–Researchers find that exposing cells to small molecule drugs improves fitness during hematopoietic stem cell transplantation, which could expand access to in vitro gene therapy and improve outcomes did-
Philadelphia, September 27, 2023 /PRNewswire/ — Readily available, inexpensive small molecule drugs can improve the fitness of in vitro engineered hematopoietic stem and progenitor cells (HSPCs), improving success rates for procedures such as: There is a possibility. ex vivo According to a new study by researchers at Children’s Hospital, gene therapy 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 initially embarked on this project to better understand the role of vesicles, but it turned out that we assumed, incorrectly, that inhibiting vesicle function would have negative effects on cells. ” said the first author. Stephanie HurwitzMD, PhD, Researcher never lab CHOP and hematopathologist 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 the quality of implant products used for treatments such as: ex vivo Gene therapy improves patient outcomes. ”
Hematopoietic stem cell transplantation (HSCT) involves the transplantation of HSPCs from a donor into patients with both benign and malignant diseases.In some cases, as follows ex vivo In gene therapy, the patient acts as his or her own donor. That is, a patient’s HSPCs are removed, modified outside the body using gene addition or gene editing, and then transplanted into the body. This strategy has proven effective when sufficient cells are available for modification. It is a powerful platform for treating inherited blood disorders 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 hours of exposure led to sustained improvements in subsequent cell compatibility and engraftment efficiency. ex vivo Culture increased the speed 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.
“Over the past few decades, numerous advances have been made to improve the safety and efficiency of HSPC transplantation, but ex vivo “Gene therapy, cell volume constraints, and transplant success continue to limit outcomes,” said the lead author. peter never, MD, Director of CHOP Children’s Comprehensive Bone Marrow Failure Center. “This important study links EV trafficking and the integrated stress response as a regulatory dual that protects HSPC integrity and long-term health, potentially expanding patient eligibility. It has an important meaning.” ex vivo Gene therapy. Researchers should continue to explore the potential of this small molecule drug in improvement. ex vivo HSPC culture and transplantation. ”
This research was supported by NIH grants R01-HL164633, 4-R38-HL143613-04, T32 HL-07439, and P30ES013508. This analysis was conducted by the CHOP Flow Cytometry Core Laboratory, CHOP Veterinary Resources Department, University of Pennsylvania stem cell and xenograft core, University of Pennsylvania Hematopoietic Stem Cell Research Institute, CHOP-PENN Proteomics Core Facility, CHOP Applied Genomics Center Core Laboratory.
Hurwitz et al. “Blocking neutral sphingomyelinase enhances hematopoietic stem cell fitness through an integrated stress response”, Blood, online September 12, 2023DOI: 10.1182/blood.2023022147
About children’s hospital Philadelphia: Nonprofit charity, children’s hospital Philadelphia It was established in 1855 as the nation’s first children’s hospital. Through a long history of providing excellent patient care, training a new generation of pediatric health professionals, and pioneering major research efforts, the 595-bed hospital has made many discoveries that benefit children around the world. I have nurtured it. Its pediatric research program is one of the largest in the country. The facility has a well-established history of providing advanced pediatric care close to home. CHOP Care Networkwhich includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital affiliates. pennsylvania and new jersey,but also, Inpatient hospital Equipped with a specialized pediatric emergency department king of prussia.Additionally, with its unique family-centered care and public service programs, Children’s Hospital Philadelphia Recognized as a leading advocate for children and youth. For more information, please visit: https://www.chop.edu.
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Source: Children’s Hospital Philadelphia