Gene therapy in rare diseases

Purpose Stargardt disease is caused by a mutation of the ABCR gene leading to photoreceptor degeneration and vision loss. Genetic replacement StarGen™ uses LentiVector® technology to deliver a corrected version of the ABCR gene. A single administration of the product directly to the retina could provide long‐term or potentially permanent correction. The primary objective of StarGen™ study is to assess the safety and tolerability of ascending doses of StarGen™ in adult patients with Stargardt macular degeneration. Up to 28 patients 18 years or older with a differing level of advancement of SMD will be included in this study in which a dose‐escalation phase of StarGen™ is followed by a dose confirmation phase. In Retinitis Pigmentosa, preservation or partial restoration of impaired cone function offers very promising perspectives based on neuroprotection, prosthetics or optogenetics. We demonstrated that cone cell function loss might result from the loss of expression of Rod‐derived Cone Viability Factor (RdCVF) consecutive to degeneration of rod photoreceptors directly affected by causative mutations. Administration of RdCVF, irrespective of the gene defect, induced in relevant animal models a strong preservation of cone cell function related to the maintenance of rod outer segments (1). Recently, work conducted by Botond Roska and our group showed that in advanced cases, cone cell bodies of dormant cones can be reactivated by vectorization of halorhodopsins (2). Over the past years we have followed a cohort of over 3000 patients and studied the morphology and function of cone photoreceptors, using novel high resolution imaging.. We showed that cone outer segment degeneration during the disease course can be documented and that patients suitable for clinical trials testing neuroprotection or optogenetics can be selected on this basis. A comprehensive personalized set of therapeutic strategies can be tailored on this basis. Such advances, unprecedented in the field of currently untreatable retinal diseases, offer hope for visual rehabilitation. To evaluate and document such functional outcomes, we have developed novel tools for assessing reproducibly visual impairment and restoration, as well as palliative aids and associated training protocols. Conclusion StarGen™: A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected StarGen™ Administered to Patients With Stargardt Macular Degeneration Sponsored by Oxford BioMedica UK Ltd. Principal Investigator Prof. Jose‐Alain Sahel Centre Hospitalier National d’Ophtalmologie des Quinze‐Vingts, Paris France – Professor David Wilson ‐Casey Eye Institute, Portland Oregon Léveillard T, Sahel JA. Rod‐derived cone viability factor for treating blinding diseases: from clinic to redox signaling. Sci Transl Med. 2010 Apr 7;2(26):26ps16. Busskamp V et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science. 2010 Jul 23;329(5990):413‐7.