Readily available and inexpensive small molecule drugs have the potential to improve the fitness of in vitro modified hematopoietic stem and progenitor cells (HSPCs) and increase the success rate of procedures such as in vitro gene therapy. , according to a new study by researchers at the National Academy of Sciences. Children’s Hospital of Philadelphia (CHOP).
Research published in journals bloodshowed that targeting components within cells called extracellular vesicles (EVs) reduces stress on cells outside the body and improves their performance when they are returned to the body. I did.
“We originally embarked on this project to better understand the role of vesicles, but our idea, which turned out to be wrong, was that inhibiting vesicle function would have negative effects on cells. “We assumed he would be deaf,” said lead author Stephanie Hurwitz, MD. , a research fellow in CHOP’s Kure Institute and a hematopathologist at the University of Pennsylvania.
“We found that the opposite is true. Blocking the formation of these vesicles over a relatively short period of time actually improves cellular fitness, an adaptation that protects cells from the stresses of being outside the body. Ultimately, this fortuitous event could lead to improvements in patient outcomes by improving the quality of transplant products used for treatments such as in vitro gene therapy. There is a gender.”
Hematopoietic stem cell transplantation (HSCT) involves the transplantation of HSPCs from a donor into patients with both benign and malignant diseases. In some cases, patients act as their own donors, similar to in vitro gene therapy. That is, a patient’s HSPCs are removed, modified outside the body using gene addition or gene editing, and then transplanted into the body. If sufficient cells become available for modification, this strategy has proven to be a powerful platform for treating inherited blood diseases such as sickle cell disease and beta-thalassemia.
However, maintaining the fitness of these cells outside the body is difficult, and loss of fitness risks the cells not being able to properly restore the patient’s blood and immune cell system. For this reason, researchers have sought to better understand HSPC programming and signaling so that every attempt can be made to maintain cell health prior to transplantation.
We now know that one of the processes that contributes to cellular equilibrium is the secretion of EVs, which is important for transmitting messages from cell to cell and maintaining proper cellular function. However, technical challenges have until now prevented researchers from fully understanding the role these EVs play in HSPC fitness in vitro.
To investigate the role of EVs, the researchers exposed both mouse and human HSPCs to GW4869. GW4869 is a readily available small molecule drug that blocks neutral sphingomyelinase-2 (nSMase2), an enzyme involved in EV formation. The researchers found that 24-hour exposure led to sustained improvements in cell compatibility and engraftment efficiency after in vitro culture, and improved rates of blood cell function in a mouse model.
Additionally, the researchers found that blocking nSMase2 in human CD34+ cells smoothed out differences in how well cells of different HLA types performed after being transplanted into mice. This is particularly interesting given the important role of her HLA in long-term transplant outcomes.
After taking a closer look at the mechanisms behind these phenomena, researchers found that blocking nSMase2 activates an integrated stress response, effectively keeping cells in a quiescent state and protecting them from external stressors. It turns out that. This occurs, in part, because GW4869 interferes with sphingolipid metabolism, impairing nSMase2-dependent EV release.
“While many advances have been made over the past few decades to improve the safety and efficiency of HSPC transplantation and ex vivo gene therapy, constraints in cell volume and transplant success continue to limit outcomes.” said senior author Peter Klee, MD, director of pediatrics. CHOP’s Bone Marrow Failure Center.
“This important study links EV trafficking and the integrative stress response as a regulatory relationship that protects HSPC integrity and long-term fitness, potentially expanding patient eligibility for in vitro gene therapy. Researchers should continue to explore this potential for small molecule drugs to improve ex vivo HSPC culture and transplantation. ”
For more information:
Stephanie N Hurwitz et al, Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response. blood (2023). DOI: 10.1182/blood.2023022147
Provided by Children’s Hospital of Philadelphia
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