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FDA Focus on the Safety of Gene Therapy Products

Within the past 6 years, the US Food and Drug Administration (FDA) has approved a growing number of cellular and gene therapy products to treat a variety of conditions such as multiple myeloma, retinal dystrophy, prostate cancer, and type 1 diabetes (T1D). The FDA defines genome editing as the process by which DNA sequences are “added, deleted, altered, or replaced” at specified locations in the genome of human cells.1

Among recent product approvals in the US, Abecma (idecabtagene vicleucel), from Celgene Corporation, came to market in March 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy (e.g., immunomodulatory agent, proteasome inhibitor, anti-cluster of differentiation 38 monoclonal antibody). In June 2023, Lantidra (donislecel-jujn), from CellTrans Inc, was approved for the treatment of adults with T1D who are unable to approach target hemoglobin A1c because of current repeated episodes of severe hypoglycemia despite intensive management and education.

Applications for Cellular/Gene Therapy Products

An area in which cellular and gene therapy products are increasingly being explored is the realm of rare diseases. In April 2023, the FDA’s Office of Therapeutic Products hosted its third annual RegenMedEd workshop focused on giving rare disease patients a platform to share their experiences with gene therapy clinical trials.2 Several patients and caregivers talked about living with haemophilia, Friedreich’s ataxia, late-infantile neuronal ceroid lipofuscinosis type 2, and other conditions. One panelist who was diagnosed with haemophilia emphasized how he was able to “live fully” after taking part in a gene therapy trial and encouraged others to do so because it had significantly improved his quality of life.

During the April workshop, the FDA noted that it plays an important role in promoting the development of regenerative medicine treatments and “ensuring approved products are safe and effective for patients.” While gene editing offers curative potential for many rare and difficult-to-treat diseases, the technology is associated with a number of concerns, the agency stated.

A paper in 2021 described clustered regularly interspaced short palindromic repeat (CRISPR) and its associated protein (Cas9) as the “most effective, efficient, and accurate method of genome editing tool in all living cells.”3 The authors summarised that CRISPR/Cas9 genome editing involves 3 steps: recognition, cleavage, and repair. The investigator-designed, single-guide RNA (sgRNA) binds to a target sequence in a gene through complementary base pairing. Cas9 makes a double-stranded break in the DNA, allowing the manufactured DNA strand to be inserted into the location of the break. Finally, the double-stranded break is repaired by the body’s cellular mechanisms. Despite the promise of CRISPR/Cas9 editing, “immunogenicity, effective delivery systems, off-target effect, and ethical issues have been the major barriers to extend the technology in clinical applications,” the authors stated.