End stage retinitis pigmentosa
Some while back, I posted on the challenge, and lack of progress, in the development of drug treatments for the most common cause of adult blindness- “dry” age-related macular degeneration - dAMD (Roche’s lampalizumab disappoints- is the "dry" AMD pipeline about to dry up?).
But, as a recent article in Nature Outlook reminded me, while pharmaceutical development may be lagging, a host of technologies now in clinical and commercial development offer hope for individuals with previously untreatable forms of inherited and non-inherited retinal degeneration. Author Simon Meakin lists four technologies with the potential to revolutionise treatment: retinal prosthetics (“bionic eyes”); gene therapy; optogenetics, and cell regeneration.
The “bionic eye” approach involves fooling the brain into interpreting electrical signals delivered by an implanted microchip placed over the retina as spots of light. A microprocessor converts images captured by a miniature camera worn on a spectacles frame to electrical impulses relayed by wireless to the implant. While this cannot match the resolution achieved by the millions of photoreceptors in a healthy retina, with training, recipients can distinguish light from dark and identify high contrast objects.
The first commercial product (Argus II: Second Sight) received regulatory approval in 2011 in Europe (2013 in the US) for use in individuals with end-stage retinitis pigmentosa (RP).The device cost is widely cited as around $150,000, excluding surgical and training costs. Two other prosthetic systems in clinical development use implants placed underneath the retina; Prima (Pixium Vision) and Alpha AMS, a camera-free system developed by Retinal Implants AG, although the latter has recently entered administration. Pixium intends to begin trials of Prima in dAMD patients before the end of 2019. Second Sight is evaluating the feasibility of bypassing the retina by implanting electrodes into the visual cortex with its Orion system.
Gene therapy is now established as a viable means of bringing some degree of vision improvement to those with certain inherited conditions, with the landmark approval of Luxturna® (Spark Therapeutics) in both the US (December 2017) and Europe (November 2018). Clinical trials of other gene therapies are underway, with the aim of correcting RP-associated defects and inherited retinal conditions including Leber’s hereditary optic neuropathy; Leber’s congenital amaurosis; Stargardt disease; achromatopsia, and X-linked retinoschisis.
While not associated with any single gene detect, the “wet” (neovascular) form of AMD is also the subject of gene therapy trials aimed at neutralizing a protein (vascular endothelial growth factor- VEGF) involved in blood vessel formation. Success could replace the current treatment of regular injection of anti-VEGF antibodies into the eye.
Treatments in development require injection of viral vectors to insert functioning genes but other strategies, including gene editing and gene silencing, could potentially expand the range of treatable conditions. At a cost of around $425,000 per eye, Luxturna® has featured in the “fair value” debate around drug pricing, although the recent acquisition of NightstaRx, a gene therapy developer with a portfolio of early and clinical-stage assets by Biogen for a headline value of around $800 million, and the acquisition of Quethera and its pre-clinical glaucoma programme by Astellas are likely only the beginning of big pharma interest in next generation ophthalmology.
Optogenetic approaches, which exploit light sensitive proteins (“opsins”) to modulate biological processes, are still in early clinical development but have the potential to address a number of ophthalmologic conditions in which there are too few cells left to exploit or repair through either restoring function or inducing other types of retinal cell to become light-sensitive. A start-up company, RetroSense, initiated the first clinical studies of a viral vector delivered opsin in RP patients and was acquired by Allergan in 2016: an early-stage clinical study is ongoing.
The downside of opsins is that they respond to a limited range of light conditions. Gensight Biologics, hopes to get around this by combining video capture and electrical stimulation of retinal ganglion cells made light-sensitive through insertion of a gene coding for opsin production. The first RP patient was treated in October 2018 and the ongoing clinical study will evaluate different doses of the viral vector bearing the opsin gene.
The replacement of damaged retinal pigment epithelium (RPE) through stem cell therapy may eventually become a viable treatment for RP and AMD. Mixed results have been obtained with injected cell suspensions but implantation of pre-formed sheets of RPE cells secured within a biocompatible matrix could prove to be a significant improvement. Early clinical studies have been completed in subjects with both the wet and dry forms of AMD, and a start-up, Regenerative Patch Technology, formed to take up the challenge of financing and commercialising development.
Repairing the circuitry linking photoreceptors to the brain presents an altogether different level of technical challenge but, on the basis that non-mammalian species are capable of some degree of retinal neuron regeneration, it’s not impossible that means of reproducing this trick in humans might be developed, possibly through re-programming other cells present in the eye to regenerate lost neurons.
Complexity, cost and necessary caution over gene therapy and stem cell procedures make it likely that only a small number of individuals will initially benefit from these treatments, but advances in viral vector and stem cell-derived product manufacture, together with growing industry involvement should eventually make these life-changing treatments available to a significant minority of vision-impaired individuals.
Photo credit: Christian Hamel [CC BY 2.0]