Editor: Deborah Sesok-Pizzini, MD, MBA, adjunct professor, Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Training in cell and gene therapy manufacturing via graduate medical education
May 2026—The field of cell and gene therapy is exploding and has created a number of novel medical therapies in the form of small molecules and biologics. These include FDA-approved products, such as chimeric antigen receptor-T (CAR-T) cells and genetically modified stem cell products. Qualified clinicians, research and technical staff, regulatory experts, and others are needed to develop such products and incorporate them into patient care. Unlike minimally manipulated cellular therapy products, which require current good tissue practice standards for processing, cell and gene therapy (CGT) products are developed within more stringent good manufacturing practice (cGMP) standards. The gap in training clinical and scientific CGT leaders is due to a lack of CGT fellowships focused on manufacturing that are accredited by the Accreditation Council for Graduate Medical Education (ACGME). CGT training is often conducted as part of a blood banking and transfusion medicine fellowship. In the 57 ACGME-approved fellowships in blood banking and transfusion medicine (as of the 2024–2025 academic year), only one month of training on cellular therapies is required. The authors, as part of a working group of CGT training program directors, reviewed the need for a fellowship to develop experts in CGT manufacturing who could lead the growth and expansion of cGMP facilities. The working group of CGT experts was formed with the support of the AABB Cell Therapies Section Coordinating Committee to address concerns about gaps in CGT fellowship education. For the purposes of their article, the authors considered CGT to be any of the therapeutic products manufactured with adherence to cGMP standards, including CAR-T cells, hematopoietic progenitor cells, mesenchymal stromal cells, cell-derived products, and genetically modified cells. If cell production and manufacturing are performed by a third party, the role of the CGT director may be limited to overseeing cryostorage and thawing. A well-trained CGT laboratory/medical director can support both non-cGMP and cGMP product manufacturing. The authors noted that directors of CGT manufacturing facilities come from a variety of professional backgrounds. Due to the overlap of regulations and accreditation bodies, transfusion medicine divisions often have CGT laboratory directors. As of 2025, there were four U.S. programs offering postgraduate CGT training of one year or more. However, none of the programs were accredited. Some institutions offer shorter training programs, and some professional societies, including the AABB (Association for the Advancement of Blood and Biotherapies) and International Society for Cell and Gene Therapy, have developed programs focused on training a broader CGT workforce. Providing an accredited fellowship with a structured curriculum that includes a focus on scientific and clinical knowledge, lab operations, regulation, and quality assurance can not only help standardized training but provide a steady source of funding for the fellowship. Yet the authors emphasized that, even with an approved fellowship curriculum, there will always be new developments in this evolving field. Therefore, trainees need to be prepared for a career that requires lifelong learning. Furthermore, in addition to addressing topics directly relevant to a CGT fellowship curriculum, the CGT curriculum should address the required ACGME core competencies. The authors concluded that establishment of an accredited formalized program in CGT is the best way to train a large number of experts to be future leaders in this field.
Wang Y, McKenna D, Spitzer T, et al. Training in cell and gene therapy manufacturing: Unmet needs and arguments for graduate medical education. Transfusion. 2026;66:259–265.
Correspondence: Dr. Yongping Wang at wangy2@chop.edu
Phase one trial of CRISPR-Cas9 gene editing targeting ANGPTL3
High levels of lipoproteins contribute to atherosclerosis and its clinical sequelae, including coronary artery disease. Angiopoietin-like protein 3 (ANGPTL3), which is produced in the liver, inhibits lipoprotein lipase and endothelial lipase and affects lipid metabolism. Loss-of-function variants in ANGPTL3 result in a lifelong reduction in levels of serum triglycerides and low-density lipoprotein cholesterol and a reduced risk of atherosclerotic cardiovascular disease. This reduction in triglycerides and low-density lipoproteins can also be achieved through pharmacologic inhibition of ANGPTL3 by means of monoclonal antibodies or RNA-targeted therapeutics but requires lifelong drug administration. However, gene editing of ANGPTL3 with clustered regularly interspaced short palindromic repeats–Cas9 endonuclease (CRISPR-Cas9) can achieve sustainable genetic modification after one treatment. This may result in a permanent reduction in circulating lipoproteins. The authors conducted a study to assess the safety, side effect profile, and efficacy of single ascending doses of CTX310, an investigational lipid nanoparticle-encapsulated formulation of CRISPR-Cas9 for in vivo gene editing of ANGPTL3. This gene editing induces a loss-of-function mutation in liver hepatocytes. The ascending-dose phase one trial included 15 adults who had uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipemia and were already receiving the maximally tolerated doses of lipid-lowering therapy. The study participants received a single intravenous dose of CTX310 (0.1, 0.3, 0.6, 0.7, or 0.8 mg/kg of body weight). The primary end point was adverse events or dose-limiting toxic effects. The participants had at least 60 days of follow-up. Two participants had serious adverse events that were not related to the use of CTX310—one had a spinal disk herniation and the other died suddenly 179 days after treatment with the lowest dose. Three participants had infusion-related reactions, and one had an elevated aminotransferase, which peaked at day four and returned to baseline by day 14. No dose-limiting toxic effects or serious adverse events attributable to CTX310 were observed. The study showed a mean percent change in ANGPTL3 levels at 9.6 percent (range, −21.8 to 71.2) with the dose of 0.1 mg/kg; 9.4 percent (range, −25.0 to 63.9) with 0.3 mg/kg; −32.7 percent (range, −51.4 to −19.4) with 0.6 mg/kg; −79.7 percent (range, −86.8 to −72.5) with 0.7 mg/kg; and −73.2 percent (range, −89.0 to −66.9) with 0.8 mg/kg. The authors concluded that editing of ANGPTL3 was associated with few adverse events and a reduction from baseline in ANGPTL3 levels. Moreover, they showed that intravenous CTX310 can be administered safely to patients who have dyslipidemia that is refractory to lipid-lowering therapy.
Laffin LJ, Nicholls SJ, Scott RS, et al. Phase 1 trial of CRISPR-Cas9 gene editing targeting ANGPTL3. N Engl J Med. 2025;393(21):2119–2130.
Correspondence: Dr. Steven E. Nissen at nissens@ccf.org