Optogenetics is a form of mutation-agnostic gene therapy that is being explored in clinical trials (Figure 1). One promising therapy is MCO-010 (Nanoscope Therapeutics), which is currently being studied as a treatment for both retinitis pigmentosa (RP) and Stargardt disease. MCO-010 has received both fast track and orphan drug designations from the US Food and Drug Administration (FDA) for these conditions. The molecule is delivered by an adeno-associated virus (AAV2), introduced to the eye in a single intravitreal injection.
Figure 1. Multicharacteristic opsin (MCO) therapy uses a bioengineered light-sensitive protein to sensitize the retinal bipolar cells to detect light. This gene therapy has the potential to restore vision in patients with retinal degenerative diseases, even when there is significant photoreceptor loss. Image courtesy Nanoscope Therapeutics.
To better understand the optogenetic approach, I have asked Allen
C. Ho, MD, FACS, FASRS, Nanoscope’s chief medical advisor, and Sulagna Bhattacharya, Nanoscope’s cofounder and chief executive officer, to discuss data from the recently completed RESTORE trial and share their observations on how patients respond to the treatment.
Dr. Yasha Modi: The phase 2b/3 RESTORE study is certainly a very interesting program that allows for a gene-agnostic approach. This therapy can thus reach many patients that otherwise may have rare gene mutations in RP where no gene-specific clinical trial is occurring. Can you explain optogenetics, where opsins are normally found in the retina, and how this particular gene therapy primes bipolar cells to respond to light?
Dr. Allen C. Ho: Optogenetics is gene therapy that induces cells to express a light-sensitive opsin protein. In the mammalian retina, opsins are most prominently found in the photoreceptors and are responsible for converting light into an electrochemical signal and initiating the visual transduction cascade. Nanoscope’s MCO-010 uses a viral vector and promoter-enhancer to target bipolar cells to express a specialized multicharacteristic opsin (MCO), thereby allowing these cells to be light sensitive in advanced retinal degenerations with permanent photoreceptor loss, with the potential to restore vision. Unlike classical gene-specific therapies, the MCO-010 therapy is agnostic to any underlying gene mutation and does not require presence of outer retinal cells such as rods, cones, or retinal pigment epithelium.
Dr. Modi: Can you summarize the top line data of the phase 2b/3 study (providing VA improvement in Snellen equivalents)? Can you provide an overview of the steroid prophylaxis and what were the IOI rates and severity of these inflammatory events?
Dr. Ho: Individuals in the phase 2b/3 RESTORE randomized control trial had advanced retinitis pigmentosa and severe vision loss. Most subjects were hand motion, light perception, or worse in routine clinic settings. In RESTORE, baseline BCVA was ~20/3200 among MCO-010 treated individuals. MCO-010 achieved its primary (change in BCVA at Week 52) and key secondary (change in BCVA at Week 76) endpoints with statistical significance and no serious adverse events. Patients in the high-dose MCO-010 group achieved an improved BCVA of ~20/1500 and ~20/900 at Weeks 52 and 76, respectively. The low-dose MCO-010 group also had an improved BCVA of ~20/1300 at those time points. Approximately 40% (7/18) and 56% (10/18) gained >0.3 LogMAR (equivalent to 3 lines of 15 ETDRS letters) BCVA improvement from baseline at week 52 and 76, respectively.
A 3-week oral steroid taper was started 3 days prior to MCO-010 dosing as prophylaxis. Consistent with other intravitreal gene therapies, intraocular inflammation was observed in 12/18 individuals. This inflammation was generally limited and controllable with topical steroids — only 1 individual continued to need topical treatment at the end of the study. There was no retinitis, choroiditis, vasculitis, ischemic neuropathy, hypopyon, or hypotony in MCO-010–treated individuals.
Dr. Modi: With uniform disruption of rods, and eventually, cones, in retinitis pigmentosa, this approach seems intuitive for advanced cases of RP. As the program extends into macular disease involving both Stargardt and geographic atrophy (GA), where peripheral photoreceptors are still functioning, is there any concern about priming bipolar cells to respond to light when the normal synaptic connections away from the macula remain intact? Could this potentially degrade their peripheral vision from aberrant stimulation?
Dr. Ho: That is a consideration, but one that seems more theoretical at this time. Nanoscope has cautiously started to introduce MCO-010 to better-seeing patients, and there has been no evidence of interference or decreased vision where photoreceptors remain intact.
Dr. Modi: This program is moving forward for Stargardt’s disease, using a similar approach to the RP study, and also for age-related macular degeneration, but using a non–viral vector approach in that case. What is the difference, and when would a viral approach be preferred to a non-viral approach?
Ms. Sulagna Bhattacharya: Gene therapy involves the delivery of exogenous DNA into target cells. Because viruses have become extremely adept at doing this through millions of years of evolution, most gene therapy programs leverage viral vectors for delivery of therapeutic transgenes. Viral approach is preferred when a more durable expression and associated treatment effect is desired with a single injection.
However, there are limitations with viral vectors, such as immunogenicity and the size of the transgene payload that can be delivered, so non–viral vector delivery could allow for redosing if necessary and for larger proteins to be expressed. Further, we’re coupling the non–viral vector approach with an OCT-guided non-thermal laser we have developed to exquisitely target the retinal or macular cells and regions of interest.
Dr. Modi: It is interesting that visual acuity improves with this approach just by sensitizing bipolar cells to respond to light. What is the thought behind improving visual acuity? And based on patient comments in the clinical trials, what are they perceiving after treatment relative to before they lost vision from RP or Stargardt?
Ms. Bhattacharya: By targeting bipolar cells to express the ambient light-sensitive MCO, it gives them the ability to function as de facto photoreceptors, which initiate visual transduction for the transmission of the signal through the remaining retinal layers in the photoreceptor-degenerated retina, the optic nerve, and ultimately to the brain. The proximity of bipolar cells to the photoreceptor layer in the healthy retina as well as bipolar cells’ relative number, distribution, and alignment provides the potential for greater visual acuity compared to targeting cells further down the line like retinal ganglion cells.
The individuals who have been treated with MCO-010 had severe to profound vision loss — many were only light perception, and there has been a spectrum into the degree of improvements that have been observed. Commonly, better perception of shapes is reported, leading to increased confidence in mobility, navigation, and interaction with loved ones. Some patients with better results report being able to read the time on a phone, recognize faces, and even perceive colors, just as they were able to do before losing vision from RP or Stargardt disease. We look forward to the opportunity to dose more patients to get a better understanding of the visual potential of the MCO optogenetic platform. RP
