Gene therapy

[caption id="attachment_6172" align="alignnone" width="700"] Jean Bennett MD, PhD[/caption] Yearly data on the number of investigational new drug submissions received by the US FDA provide a clear indication that gene therapy for ophthalmic diseases is an active and growing field of research. At a session during the 2016 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Seattle, USA, speakers shared insights aimed to help researchers bring ocular gene therapies from bench to bedside. Wilson W Bryan MD, Director, Division of Clinical Evaluation and Pharmacology/Toxicology, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, US FDA, noted that successful clinical development of gene therapy for rare diseases that have been genetically defined requires understanding of the corresponding phenotype and disease course. This means there is a need for natural history studies to characterise the incidence, demographics, clinical presentation and prognosis of the targeted disorder. Natural history studies can also help identify novel outcome measures and biomarkers that may be used in clinical trials for optimising patient selection and/or as surrogate endpoints. At the same time, they provide an opportunity to collect blood samples for molecular definition. Recognising that natural history studies can take several years to complete, however, Dr Bryan encouraged basic scientists who are working on a gene for a particular disease to reach out early to clinicians, so that natural history studies can be completed in parallel with the preclinical work, minimising any delay in initiating clinical testing when the time comes. If a novel endpoint is being considered as an appropriate clinical trial outcome measure, then validation study planning must also begin, said Jean Bennett MD, PhD. Dr Bennett is Professor, Ophthalmology, Cell and Developmental Biology, University of Pennsylvania, Philadelphia, USA, and a pioneer in developing RPE65 gene therapy for Leber congenital amaurosis (LCA). “Visual acuity and visual field results have been standard primary endpoints in ophthalmology, but they may not be relevant to patients with low and ultra-low vision. Mobility testing is the primary outcome measure in the phase 3 studies of RPE65 gene therapy for LCA, and it took two years to complete the studies to validate its use,” she noted. TECHNICAL ISSUES Numerous technical issues need to be addressed when developing a gene therapy product, one of which is picking the right vector. Factors to consider include availability, i.e. whether the vector is in the public domain, as well as genetic cargo capacity, transfection (or infection) efficiency, mode of delivery, and the existence of a GMP purification protocol facility, Dr Bennett said. She also stressed the importance of optimising the safety and potency of the construct early on through preclinical toxicity and efficacy studies, in order to avoid wasting time and money on re-engineering once clinical testing begins. Dr Bryan noted that for better translation, preclinical studies may ideally be performed in larger versus smaller animals. Dr Bennett concurred. “We can’t assume what we see in a mouse will be seen in a larger animal or that results in animal models are predictive of outcomes in humans,” she said. Illustrating her latter point, Dr Bennett noted that while robust restoration of ERGs was achieved with RPE65 gene therapy in dog and mouse models, this effect has not yet been reported in clinical trials. Dr Bennett also advised researchers to choose equipment and procedures that are already approved, readily available, and expected to remain accessible and practical for the duration of the project and even into the post-marketing phase. Referring to potency assays, she said: “It may be tempting to use animal models, but remember that this testing will still need to be done years after product approval.” With safety in mind, new therapies will be evaluated first in one eye only. Eventually, clinical trials will have to investigate bilateral treatment for genetic disorders that affect both eyes, and if there is loss of efficacy over time, the safety profile with repeat treatment. In addition, when gene therapy administration involves a new procedure, the developer may be asked to create a surgeon training programme along with monitoring plans, Dr Bryan said. Dr Bennett echoed that idea. “There is a learning curve in carrying out subretinal injections, and we think it is important to have a surgical training package to ensure proper delivery of the gene therapy. One bad move might derail the field,” she said. Finally, while clinicians may be encouraged by positive results, Dr Bennett advised caution in promising a specific timeline. “Patients are always asking when a new treatment will be available. Remember that is something over which you have no control,” she said. Wilson W Bryan: 
wilson.bryan@fda.hhs.gov Jean Bennett: 
jebennet@mail.med.upenn.edu

Tags: gene therapy, retina