CRISPR-based sickle cell treatment inches closer to FDA approval

USA — A cutting-edge sickle cell disease treatment utilizing CRISPR technology has achieved a significant step to gaining approval in the United States.

A recent report by Medtechdive highlights the encouraging progress in this groundbreaking approach, which has garnered positive feedback from FDA advisors.

The FDA advisory panel, comprised of scientists and medical professionals, engaged in extensive discussions, primarily focusing on the intricacies of evaluating potential off-target DNA modifications associated with CRISPR—a gene-editing tool often likened to molecular scissors.

Leading the forefront of this innovative treatment is Vertex Pharmaceuticals, known as exa-cel.

Taby Ahsan, Vice President of Cell Therapy Operations at City of Hope and committee chair, underscored the comprehensive approach to identifying off-target genetic edits.

He expressed the potential to generate more data by continuously monitoring patients who have undergone the therapy.

The unconventional aspect of this FDA advisory committee meeting was its unique approach—there was no formal evaluation of the therapeutic effectiveness of Vertex’s exa-cel, a treatment crafted using patients’ own stem cells.

The primary focus instead rested on the CRISPR technology itself, along with the challenging issue of ensuring that treatments do not inadvertently induce unintended genetic alterations.

Committee member Scot Wolfe, a Professor of Molecular, Cell, and Cancer Biology at the University of Massachusetts Chan Medical School, acknowledged the importance of striking a balance between perfection and feasibility. Wolfe emphasized the substantial unmet medical need in this context.

Recognizing the substantial potential of exa-cel in delivering significant benefits to individuals suffering from sickle cell disease, both the FDA and the advisory panel noted the potential of this treatment.

Sickle cell disease is a hereditary blood disorder infamous for causing severe pain and organ damage. The transformative impact of the treatment was further substantiated by testimonials from over half a dozen patients who underwent the therapy and are now free from the most debilitating symptoms of the disease.

One patient, Jimi Olaghere, vividly conveyed the profound change in his life through this gene therapy. He emphasized he regained control over his life in a world where the odds had been stacked against him.

In a collaborative effort with CRISPR Therapeutics, Vertex has taken the crucial step of submitting an application for FDA approval of exa-cel.

It is intended to serve as a treatment for individuals aged 12 and above who suffer from sickle cell disease and experience recurring pain crises.

The FDA’s decision, expected by December 8, could potentially mark exa-cel as the first CRISPR-based medicine to receive approval in the U.S.

While documents released last week supported the clinical trial results for Vertex’s exa-cel, raising positive outcomes for nearly all participants, concerns have arisen regarding the comprehensive documentation of the therapy’s risk of off-target genetic editing. Vertex adopted two primary strategies for assessment.

The first involved the use of computer algorithms to predict erroneous edit sites, followed by comprehensive studies.

The second approach included the sequencing of edited cells from various donors. Vertex’s findings reported no signs of off-target editing.

However, FDA staff raised valid questions concerning the representativeness of the databases used by Vertex to predict off-target edit sites, in addition to the relatively small sample size in the company’s cellular analysis.

Fyodor Urnov, a renowned gene editing expert from the University of California, Berkeley, acknowledged that there are inherent limitations to laboratory work in this context.

He stated, “The technology is, in fact, ready for prime time,” emphasizing the potential value of further analysis on treated patients’ cells as part of Vertex’s planned long-term follow-up.

Chairperson Ahsan also emphasized, “It would be nice to see some evaluation of monitoring the edits over real time. But it’s uncertain which technology would be used for that, whether whole genome sequencing or another method, to attain detection levels that provide us with meaningful information.”

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