Amy Del Medico: Hello, I’m Amy del Medico. I’m VP of Ophthalmology here at Vial. I’m here talking today with Samar Mohanty from Nanoscope Therapeutics. Hi Samar, welcome.
Samarendra Mohanty: Hello, Amy
Amy Del Medico: What inspired you to focus on gene therapies for retinal diseases? What led to the founding of Nanoscope?
Samarendra Mohanty: Since its inception of optogenetics, researchers have been focused on making optogenetics as a toolkit to modulate activities of selected neurons by light activation to understand how the neural circuitry functions. In my career, I’ve had a chance to lead optogenetics programs at multiple institutions wherein I met key contributions such as past demonstrations of near infrared optogenetics stimulation in cells and in animals.
But, I found out patients with retinal degenerative disease lose their sight, and light-sensitive retinal cells, namely rods and cones. Since eyes are transparent, it led me to wonder if we could impart high enough light sensitivity to the remaining cells of the retina. Namely, bipolar cells, so that we can desensitize them to ambient light. And thus, we would have sight-restoring potential.
This prospect became very compelling and exciting to me after reading on retinal degeneration and realizing there were no available treatments. However, to be restorative to ambient light, in addition to high light sensitivity of the optogenetic molecules or called obscene. They need to have light sensitivity across the visual spectrum that is from blue to the red, and be able to address retinal degeneration patients with highest unmet need, optogenetics provide the best from cell and gene therapy. We repurpose the existing cells as de facto photoreceptors, which remain intact and integrated in the retina, even in the advanced stage of the disease. A significant market opportunity existed for an optogenetic platform that could restore high-quality real life vision.
After observing the robust efficacy and safety of MCO in multiple mice models of retinal degeneration, we founded NanoScope for clinical translation of this transformative therapy.
Amy Del Medico: Thank you. I do think this is one of the most exciting areas of ophthalmology. I wondered if you could elaborate a bit more on the science behind the MCOs and how they restore vision?
Samarendra Mohanty: An MCO is an optogenetic biotherapeutic platform comprised of a multi component transgene. A cell-specific promoter enhancer, and a proprietary delivery system. The bioengineering we conducted to develop MCO platforms is unlike anything that has ever been tried in optogenetics and for retinal degenerative patients.
The transgene is made up of three distinct light-sensitive molecules fused into a single contiguous protein when expressed. Unlike classical optogenetics, two of these three light-sensitive molecules are not transmembrane. Each of these light-sensitive molecules is highly sensitive to different parts of the visible spectrum. So, that the overall fusion protein is highly sensitive to the broadband ambient light that normal eyes are sensitive to.
The components of the MCO platform, the promoter enhancer, and each light-sensitive molecule in the MCO are tunable, making it possible for us to optimize the characteristics, such as kinetics, sensitivity, and target cell type that are tailored to the needs of patients, and underlying pathology for specific indications.
I would like to note that while our proprietary AV vector allows efficient manufacturability and tropism for targeted retinal cells via intravitreal delivery, we have a non-viral delivery approach to target central retina, which matches the geographic atrophies.
Amy Del Medico: The non-viral approach that you’ve developed, the laser delivered NOD technology, what are its main advantages, would you say, compared with traditional gene therapy delivery methods?
Samarendra Mohanty: The viral package gene therapy has been shown to target well in ophthalmic conditions, but is known to evoke inflammation primarily due to the viral capsid. While the inflammation can be controlled and tolerated, especially in advanced retinal degeneration patients, we envision a non-viral approach may be better suited for mass indication, such as geographic atrophies.
Furthermore, it will be ideal for targeting the atrophic areas of GA with therapeutic genes, leaving the surrounding healthy retina intact. Our non-viral laser delivery approach overcomes the challenges of viral delivery and provides a unique opportunity to efficiently deliver obscene encoding genes to GA lesions via OCT image guidance.[00:05:00]
In the nano-enhanced optical delivery or NOD method, the nanoparticles are mixed with plasmids and injected intravitreally. Before low power near infrared irradiation of targeted retina occurs to transiently and locally enhance the light intensity, leading to permeabilization of the cells and uptake of the plasmid.
Another key advantage of a non-viral laser -based NOD method is the ability to re-dose precisely. As atrophy has a certain progression rate. An OCT-guided laser beam can paint the new atrophic areas and sensitize those photoreceptor-lacking regions with the therapeutic obscene without being hindered by immune rejection.
Amy Del Medico: Thanks, Mar. Geographic atrophy is certainly a hot topic at the moment, and I know from what you said previously, MCO-010 does target a broad spectrum of retinal diseases. How does this address the genetic variations present in these conditions?
Samarendra Mohanty: Optogenetics as a method has long been considered a gene agnostic approach for restoring vision due to a variety of genetic mutations. In preclinical models and now in clinical studies, we have shown that MCO-010 can restore vision not just in a mutation-independent manner, but in a disease-agnostic manner for all outer retinal degenerative disease.
Since advanced retinal desensitization patients have no photoreceptors, we target the next layer of retinal bipolar cells, which are intact. Thus, irrespective of gene mutation and underlying pathology, we can restore light sensitivity and high-quality vision by repurposing the bipolar cells as de facto photoreceptors.
We have so far treated 35 patients across three trials and therefore have the largest population of optogenetically treated patients. I want to emphasize here that before there has been no approach like MCO that restored sensitivity to ambient light across the visual spectrum in real-time in these patients across dozens of mutations that cause the retinal dystrophy.
Amy Del Medico: Extremely interesting, Samar. Very exciting, too. I wondered about one aspect of your therapy. That it can be applied in different lighting conditions. Can you describe the mechanism that allows for this?
Samarendra Mohanty: You are right in noting that, historically, the optogenetic field has struggled to realize the therapeutic potential because no one light-sensitive molecule can perform well across different intensities. And colors of light presented to us in our daily living in real-time as they are presented. Thus, prior attempts have used light-intensifying goggles and have struggled to truly benefit patients with regard to restoring high-quality vision.
The simple answer to the unique mechanism by which MCOs can work in ambient light. That lies in the structure of the fused protein. Each of the three components are highly sensitive to different colors of light. If you think of ambient light, whether it be sunlight or office lighting. We are generally talking about some type of white light where a mixture of colors is present that we see blended.
One is sensitive to any given color, then it is only sensitive to a fraction of the light in most common places, and thus effectively not that sensitive at all. But if a highly sensitive obscene to multiple colors of light that span across the visible spectrum of white light. Such as MCO, then one will not only be highly sensitive to those individual colors, but the ambient light conditions are sufficient for MCO to generate a vision signal.
The components of MCO amplify light and light-induced photocurrent by acting in unison. The unique structure of MCO also provides a high dynamic range. It means the treated patient can See in a bright sunny day in an office building and even under starlight in a cloudy moonlight,
Amy Del Medico: It’s very impressive. I imagine developing a therapy like yours has met with some challenges along the way, as any sort of development program does. Are you able to discuss some of the more significant hurdles that nanoscope has overcome in developing the technology?
Samarendra Mohanty: From the start, the selection of multiple light-sensitive molecules from nature required significant R&D activities. Further, a significant amount of bioengineering had to be deployed to fuse them together in a manner that allowed each component to not only add but multiply the effect without compromising the kinetics.
There is also a limit to the size of the transgene that AAV vector can package. While this is not a concern in classical optogenetics, because the microbial option sizes are within the AAV payload capacity, the MCO fusion protein size [00:10:00] is rather large. So we have to remain within the limit imposed by the AV capacity.
Getting sufficient AV yield with an acceptable full-to-empty ratio was a challenge. It required us to utilize a proprietary vector that could handle the large transgene. A lot of virgin ground remains in the regulatory landscape for gene therapy, specifically with ocular gene therapy for patients with severe vision loss.
First, MCO is a mutation agnostic gene therapy, and therefore will be the fastest therapy in the gene therapy space for any indication. We have to develop the strategy and relevant functional potency assay for the new mechanism of action. Second, there is no approved therapy for severe vision loss patients, therefore no precedence on the endpoint.
Something as simple as a validated test to measure vision and vision improvement in this patient simply did not exist when we started. In this instance, we not only had to develop a novel test to assess these patients, but also validate them and then educate the regulators on their usefulness. Still, there is work to be done to establish clinical meaningfulness.
Lastly, retinal degenerative patients are constantly on a decline in vision, and it may take years before the true impact and magnitude of such restorative therapies can be assessed with respect to the control group. Further, there is no natural history for these patients, especially very low vision patients. Therefore, we are working with regulators to define intermediate clinical endpoints so that the clinical outcome assessments measured at earlier time points can reasonably predict the future impact of this restorative therapy.
Amy Del Medico: It sounds like you’re leading the way with novel endpoint development and certainly novel testing and validation. Given the potential life altering effects of your therapies, how is Nanoscope working towards making these treatments accessible to a wider range of patients in the future?
Samarendra Mohanty: Absolutely. We believe these retinal degeneration patients have been waiting long enough. Now IRDs are the leading cause of blindness in the working age population. The patients can’t wait anymore and we have to find expedited pathways to make these transformative therapies available to them on an urgent basis.
FDA and specifically CBER leadership has been publicly vocal that gene therapy approvals are a priority in this season and that avenues such as accelerated approval are attractive paths and becoming the norm to get these life changing therapies to patients. So our strategy within IRDs. Is twofold.
Firstly, within IRDs, we hope that initial approval for advanced RP patients will be followed by a level expanding approvals to all IRD indications. Secondly, we hope to expand the approval to moderate vision loss patients so that it can benefit a large majority of all legally blind IRD patients. We also see our results in Stargardt macular degeneration as a read through to the benefit that MCO treatment can provide to advanced AMD patients, specifically those suffering from geographic atrophy, we are working towards taking it to the clinic towards the end of this year.
Amy Del Medico: Yeah, there’s no doubt about the level of unmet needs. It’s very exciting for those patients. My final question really is just to do with looking ahead to the future. I wonder what your thoughts are on the state of gene therapy research for retinal disease? How do you see Nanoscope further contributing to advancements in this particular field?
Samarendra Mohanty: Since most rare diseases in the retinal degeneration space have an underlying genetic mutation, gene therapies are going to be an obvious choice for restorative and durable outcomes. I see Nanoscope as pioneering mutation agnostic gene therapy so that the therapy can be democratized to a wider population irrespective of the underlying mutation.
That has been known to be associated with the diseases, or there are mutations that are yet to be identified. Our clinical programs have shown that such mutation agnostic therapies are safe, durable and beneficial to patients. I hope that the groundwork we have done in this space will not only make it easier for our pipeline programs to advance at a rapid pace, but also help other retinal gene therapy programs in development.
My view is that a historic opportunity for retinal gene therapy is emerging, where technological advances, efficacies, clinical data, and regulatory momentum are coming together in a way we have not seen before. I believe that Nanoscope holds a strong position within this historic opportunity to serve patients with highest unmet [00:15:00] needs globally.
Amy Del Medico: Samar, thank you. That was absolutely fascinating to hear you talk about what you’ve been developing. We appreciate your time.
Samarendra Mohanty: Thank you, Amy. Thank you for the opportunity.
