Oxford team treats first patient in ground-breaking retinal gene therapy trial

The first patient has been treated in Oxford in the second phase of an international clinical trial testing a new gene therapy for Stargardt disease - a rare inherited eye condition that leads to progressive vision loss and eventually blindness in children and adults.

The ASTRA trial is evaluating a treatment called SB-007, developed by SpliceBio, a genetic medicines company pioneering protein splicing to address diseases caused by mutations in large genes. Stargardt disease affects an estimated 1 in 8,000 to 10,000 children and adults worldwide.

The innovative therapy being tested uses two harmless viruses to deliver a healthy version of the ABCA4 gene into the retina. Stargardt disease is caused by faults in this gene, and until now, its large size has made it impossible to replace using standard gene therapy methods.

Robert MacLaren, Professor of Ophthalmology at the University of Oxford and Gene and Cell Therapy Research Lead at Oxford University Hospitals NHS Foundation Trust, explained: “The use of two viral vectors that recombine once inside retinal cells is a unique approach to restoring the large gene needed in Stargardt disease, and dual vectors might have implications for treating other retinal degenerations.

“This unique gene therapy modality has the potential to slow or even halt progression of this debilitating disease, which is the most common cause of inherited blindness in children. We are delighted to have treated the first patient in the critical second phase of the trial here in Oxford.”

Professor MacLaren’s groundbreaking gene and cell therapy work at the Oxford Eye Hospital is supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre.

“Gene therapy has transformative promise in ophthalmology, but its application has been limited by the inability of single adeno-associated viral (AAV) vectors to accommodate large, complex genes such as ABCA4. SB-007 harnesses our protein splicing platform and dual-AAV approach and is designed to reconstitute the full-length therapeutic ABCA4 protein,” said Aniz Girach, Chief Medical Officer of SpliceBio. 

“Starting the dose expansion phase of the ASTRA trial is a key milestone for our programme, and we look forward to continuing this progress with the support of the trial’s participants and investigators.” 

Part B of the trial will evaluate two dose levels of SB-007 versus an untreated control in patients with Stargardt disease, which has no approved treatments.

SB-007 is designed to address the underlying genetic cause by restoring expression of a functional, full-length ABCA4 protein in the retina, with the potential to treat patients across all ABCA4 mutations. 

SpliceBio’s proprietary technology makes use of engineered segments of proteins called inteins to enable protein trans-splicing. This allows the otherwise-too-large ABCA4 gene to be split into two smaller parts and delivered using the dual viral vectors. Once inside the target cells in the retina, the two protein segments join together to form a complete, working ABCA4 protein. 

Mariya Moosajee, Professor of Molecular Ophthalmology, at University College London Institute of Ophthalmology, and Consultant Ophthalmologist and Head of the Genetics Service, Moorfields Eye Hospital, added: “The ASTRA study is a critical step toward expanding our understanding of Stargardt disease and evaluating the potential of SB-007. The clinical insights generated through this study have the potential to advance medicine and, critically, bring new hope to patients and families living with this condition.”

SpliceBio expects to enrol around 57 patients aged 12 to 65 with Stargardt disease into Part B of the global, multi-centre ASTRA trial. Part B is randomised, controlled and masked, and will evaluate two dose levels of subretinal SB-007 compared to an untreated control group. Part A of the study evaluated three dose levels of subretinal SB-007 in an open-label, dose-escalation design.