World's First Gene Therapy Intervention for a Rare Retinal Disease in Naples

Naples, September 16, 2024 — The world's first gene therapy for a rare hereditary eye disease associated with deafness, Usher Syndrome Type 1B, has been administered at the Ophthalmic Clinic of the University of Campania “Luigi Vanvitelli” in Naples. This pioneering intervention was made possible through an innovative gene therapy platform developed by the Telethon Institute of Genetics and Medicine (TIGEM) in Pozzuoli, which allows the transfer of large genes, expanding the potential applications of this therapeutic approach to hundreds of other genetic diseases that currently have no cure.

Background on the Usher Syndrome Type 1B and Gene Therapy

Usher Syndrome Type 1B is a hereditary disease that affects both the retina and the inner ear, estimated to impact around 20,000 people in the United States and the European Union. Children born with this syndrome are deaf, exhibit vestibular dysfunctions, and progressively lose their vision, starting in the first decade of life. While surgical treatments are available to address hearing loss, no treatments currently exist for the progressive loss of vision and blindness.

The disease is caused by mutations in the MYO7A gene, which is too large to be inserted into the most commonly used vectors for correcting genetic defects in the eye, derived from small viruses in the family of the common cold virus, called adeno-associated viruses (AAV). For this syndrome, as well as for over a hundred other genetic diseases caused by genes too large to be "packaged" in current vectors, gene therapy was previously not an option. At TIGEM, a team led by Alberto Auricchio, professor of Medical Genetics at the University “Federico II of Naples,” has been working for many years to overcome this technical limitation.

The Breakthrough: Dual-AAV Technology

To address the challenge of delivering large genes into cells, Auricchio’s group at TIGEM developed a novel "dual-AAV" technology. This approach involves using two separate AAV-type vectors, each carrying a different portion of the therapeutic gene. Once these vectors enter the target cell, special sequences within the genetic material guide the reassembly of the full gene, enabling the production of a functional therapeutic protein. This innovative technique allows for the transfer of large genes that cannot fit into a single AAV vector, thereby overcoming one of the main limitations in gene therapy related to the size capacity of viral vectors.

The dual-AAV technology is crucial because it enables gene therapy to be applied to a wide range of genetic diseases involving large genes, significantly expanding the potential of gene therapy. This technology has been licensed exclusively to AAVantgarde Bio, a biotech startup established in 2021 as a spin-off of TIGEM, supported by investment from the Sofinnova-Telethon fund. AAVantgarde Bio is also the sponsor and owner of the ongoing LUCE-1 clinical trial, which aims to evaluate the safety and tolerability of this gene therapy for retinitis pigmentosa related to Usher Syndrome Type 1B.

The First Clinical Trial and its Significance

The first-ever treatment using this technology was conducted on a patient affected by Usher Syndrome Type 1B at the Ophthalmic Clinic of the University of Campania “Luigi Vanvitelli,” under the leadership of Professor Francesca Simonelli, one of the foremost experts in ocular gene therapy worldwide. The clinic is one of three centers selected across Europe for this study, and Simonelli is the principal investigator.

The procedure involved injecting the vector into the sub-retinal space of the eye under general anesthesia. The objective of the LUCE-1 study, a Phase 1/2 trial, is to evaluate the safety and tolerability of this gene therapy in people with retinitis pigmentosa related to Usher Syndrome Type 1B.

Scientific Insights from the Technology Developed at TIGEM

The development of dual-AAV technology began in 2012 with support from Telethon and competitive funds, such as those provided by the European Research Council (ERC). Auricchio and his team developed two platforms — the 'Dual Hybrid' system and the intein-based system — to split the genetic material into multiple viral vehicles, which then form the complete therapeutic protein inside the cell. The Dual Hybrid System, for instance, is licensed to Akouos, Inc., a subsidiary of Eli Lilly and Company, and is aimed at restoring, improving, and preserving high-acuity physiological hearing in people with hearing loss.

These new gene therapy platforms mark a significant milestone that opens new possibilities for treating a variety of genetic diseases. They also provide a foundation for future advancements in genetic medicine, demonstrating the innovative capabilities of the research teams at TIGEM.

Looking Ahead: The Future of Gene Therapy

The pioneering treatment in Naples is an exciting milestone, providing new hope for patients with rare genetic diseases. As gene therapy continues to evolve, the dual vector technology developed at TIGEM and licensed to AAVantgarde Bio may serve as a foundation for breakthroughs in treating a wide range of genetic disorders that were previously considered untreatable due to the size limitations of current vectors. This advancement could significantly enhance the quality of life for countless patients worldwide.

Researchers and clinicians remain optimistic that this innovative approach will yield positive results in clinical trials and pave the way for broader applications in genetic medicine. The continued investment in scientific research and the collaboration between academic institutions, biotechnology companies, and healthcare providers are crucial to making these promising therapies accessible to patients who need them most.

Conclusion

The world's first gene therapy intervention for Usher Syndrome Type 1B marks a significant step forward in genetic medicine. Through the innovative dual-AAV technology developed at TIGEM and licensed to AAVantgarde Bio, the potential to treat numerous genetic diseases has expanded, promising a future where previously untreatable conditions may be effectively managed or cured. This groundbreaking achievement underscores the importance of continued research, collaboration, and investment in the field of genetic therapy, offering hope to patients and families affected by rare and challenging genetic disorders.