ASA Monitor December 2023, Vol. 87, 18.
Small molecule drug for gene therapies
Researchers at the Children’s Hospital of Philadelphia have discovered that a readily available and inexpensive small-molecule drug can enhance the fitness of hematopoietic stem and progenitor cells (HSPCs) when they are modified outside the body, potentially improving the success of procedures like ex vivo gene therapy. By targeting components within extracellular vesicles (EVs), it is possible to relieve the stress on HSPCs when they are outside the body, thereby improving their performance upon transplantation. Maintaining the fitness of HSPCs outside the body has historically been a challenge during hematopoietic stem cell transplantation (HSCT), but researchers found that blocking a specific enzyme involved in EV formation, neutral sphingomyelinase-2 (nSMase2), with GW4869 led to sustained improvements in cell fitness and transplantation efficiency. This drug also leveled performance differences among cells of varying human leukocyte antigen (HLA) types when transplanted into mice. Blocking nSMase2 activated an integrated stress response in the cells, putting them into a state of quiescence and protecting them from external stressors. This discovery could enhance the quality of transplant products used in treatments and broaden patient eligibility for ex vivo gene therapies.