Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model.
Naoya UchidaUlana StasulaSelami DemirciPaula Germino-WatnickMalikiya HindsAnh LeRebecca ChuAlexander BergXiong LiuLing SuXiaolin WuAllen E KrouseN Seth LindeAylin BonifacinoSo Gun HongCynthia E DunbarLeanne LanieriAnjali BhatRahul PalchaudhuriBindu BennetMegan HobanKirk BertelsenLisa M OlsonRobert E DonahueJohn F TisdalePublished in: Nature communications (2023)
Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
Keyphrases
- gene therapy
- diffusion weighted imaging
- diffusion weighted
- cancer therapy
- hematopoietic stem cell
- allogeneic hematopoietic stem cell transplantation
- bone marrow
- stem cell transplantation
- endothelial cells
- oxidative stress
- contrast enhanced
- magnetic resonance
- genome wide
- magnetic resonance imaging
- rheumatoid arthritis
- type diabetes
- induced apoptosis
- low dose
- dna methylation
- mesenchymal stem cells
- adipose tissue
- drug delivery
- childhood cancer
- climate change
- systemic lupus erythematosus
- high dose
- polycystic ovary syndrome
- disease activity
- ankylosing spondylitis