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Vedere Bio was founded in June 2019 with $21 million series A funding and was acquired by Novartis in a lucrative deal valued at up to $280 million ($150 million upfront)¹ 18 months later. This is exceptional even in the fast-paced M&A world and one contributing factor may be that Vedere’s technology has the potential to be a game changer in gene therapy. Vedere’s novel optogenetics platform could be used to develop novel gene therapies for retinal disorders like age-related macular degeneration (AMD) and retinitis pigmentosa that can lead to blindness. It’s well known that cataracts and retinal eye diseases are the most common causes of permanent blindness, and while cataracts are treated surgically, retinal eye diseases typically do not have a standard treatment regimen. In developed countries, retinal diseases are the most common cause of irreversible blindness and AMD is the most common retinal eye disease in older people. AMD does have a few therapeutic options such as laser photocoagulation and anti-angiogenic therapies (for wet AMD) but there is an unmet clinical need for long-term therapies and the more prevalent dry form of AMD has very limited therapeutic options. Gene therapies are being actively investigated but one of the complications is the fact that there are several therapeutic targets for retinal disease – more than 250 different genetic mutations have been reported for retinitis pigmentosa alone. Gene therapy that targets a specific disease driver gene would be beneficial only to the patients with that mutation, thus limiting the addressable patient population.

Vedere Bio’s technology is unique in that it does not depend on the presence of specific genetic mutations and can address a broader patient population. Some retinal diseases like AMD and retinitis pigmentosa can cause widespread death of photoreceptor cells (rods and cones) resulting in vision loss. Vedere’s strategy is to target retinal cells that are not destroyed during the disease process. The technology was originally developed at UC Berkeley in the labs of Ehud Isacoff and John Flannery and focuses on the development of adeno-associated virus (AAV) vectors that express light sensing opsin proteins and can be directly injected into the vitreous space. The goal of this approach is to reverse blindness by using an AAV expressing green cone opsin targeted to retinal ganglion cells in the inner retina. Normally, these cells are not sensitive to light but the presence of the green cone opsin protein makes them light sensitive, so they are able to function as surrogates for photoreceptor cells and generate electrical signals for the brain to interpret as vision.

Another unique feature is the AAV vector that was engineered to specifically infect cells in the inner retina. The AAV serotype 2 viruses with tissue specific opsin expression infect the retinal ganglion cells in the inner retina– the tissue specific expression simplifies the delivery method as the virus can be directly injected into the vitreous space instead of the subretinal area, which is a more complicated process. The use of the green cone opsin is a technological innovation as optogenetic methods have used microbial opsins that have high response rates but need a strong light stimulus which could damage the retina. Conversely, rhodopsin and melanopsin from retinal ganglion cells are sensitive but have a slow response to light. The medium wavelength green cone opsin solves both challenges as it is sensitive to dim light and has a fast response rate. An added benefit is that the green cone opsin protein allows visual adaptation in normal light for 3D object visualization.

This opens up the possibility that people with advanced retinal disease may be able to see again and regain a better quality of life so Vedere’s innovative technology could be a true game changer in ocular gene therapy.

Interested in reading more about the development and testing of the AAV in the rd1 mouse model of blindness? Check out the original paper from March 2019.

¹ https://www.prnewswire.com/news-releases/novartis-acquires-vedere-bio-a-novel-optogenetics-aav-gene-therapy-company-301162269.html

Chinese

Neurodegenerative diseases encompass several disorders that are typically associated with the death of specific neuron types resulting in loss of motor, cognitive and other abilities, and most of these diseases are ultimately fatal. It is estimated that there are more than 600 neurodegenerative disorders that impact 50 million Americans each year¹. Despite the growing unmet clinical needs, there has been limited progress in developing new therapies for neurodegenerative diseases. Drug discovery and development rely heavily on preclinical in vitro and in vivo models to study disease biology, identify new drug targets and test therapies. While different models have distinct advantages and drawbacks, the selection of a given model should be carefully done to answer specific biological questions. For example, cell-based models derived from primary disease state neurons or induced pluripotent stem cells (iPSC) lines are widely used to study disease pathology and identify mechanism of action for new drug targets². Additionally, cell-based models are well suited to screen small molecules or biomolecules to identify candidate therapies to test in animal models. Traditionally, cell-based models consisted of simple 2D cell cultures but increasingly there is a shift towards using more complex 3D cell models that are cultured on a scaffold to mimic the tissue environment². While the in vitro models are useful in the early stages of drug discovery, the gold standard to evaluate therapeutic efficacy and safety are animal models.

Several rodent models of neurodegenerative disease are used in preclinical discovery programs for new therapies. These models include transgenic models where specific disease-causing mutations are introduced or chemically induced models to induce neurological damage³. Despite the large number of publications and funding, mouse models of neurodegenerative disease have been shown to have limited translation to human patients as therapies that were shown to be efficacious in mouse models had very limited effect in humans3. One of the key reasons for this is that the rodent CNS is very different from the human CNS in terms of anatomy, physiology and neuronal complexity³. Additionally, rodents have a short lifespan so it is difficult to model age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Nonhuman primates (NHPs) are better suited to model neurodegenerative diseases as the NHP CNS is well suited to evaluate changes in cognition, brain function and motor skills that are hallmarks of neurodegenerative diseases. Aged NHPs have been reported to develop age-related issues such as neuron loss, plaque formation and cognitive deficits similar to humans⁴. However, it is expensive and complicated to maintain an NHP colony for long time periods to study the natural development of neurodegenerative diseases. Therefore, the development of induced disease models is of interest. For example, the injection of beta-amyloid containing brain tissues into NHP brains were shown to induce plaque formation, neuroinflammation and other neuronal issues4 associated with Alzheimer’s disease. However, NHP models of Alzheimer’s disease have not been widely adopted likely due to ethical and cost issues. Animal models of Parkinson’s disease can be induced by the injection of specific chemicals such as MPTP or 6-hydroxydopamine. These compounds can be injected directly into the brain or systemically into the vasculature, skin or muscle. NHP models injected with MPTP recapitulated the motor skill deficits associated with Parkinson’s disease⁴. More recently, intracerebral injections of gene therapy vectors encoding mutant alpha-synuclein or Lewy body extracts in rhesus macaques and cynomolgus NHPs induced neuronal cell loss and increased expression of alpha-synuclein but these physiologic changes did not translate to motor skill changes⁴.

While Alzheimer’s disease and Parkinson’s disease are challenging to model since the exact genetic drivers of disease development are not fully known. In contrast, the disease driver for Huntington’s disease has been identified as an expansion in the number of CAG repeats in the huntingtin gene. Researchers have introduced the mutant huntingtin gene using lentiviral vectors into specific brain regions of cynomolgus macaques and demonstrated the development of Huntington’s disease symptoms⁴. An attempt to develop a transgenic NHP model was reported but the animals with the mutant huntingtin gene had very short lifespans⁴. To overcome this disease-related challenge, researchers have developed iPS cell lines from transgenic NHP models of Huntington’s disease to study disease biology and reported the development of an NHP iPSC-derived astrocyte model for Huntington’s disease⁵.

In summary, while NHP models are highly translational and recapitulate several hallmarks of neurodegenerative diseases, the complexity of developing and maintaining these models pose significant challenges.

References:

¹https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280411/

²https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063566/

³https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/

⁴https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886328/

⁵https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428250/