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Children’s Research Hospital
Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.
All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.
In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.
“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Sorrentino and his colleagues described this research in Science Translational Medicine.
The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.
With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.
The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.
More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.
Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.
However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.
Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.
The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.
As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.
“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.
To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.
“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said. 
Photo courtesy of St. Jude
Children’s Research Hospital
Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.
All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.
In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.
“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Sorrentino and his colleagues described this research in Science Translational Medicine.
The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.
With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.
The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.
More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.
Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.
However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.
Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.
The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.
As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.
“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.
To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.
“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.
Photo courtesy of St. Jude
Children’s Research Hospital
Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.
All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.
In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.
“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Sorrentino and his colleagues described this research in Science Translational Medicine.
The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.
With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.
The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.
More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.
Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.
However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.
Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.
The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.
As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.
“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.
To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.
“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.