Award Title: Evaluating Patient Outcomes and Therapies for Inherited Optic Neuropathies
Funder: Department of Health and Social Care

Abstract: Background Inherited optic neuropathies are a group of disorders characterised by severe bilateral loss of central vision. The two most common forms are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON patients carry one of three mitochondrial DNA (mtDNA) mutations (m.3460G>A, m.11778G>A, and m.14484T>C), whereas most patients with DOA harbour pathogenic mutations in the nuclear gene OPA1 (3q28-q29). Recent studies have shown promising results with gene replacement therapy in LHON patients carrying the m.11778G>A mutation treated within 1 year of disease onset. As part of this major translational drive for inherited optic neuropathies, it is imperative that we clearly define the natural history of the disease in treatment nave patients and establish better outcome measures to evaluate the benefit of potential interventions on quality of life (QoL). Aims and objectives As part of this NIHR Advanced Fellowship, I will:	Investigate the natural history of LHON. 	Evaluate if gene therapy can benefit patients carrying the m.11778G>A mutation who have been affected for longer than 1 year (i.e. chronic LHON). 	Develop a patient-reported outcome measure (PROM) for patients with LHON and DOA.Design and Methods	Prospective Natural History Study of LHONI will recruit 120 patients with LHON carrying one of the three common mtDNA mutations and with disease duration of up to 10 years. Patients will be seen at baseline and on a 6-monthly basis thereafter. A standard assessment protocol will be used to collect data on best-corrected visual acuity (BCVA) and other parameters of optic nerve structure and function.	Gene Therapy Trial for Chronic LHONI will recruit 30 patients carrying the m.11778G>A mutation with disease duration of more than 1 year and up to 5 years into a randomised, double-masked, sham-controlled, clinical trial of rAAV2/2-ND4 (GS010). Patients will be randomised in a 1:1 ratio to an intravitreal injection of GS010 or sham treatment in both eyes. The follow-up period will be 24 months. The primary efficacy endpoint will be the change in LogMAR BCVA from the pre-treatment baseline to 24 months post-treatment. A mixed-effects analysis of covariance (ANCOVA) will be used to determine the effect of treatment.	Patient-Reported Outcome Measure (PROM) for Inherited Optic NeuropathiesA conceptually grounded and psychometrically robust PROM will be developed that assesses and measures the QoL of individuals with LHON and DOA, across multiple domains. Anticipated Impact and Dissemination This NIHR Advanced Fellowship will provide valuable information on the evolution of visual parameters in LHON, which can be used both in clinical practice to advise patients and to evaluate therapies. The gene therapy trial for chronic LHON will inform us if this approach can be beneficial in later stages of the disease, and if relevant, the data can be used to power and plan for a larger study. A validated PROM to assess QoL in LHON and DOA will be useful, not only for monitoring disease, but also as an important outcome measure of the patient experience in future clinical trials.

Lay Abstract: Background Inherited optic neuropathies are genetic diseases that damage the optic nerve - the specialised cable that sends visual information from the eye to the brain. They affect at least 1 in 10,000 individuals in the United Kingdom, resulting in severe loss of vision and blindness in the young adult population. Although a large number of genetic defects (mutations) can cause inherited optic neuropathies, the damage caused to the optic nerve is invariably due to impaired function of mitochondria, which are the powerhouses producing all the energy that a cell needs to survive. The two most common inherited optic neuropathies are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 70% of all patients affected with LHON carry a particular mutation in mitochondrial DNA, m.11778G>A, with the number referring to its location in the mitochondrial genetic code. Most patients with DOA carry a mutation in the gene OPA1 which is located on chromosome 3 (3q28-q29). The management of patients with inherited optic neuropathies remains challenging as there are limited treatment options to slow or prevent ongoing loss of vision. This situation is further complicated by important gaps in our understanding of how the disease progresses over time and how best to measure the significant visual impairment that patients face in their day to day lives. Fortunately, important progress is being made. We have successfully used a gene therapy product (GS010) injected in the eye to replace the defective gene that causes LHON in patients carrying the m.11778G>A mutation. Patients who were treated within 1 year of being affected experienced significant improvement in their vision. Aims The aim of this fellowship is to improve the management of patients with LHON and DOA. It will provide us with the tools needed to evaluate the benefits of potential treatments for these blinding diseases. Design and Methods	Prospective Natural History Study of LHONI will recruit 120 patients with LHON who have lost vision for up to 10 years. The participants will be assessed every 6 months to measure their vision and determine how well their optic nerves are working.	Gene Therapy Trial for Chronic LHONI will recruit 30 patients with LHON carrying the m.11778G>A mutation who have experienced visual loss for more than 1 year and up to 5 years (i.e. chronic disease). The participants will be split equally into two groups. One group of 15 patients will receive the gene therapy injection (GS010) in both eyes. The other group will receive a sham injection in both eyes (i.e. the eye will be pressed with a syringe that has no needle to simulate that an injection has been given). All participants will be followed for a period of 24 months to monitor their vision. This study will tell us if patients with LHON can experience visual improvement when treated later in the course of their disease with gene therapy.	Patient-Reported Outcome Measure (PROM) for Inherited Optic NeuropathiesThrough a series of patient interviews, we will develop, refine, and then validate a questionnaire (PROM) that enables patients with LHON and DOA to report their experience of living with their condition and to assess their quality of life, which will be important when evaluating treatments. Patient and Public Involvement (PPI) I have worked closely with several patient advocacy groups to establish the aims of this fellowship proposal. I will discuss the progress made and the results obtained as part of the PPI activities planned during the course of this research programme. I will disseminate our results to the wider research community through publications in peer-reviewed journals and presentations at scientific conferences.

Research Activity Codes: 6.2 CELLULAR AND GENE THERAPIES
Health Categories: EYE