![]() We also demonstrated that the biodistribution of HIV/VSV in rhesus monkeys was comparable to the biodistribution of SIV/VSV, but that only SIV/VSV was detectable in bone marrow CD34 + cells and in some lymphocyte subsets. We demonstrated that systemic delivery of an HIV-1-based lentiviral vector resulted in the highest tissue vector copy number compared to the murine gRV vector pseudotyped with VSV or murine envelopes in ADA −/− mice. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Gene Editing: Technology & Applications. ![]()
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