Although initial setbacks caused skepticism and reduced funding, recent innovations have rekindled optimism about the potential of gene therapy.

Jesse Gelsinger's death on September 17, 1999, during a gene therapy trial at the University of Pennsylvania marked a pivotal moment in medical history as the first reported death due to gene therapy.

Gelsinger, who had OTC deficiency, participated in a trial testing a gene therapy using a weakened adenovirus, but developed severe symptoms leading to organ failure and his death four days after infusion, caused by a severe immune reaction to the vector.

An investigation revealed that Gelsinger was ineligible due to high ammonia levels and poor liver function, with prior animal trials showing fatal outcomes, raising serious concerns about trial safety and oversight.

The FDA investigation uncovered multiple issues, including inadequate patient assessment, undisclosed animal deaths, and conflicts of interest involving lead researcher Dr. James Wilson, who owned stock in the developing company.

Following Gelsinger's death, the trial was halted, and the FDA implemented stricter regulations, improved informed consent procedures, and enhanced monitoring, leading to increased scrutiny of gene therapy research.

The tragedy caused a decade-long decline in gene therapy funding and progress due to safety and ethical concerns, but recent advances have revitalized the field.

Since then, technological progress such as CRISPR has led to successful treatments for various genetic disorders, including the recent approval of a CRISPR-based therapy for sickle cell anemia in January 2024.

By 2025, gene therapy has made significant progress, exemplified by the treatment of a newborn with a rare genetic syndrome using customized CRISPR technology, demonstrating the field's advancements.

Despite limited approvals, successful treatments like the OTC deficiency therapy in 2021 highlight promising future developments in gene therapy.

Advances in understanding viral vectors and gene editing have revitalized the field, leading to successful treatments for conditions like severe combined immune deficiency and certain blindness forms.