Our group studies disease mechanisms in inherited retinal degenerations (IRDs), and evaluates efficacy and safety of potential treatments. IRDs result in vision loss due to mutations in more than 200 different genes and include diagnoses such as Retinitis Pigmentosa, Stargardt Disease, Leber Congenital Amaurosis, and others. There are multitudes of different pathological mechanisms resulting from different mutations. Our group uses non-invasive tests to link changes in retinal structure and function to underlying molecular pathology. We also develop and evaluate novel outcome measures for use in clinical trials.

April 1, 2021: Personalized RNA therapy reverses blindness with lasting effect – publication in Nature Medicine

A Phase I/II clinical trial involving intravitreal injections of the anti-sense oligonucleotide sepofarsen for patients with LCA caused by CEP290 mutations has been ongoing at our center since November 2017. Previously we reported in Nature Medicine significantly improved vision. In a second Nature Medicine article published today, we now report unexpected durability of the improvement after a single intravitreal injection. Four genetic forms of LCA, caused by RPE65, CEP290, NPHP5 or GUCY2D gene mutations, are known to demonstrate severe visual dysfunction despite preserved photoreceptor cells. This unusual disconnect between structure and function allows for a large therapeutic potential. We used sepofarsen (designed to enhance normal protein production by blocking access to the mutant site) in an ongoing clinical trial with LCA patients due to CEP290 mutations. One of the patients provided a rare opportunity to measure long-term pharmacodynamics following a single bolus of sepofarsen. The patient before the treatment had reduced visual acuity, small visual fields and no night vision. After a single intravitreal injection of sepofarsen scores of visual function and retinal structure measurements showed large improvements congruent in time and space supporting an incontrovertible biological effect at foveal cone photoreceptors. The peak effect occurred near 3 months and remained easily detectable at 15 months. Studies are ongoing to better understand the details of pharmacodynamics and potential biological underpinnings.

Cideciyan AV, et al. Durable vision improvement following a single treatment with antisense oligonucleotide sepofarsen: a case report. Nature Medicine, 2021. [PubMed] [DOI] [Clinicaltrials.gov] [UPenn Press Release]