combination with other light sources, and algorithms that analyze the color of a patient’s blood to estimate hemoglobin levels.

In a trial of 31 patients, HemaApp’s results compared favorably to an approved medical device that measures hemoglobin non-invasively.

Researchers described HemaApp in a paper presented at the Association for Computing Machinery’s 2016 International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp 2016).

“In developing countries, community health workers have so much specialized equipment to monitor different conditions that they literally have whole bags full of devices,” said study author Edward Wang, a doctoral student at the University of Washington in Seattle.

“We are trying to make these screening tools work on one ubiquitous platform—a smartphone.”

How the app works

By shining light from the phone’s camera flash through the patient’s finger, HemaApp analyzes the color of the patient’s blood to estimate hemoglobin concentrations.

HemaApp bombards the finger with different wavelengths of light and infrared energy and creates a series of videos. By analyzing how colors are absorbed and reflected across those wavelengths, it can detect concentrations of hemoglobin and other blood components like plasma.

To ensure that the app works on different skin tones and body masses, the researchers developed processing algorithms that use the patient’s pulse to distinguish between the properties of the patient’s blood and the physical characteristics of his or her finger.

Testing

The researchers tested HemaApp on 31 subjects, including healthy students and staff at the University of Washington, inpatients at a children’s cancer and transfusion clinic, and inpatients at an adult cancer and bone marrow transplant clinic.

The subjects ranged in age from 6 to 77. Their hemoglobin levels ranged from 8 to 16 g/dL, and they had skin tones ranging from pale to dark.

The researchers compared results with HemaApp to results obtained via a complete blood count (CBC) and via the Masimo Pronto 7, a device that non-invasively measures hemoglobin by clipping a sensor onto a person’s finger.

The team tested HemaApp under 3 different scenarios—using the smartphone camera’s flash alone, in combination with a common incandescent lightbulb, and with a low-cost LED lighting attachment.

The additional illumination sources tap into other parts of the electromagnetic spectrum that have useful absorption properties but that aren’t currently found on all smartphone cameras.

“New phones are beginning to have more advanced infrared and multi-color LED capabilities,” said study author Shwetak Patel, PhD, of the University of Washington.

“But what we found is that even if your phone doesn’t have all that, you can put your finger near an external light source like a common lightbulb and boost the accuracy rates.”

Results

HemaApp’s hemoglobin measurements using a smartphone camera alone had a 69% correlation to results with the CBC. The app had a 74% correlation with the CBC when used with an incandescent light bulb and an 82% correlation when used with the LED lights.

In comparison, the Masimo Pronto 7’s measurements had an 81% correlation to the CBC.

When used to screen for anemia, HemaApp had higher sensitivity than the Masimo Pronto but lower specificity.

The app’s sensitivity was 79% using just the phone camera and 86% when used with the incandescent light bulb or LED lights, whereas Masimo Pronto’s sensitivity was 69%.

The app’s specificity was 71% when using just the phone or the incandescent light bulb and 77% with the LED lights, whereas Masimo Pronto’s specificity was 88%.

Next steps

The researchers said HemaApp is not intended to replace blood tests, which remain the most accurate way to measure hemoglobin. But the early test results suggest HemaApp can be an effective and affordable initial screening tool to determine whether further blood testing is warranted.

“Anemia is one of the most common problems affecting adults and children worldwide,” said study author Doug Hawkins, MD, of Seattle Children’s Hospital.

“The ability to screen quickly with a smartphone-based test could be a huge improvement to delivering care in limited-resource environments.”

Next research steps include wider national and international testing of HemaApp, collecting more data to improve accuracy rates, and using smartphones to try to detect abnormal hemoglobin properties that could help screen for sickle cell disease and other blood disorders.

“We’re just starting to scratch the surface here,” Dr Patel said. “There’s a lot that we want to tackle in using phones for non-invasively screening disease.”

Doctor using a smartphone

Photo by Daniel Sone

HEIDELBERG, GERMANY—Scientists have developed a smartphone application called HemaApp that can be used to measure hemoglobin levels and screen for anemia non-invasively.

HemaApp uses illumination sources from a smartphone, in combination with other light sources, and algorithms that analyze the color of a patient’s blood to estimate hemoglobin levels.

In a trial of 31 patients, HemaApp’s results compared favorably to an approved medical device that measures hemoglobin non-invasively.

Researchers described HemaApp in a paper presented at the Association for Computing Machinery’s 2016 International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp 2016).

“In developing countries, community health workers have so much specialized equipment to monitor different conditions that they literally have whole bags full of devices,” said study author Edward Wang, a doctoral student at the University of Washington in Seattle.

“We are trying to make these screening tools work on one ubiquitous platform—a smartphone.”

How the app works

By shining light from the phone’s camera flash through the patient’s finger, HemaApp analyzes the color of the patient’s blood to estimate hemoglobin concentrations.

HemaApp bombards the finger with different wavelengths of light and infrared energy and creates a series of videos. By analyzing how colors are absorbed and reflected across those wavelengths, it can detect concentrations of hemoglobin and other blood components like plasma.

To ensure that the app works on different skin tones and body masses, the researchers developed processing algorithms that use the patient’s pulse to distinguish between the properties of the patient’s blood and the physical characteristics of his or her finger.

Testing

The researchers tested HemaApp on 31 subjects, including healthy students and staff at the University of Washington, inpatients at a children’s cancer and transfusion clinic, and inpatients at an adult cancer and bone marrow transplant clinic.

The subjects ranged in age from 6 to 77. Their hemoglobin levels ranged from 8 to 16 g/dL, and they had skin tones ranging from pale to dark.

The researchers compared results with HemaApp to results obtained via a complete blood count (CBC) and via the Masimo Pronto 7, a device that non-invasively measures hemoglobin by clipping a sensor onto a person’s finger.

The team tested HemaApp under 3 different scenarios—using the smartphone camera’s flash alone, in combination with a common incandescent lightbulb, and with a low-cost LED lighting attachment.

The additional illumination sources tap into other parts of the electromagnetic spectrum that have useful absorption properties but that aren’t currently found on all smartphone cameras.

“New phones are beginning to have more advanced infrared and multi-color LED capabilities,” said study author Shwetak Patel, PhD, of the University of Washington.

“But what we found is that even if your phone doesn’t have all that, you can put your finger near an external light source like a common lightbulb and boost the accuracy rates.”

Results

HemaApp’s hemoglobin measurements using a smartphone camera alone had a 69% correlation to results with the CBC. The app had a 74% correlation with the CBC when used with an incandescent light bulb and an 82% correlation when used with the LED lights.

In comparison, the Masimo Pronto 7’s measurements had an 81% correlation to the CBC.

When used to screen for anemia, HemaApp had higher sensitivity than the Masimo Pronto but lower specificity.

The app’s sensitivity was 79% using just the phone camera and 86% when used with the incandescent light bulb or LED lights, whereas Masimo Pronto’s sensitivity was 69%.

The app’s specificity was 71% when using just the phone or the incandescent light bulb and 77% with the LED lights, whereas Masimo Pronto’s specificity was 88%.

Next steps

The researchers said HemaApp is not intended to replace blood tests, which remain the most accurate way to measure hemoglobin. But the early test results suggest HemaApp can be an effective and affordable initial screening tool to determine whether further blood testing is warranted.

“Anemia is one of the most common problems affecting adults and children worldwide,” said study author Doug Hawkins, MD, of Seattle Children’s Hospital.

“The ability to screen quickly with a smartphone-based test could be a huge improvement to delivering care in limited-resource environments.”

Next research steps include wider national and international testing of HemaApp, collecting more data to improve accuracy rates, and using smartphones to try to detect abnormal hemoglobin properties that could help screen for sickle cell disease and other blood disorders.

“We’re just starting to scratch the surface here,” Dr Patel said. “There’s a lot that we want to tackle in using phones for non-invasively screening disease.”

Doctor using a smartphone

Photo by Daniel Sone

HEIDELBERG, GERMANY—Scientists have developed a smartphone application called HemaApp that can be used to measure hemoglobin levels and screen for anemia non-invasively.

HemaApp uses illumination sources from a smartphone, in combination with other light sources, and algorithms that analyze the color of a patient’s blood to estimate hemoglobin levels.

In a trial of 31 patients, HemaApp’s results compared favorably to an approved medical device that measures hemoglobin non-invasively.

Researchers described HemaApp in a paper presented at the Association for Computing Machinery’s 2016 International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp 2016).

“In developing countries, community health workers have so much specialized equipment to monitor different conditions that they literally have whole bags full of devices,” said study author Edward Wang, a doctoral student at the University of Washington in Seattle.

“We are trying to make these screening tools work on one ubiquitous platform—a smartphone.”

How the app works

By shining light from the phone’s camera flash through the patient’s finger, HemaApp analyzes the color of the patient’s blood to estimate hemoglobin concentrations.

HemaApp bombards the finger with different wavelengths of light and infrared energy and creates a series of videos. By analyzing how colors are absorbed and reflected across those wavelengths, it can detect concentrations of hemoglobin and other blood components like plasma.

To ensure that the app works on different skin tones and body masses, the researchers developed processing algorithms that use the patient’s pulse to distinguish between the properties of the patient’s blood and the physical characteristics of his or her finger.

Testing

The researchers tested HemaApp on 31 subjects, including healthy students and staff at the University of Washington, inpatients at a children’s cancer and transfusion clinic, and inpatients at an adult cancer and bone marrow transplant clinic.

The subjects ranged in age from 6 to 77. Their hemoglobin levels ranged from 8 to 16 g/dL, and they had skin tones ranging from pale to dark.

The researchers compared results with HemaApp to results obtained via a complete blood count (CBC) and via the Masimo Pronto 7, a device that non-invasively measures hemoglobin by clipping a sensor onto a person’s finger.

The team tested HemaApp under 3 different scenarios—using the smartphone camera’s flash alone, in combination with a common incandescent lightbulb, and with a low-cost LED lighting attachment.

The additional illumination sources tap into other parts of the electromagnetic spectrum that have useful absorption properties but that aren’t currently found on all smartphone cameras.

“New phones are beginning to have more advanced infrared and multi-color LED capabilities,” said study author Shwetak Patel, PhD, of the University of Washington.

“But what we found is that even if your phone doesn’t have all that, you can put your finger near an external light source like a common lightbulb and boost the accuracy rates.”

Results

HemaApp’s hemoglobin measurements using a smartphone camera alone had a 69% correlation to results with the CBC. The app had a 74% correlation with the CBC when used with an incandescent light bulb and an 82% correlation when used with the LED lights.

In comparison, the Masimo Pronto 7’s measurements had an 81% correlation to the CBC.

When used to screen for anemia, HemaApp had higher sensitivity than the Masimo Pronto but lower specificity.

The app’s sensitivity was 79% using just the phone camera and 86% when used with the incandescent light bulb or LED lights, whereas Masimo Pronto’s sensitivity was 69%.

The app’s specificity was 71% when using just the phone or the incandescent light bulb and 77% with the LED lights, whereas Masimo Pronto’s specificity was 88%.

Next steps

The researchers said HemaApp is not intended to replace blood tests, which remain the most accurate way to measure hemoglobin. But the early test results suggest HemaApp can be an effective and affordable initial screening tool to determine whether further blood testing is warranted.

“Anemia is one of the most common problems affecting adults and children worldwide,” said study author Doug Hawkins, MD, of Seattle Children’s Hospital.

“The ability to screen quickly with a smartphone-based test could be a huge improvement to delivering care in limited-resource environments.”

Next research steps include wider national and international testing of HemaApp, collecting more data to improve accuracy rates, and using smartphones to try to detect abnormal hemoglobin properties that could help screen for sickle cell disease and other blood disorders.

“We’re just starting to scratch the surface here,” Dr Patel said. “There’s a lot that we want to tackle in using phones for non-invasively screening disease.”

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to Coversin as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and Coversin can achieve full complement inhibition in the blood of PNH patients who are resistant to eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is enrolling patients with eculizumab-resistant PNH in a phase 2 trial.

The company has also been administering Coversin to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. The only drug-related adverse event has been occasional local and transient irritation at the injection site.

“We have continued to see complete complement inhibition and symptom control in a PNH patient with resistance to eculizumab, who has been self-administering subcutaneous Coversin for over 7 months,” said Gur Roshwalb, MD, CEO of Akari Therapeutics.

“We believe that Coversin, when approved, could provide important benefits for all patients with PNH.”

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to Coversin as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and Coversin can achieve full complement inhibition in the blood of PNH patients who are resistant to eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is enrolling patients with eculizumab-resistant PNH in a phase 2 trial.

The company has also been administering Coversin to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. The only drug-related adverse event has been occasional local and transient irritation at the injection site.

“We have continued to see complete complement inhibition and symptom control in a PNH patient with resistance to eculizumab, who has been self-administering subcutaneous Coversin for over 7 months,” said Gur Roshwalb, MD, CEO of Akari Therapeutics.

“We believe that Coversin, when approved, could provide important benefits for all patients with PNH.”

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to Coversin as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

Coversin is a recombinant small protein (16,740 Da) derived from a native protein found in the saliva of the Ornithodoros moubata tick.

The drug is a second-generation complement inhibitor that acts on complement component C5, preventing release of C5a and formation of C5b-9 (also known as the membrane attack complex).

Coversin is being developed by Akari Therapeutics.

In vitro experiments have shown that Coversin inhibits red blood cell lysis in PNH, and Coversin can achieve full complement inhibition in the blood of PNH patients who are resistant to eculizumab.

In a phase 1a trial of healthy volunteers, Coversin completely inhibited complement C5 activity within 12 hours of administration.

Akari Therapeutics is currently conducting a phase 1b study of Coversin in healthy volunteers and is enrolling patients with eculizumab-resistant PNH in a phase 2 trial.

The company has also been administering Coversin to a patient with eculizumab-resistant PNH. Thus far, Coversin has prevented hemolytic episodes and improved disease symptoms in this patient. The only drug-related adverse event has been occasional local and transient irritation at the injection site.

“We have continued to see complete complement inhibition and symptom control in a PNH patient with resistance to eculizumab, who has been self-administering subcutaneous Coversin for over 7 months,” said Gur Roshwalb, MD, CEO of Akari Therapeutics.

“We believe that Coversin, when approved, could provide important benefits for all patients with PNH.”

Coversin is also being studied in atypical hemolytic uremic syndrome and Guillain Barré syndrome.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Cord blood donation

Photo courtesy of NHS

A cord blood transplant (CBT) may be the best option for patients with acute leukemia or myelodysplastic syndrome who have minimal residual disease (MRD) and no related donor, according to the senior author of a study published in NEJM.

This retrospective study showed that patients with MRD at the time of transplant were less likely to relapse if they received CBT rather than a graft from an unrelated adult donor, whether HLA-matched or mismatched.

In addition, the risk of death was significantly higher for patients with a mismatched donor than for CBT recipients, although there was no significant difference between those with a matched donor and CBT recipients.

Among patients without MRD, there were no significant differences between the transplant types for the risk of relapse or death.

“This paper shows that if you’ve got high-risk disease and are at high risk for relapse post-transplant, transplant with a cord blood donor may be the best option,” said Colleen Delaney, MD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Delaney and her colleagues analyzed data on 582 patients—300 with acute myeloid leukemia, 185 with acute lymphoblastic leukemia, and 97 with myelodysplastic syndromes.

Most patients received a transplant from an HLA-matched unrelated donor (n=344), 140 received a CBT from an unrelated donor, and 98 received a transplant from an HLA-mismatched unrelated donor.

The researchers calculated the relative risks of death and relapse for each transplant group, and they found that a patient’s MRD status prior to transplant played a role.

Presence of MRD

Among patients with MRD, the risk of death was significantly higher for recipients of mismatched grafts than for CBT recipients, with a hazard ratio (HR) of 2.92 (P=0.001).

However, the risk of death was not significantly different for recipients of matched grafts compared to CBT recipients. The HR was 1.69 (P=0.08).

The risk of relapse was about 3 times higher for recipients of mismatched grafts (HR=3.01, P=0.02) or matched grafts (HR=2.92, P=0.007) than for CBT recipients.

No MRD

Among patients without MRD, there was no significant difference in the risk of death for recipients of CBT, mismatched grafts (HR=1.36, P=0.30), or matched grafts (HR=0.78, P=0.33).

And there was no significant difference in the risk of relapse for recipients of CBT, mismatched grafts (HR=1.28, P=0.60), or matched grafts (HR=1.30, P=0.46).

“This brings home the point that cord blood shouldn’t be called an alternative donor,” Dr Delaney said. “The outcomes are the same as a conventional donor.”

Cord blood donation

Photo courtesy of NHS

A cord blood transplant (CBT) may be the best option for patients with acute leukemia or myelodysplastic syndrome who have minimal residual disease (MRD) and no related donor, according to the senior author of a study published in NEJM.

This retrospective study showed that patients with MRD at the time of transplant were less likely to relapse if they received CBT rather than a graft from an unrelated adult donor, whether HLA-matched or mismatched.

In addition, the risk of death was significantly higher for patients with a mismatched donor than for CBT recipients, although there was no significant difference between those with a matched donor and CBT recipients.

Among patients without MRD, there were no significant differences between the transplant types for the risk of relapse or death.

“This paper shows that if you’ve got high-risk disease and are at high risk for relapse post-transplant, transplant with a cord blood donor may be the best option,” said Colleen Delaney, MD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Delaney and her colleagues analyzed data on 582 patients—300 with acute myeloid leukemia, 185 with acute lymphoblastic leukemia, and 97 with myelodysplastic syndromes.

Most patients received a transplant from an HLA-matched unrelated donor (n=344), 140 received a CBT from an unrelated donor, and 98 received a transplant from an HLA-mismatched unrelated donor.

The researchers calculated the relative risks of death and relapse for each transplant group, and they found that a patient’s MRD status prior to transplant played a role.

Presence of MRD

Among patients with MRD, the risk of death was significantly higher for recipients of mismatched grafts than for CBT recipients, with a hazard ratio (HR) of 2.92 (P=0.001).

However, the risk of death was not significantly different for recipients of matched grafts compared to CBT recipients. The HR was 1.69 (P=0.08).

The risk of relapse was about 3 times higher for recipients of mismatched grafts (HR=3.01, P=0.02) or matched grafts (HR=2.92, P=0.007) than for CBT recipients.

No MRD

Among patients without MRD, there was no significant difference in the risk of death for recipients of CBT, mismatched grafts (HR=1.36, P=0.30), or matched grafts (HR=0.78, P=0.33).

And there was no significant difference in the risk of relapse for recipients of CBT, mismatched grafts (HR=1.28, P=0.60), or matched grafts (HR=1.30, P=0.46).

“This brings home the point that cord blood shouldn’t be called an alternative donor,” Dr Delaney said. “The outcomes are the same as a conventional donor.”

Cord blood donation

Photo courtesy of NHS

A cord blood transplant (CBT) may be the best option for patients with acute leukemia or myelodysplastic syndrome who have minimal residual disease (MRD) and no related donor, according to the senior author of a study published in NEJM.

This retrospective study showed that patients with MRD at the time of transplant were less likely to relapse if they received CBT rather than a graft from an unrelated adult donor, whether HLA-matched or mismatched.

In addition, the risk of death was significantly higher for patients with a mismatched donor than for CBT recipients, although there was no significant difference between those with a matched donor and CBT recipients.

Among patients without MRD, there were no significant differences between the transplant types for the risk of relapse or death.

“This paper shows that if you’ve got high-risk disease and are at high risk for relapse post-transplant, transplant with a cord blood donor may be the best option,” said Colleen Delaney, MD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Delaney and her colleagues analyzed data on 582 patients—300 with acute myeloid leukemia, 185 with acute lymphoblastic leukemia, and 97 with myelodysplastic syndromes.

Most patients received a transplant from an HLA-matched unrelated donor (n=344), 140 received a CBT from an unrelated donor, and 98 received a transplant from an HLA-mismatched unrelated donor.

The researchers calculated the relative risks of death and relapse for each transplant group, and they found that a patient’s MRD status prior to transplant played a role.

Presence of MRD

Among patients with MRD, the risk of death was significantly higher for recipients of mismatched grafts than for CBT recipients, with a hazard ratio (HR) of 2.92 (P=0.001).

However, the risk of death was not significantly different for recipients of matched grafts compared to CBT recipients. The HR was 1.69 (P=0.08).

The risk of relapse was about 3 times higher for recipients of mismatched grafts (HR=3.01, P=0.02) or matched grafts (HR=2.92, P=0.007) than for CBT recipients.

No MRD

Among patients without MRD, there was no significant difference in the risk of death for recipients of CBT, mismatched grafts (HR=1.36, P=0.30), or matched grafts (HR=0.78, P=0.33).

And there was no significant difference in the risk of relapse for recipients of CBT, mismatched grafts (HR=1.28, P=0.60), or matched grafts (HR=1.30, P=0.46).

“This brings home the point that cord blood shouldn’t be called an alternative donor,” Dr Delaney said. “The outcomes are the same as a conventional donor.”

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.

Sickled and normal red

blood cells from a mouse

Image courtesy of

University of Michigan

Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).

The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.

Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.

The team reported these findings in The Journal of Clinical Investigation.

Previous research showed that suppressing BCL11A can replace the defective beta

hemoglobin that causes sickling with healthy fetal hemoglobin.

“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.

“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).

To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.

Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.

To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.

HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.

When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers

of reticulocytes.

Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.