Choroideremia: Twenty Years from Gene Identification to Therapeutic Intervention

There are few examples globally where a molecular cell biologist starts by identifying a protein function and ends up developing a disruptive therapeutic intervention. The work of Professor Miguel C. Seabra stands out for its extraordinary impact on both molecular biology and therapeutic interventions, particularly in the field of gene therapy for rare retinal diseases. In 1992, Seabra made a groundbreaking discovery that REP1 regulates Rab GTPases, crucial for intracellular membrane trafficking. This finding was directly linked to Choroideremia (CHM), a rare X-linked retinal degeneration that leads to blindness in adulthood.

Through more than 22 years of intensive research and preclinical studies, Seabra and his team led efforts that culminated in a phase 1/2 clinical trial for CHM gene therapy, demonstrating both the safety and efficacy of this novel treatment. This trial offered a proof-of-concept for curative therapy, rrevolutionizing potential treatments for CHM and similar retinal conditions, giving hope to patients and their families.

Seabra’s contributions to innovation also extend into entrepreneurship. In 2014, he co-founded Nightstar Therapeutics, a company that launched a major phase III clinical trial for CHM gene therapy. The company went public on NASDAQ in 2017 and was later acquired by Biogen in 2019, further solidifying the real-world impact of Seabra’s research.

Seabra’s research has directly benefited around 100 patients involved in clinical trials for CHM gene therapy, but his work has broader implications for advancing treatments forretinal diseases worldwide.

Indeed, Seabra’s impact reaches far beyond this specific application. His pioneering work in gene therapy has paved the wayfor broader advancements in treating rare retinal diseases, showcasing the potential of Adeno-Associated Virus (AAV)-based therapies. Seabra’s contributions have not only reshaped therapeutic strategies but also had a lasting impact on the fundamental understanding of cell biology. His research on Rab GTPases and melanin transport from melanocytes to keratinocytes has become foundational, widely cited and integrated into biological textbooks. Recognized as one of the world’s most cited scientists, ranking in the top 0.2% according to Stanford University in 2022, Seabra is the highest-ranked biomedical scientist in Portugal, with an h-index of 74 and around 21,000 citations. His work has been published in prestigious journals such as The Lancet, Nature, and Cell, further highlighting his international standing in science.

Beyond his research and entrepreneurial ventures, Seabra has secured over €13 million in funding from prestigious organizations, including the Welcome Trust UK, MRC UK, and the Foundation Fighting Blindness USA. His legacy includes the training and mentoring of 23 postdoctoral fellows and 37 PhD students, many of whom have gone on to successful careers in academia, industry, and policy.

Patient associations in the USA, Canada, UK, and France, inspired by Seabra’s discoveries, played a crucial role in advancingresearch and raising funds, expediting the path from preclinical studies to clinical applications. Although thetherapy has not yet received FDA or EMA approval, the future is promising for thousands of patients who may eventually benefit from these life-changing treatments.

Miguel C. Seabra’s work stands as a testament to how basic scientific discovery can evolve into transformative therapeutic innovations, reshaping lives and the future of medical science.