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with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia. 
with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia.
with telomeres in green
Image by Claus Azzalin
Researchers say they have found a new way to fight aplastic anemia—using a therapy designed to delay aging.
Four years ago, the group created telomerase gene therapy, an antiaging treatment based on repairing telomeres.
Now, they have found evidence to suggest this therapy can be effective against both acquired and inherited aplastic anemia.
The team reported preclinical results with the treatment in Blood.
In 2012, Maria A. Blasco, PhD, of Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, and her colleagues described a strategy to repair telomeres.
They used adeno-associated virus (AAV9) vectors to deliver telomerase (Tert) gene therapy, which attenuated or reverted aging-associated telomere erosion in peripheral blood mononuclear cells.
For the current study, the researchers tested the therapy in a mouse model of acquired aplastic anemia and one of inherited aplastic anemia.
Acquired aplastic anemia
For the model of acquired aplastic anemia, the researchers depleted the TRF1 shelterin protein in the bone marrow. The team said this causes severe telomere uncapping and provokes a persistent DNA damage response at telomeres, which leads to fast clearance of hematopoietic stem and progenitor cells (HSPCs) deficient for Trf1.
The remaining HSPCs then undergo additional rounds of compensatory proliferation to regenerate the bone marrow, which leads to rapid telomere attrition. So this model recapitulates the compensatory hyperproliferation and short-telomere phenotype observed in acquired aplastic anemia.
The researchers induced Trf1 deletion with polyinosinic-polycytidylic acid injections given 3 times a week for 5 weeks. At that point, the mice began to show signs of aplastic anemia. A week after the last injection, the mice received either AAV9-Tert or AAV9-empty vectors.
Eighty-seven percent of the AAV9-Tert mice were still alive at 100 days, compared to 55% of mice in the empty vector group (P=0.0025).
In addition, 13% (4/31) of the mice treated with AAV9-Tert actually developed aplastic anemia, while 44% (16/36) of the control mice died showing “clear signs” of aplastic anemia (P=0.0006).
Finally, the researchers found that AAV9-Tert reversed telomere shortening in peripheral blood and bone marrow cells.
Inherited aplastic anemia
For the model of inherited aplastic anemia, the researchers transplanted irradiated wild-type mice with bone marrow from third-generation telomerase-deficient Tert knockout mice. These mice have short telomeres resulting from telomerase deficiency over 3 generations.
As with the previous model, these mice received AAV9-Tert or AAV9-empty vectors. The AAV9-Tert mice had a superior survival rate that nearly reached statistical significance (P=0.058).
The researchers also found that, compared to controls, AAV9-Tert-treated mice had significant increases in hemoglobin levels (P=0.003), erythrocyte counts (P=0.006), and platelet counts (P=0.035), as well as a trend toward an increase in leukocyte counts (P=0.09).
In addition, AAV9-Tert treatment led to a net increase in average telomere length of 5.18Kb, while control mice had a slight telomere shortening of 1.76Kb.
The researchers noted that there are types of aplastic anemia not associated with short telomeres. However, they believe these results provide proof of concept that gene therapy is a valid strategy for treating aplastic anemia.