Coave Therapeutics is a French biotech developing gene therapies for neurodegenerative and ocular diseases. The company has developed a technology platform that can be used to redecorate the outer surface of viruses, creating gene therapy vectors that are better at accurately delivering healthy genes to the right target cells, including neurons in the deep brain tissue. By combining this vector technology with transgenes restoring natural cell cleaning pathways, the company has created a pipeline of therapies for both genetically and non-genetically defined neurodegenerative diseases, such as Parkinson’s Disease, Multiple System Atrophy (MSA), and Amyotrophic Lateral Sclerosis (ALS).
By Amy LeBlanc
Q: Can you tell me about Coave Therapeutics and the ALIGATER™ (AAV-Ligand Conjugates) platform?
Rodolphe Clerval (Coave Therapeutics CEO): “The company was founded in 2015 as a spin-out from the University of Nantes and was previously named Horama. Initially it was a single-asset company focused on gene therapy in ophthalmology, but in 2020 we refocused on neurology, where our unique technology platform ALIGATER allows us to easily create viral vectors for extremely targeted gene therapy.
“If you look at the gene therapy field today, most of the products that have been approved so far use a specific type of vector called an Adeno-associated virus [AAV, ed.]. Those vectors have demonstrated some efficacy, but also a lot of limitations in terms of distribution and specificity, which have in some cases led to severe safety issues. There are many companies in the gene therapy field trying to develop better vectors, but most of them are currently using genetic engineering to slightly modify existing vectors. What we are doing with our next-generation vector technology is far more dramatic!
“Our ALIGATER technology is very versatile – theoretically we can use it to create a gene therapy for any type of cell in the body.” – Rodolphe Clerval
“The ALIGATER platform uses a pure chemical process to decorate the protein shells of viral vectors with specific small molecules called ligands. These ligands on the viral capsid bind to receptors on the outside of cells, ensuring that the viral vector is able to find and deliver its payload (i.e. the therapeutic gene) to the target cell in the right type of tissue. For example, we can modify an AAV capsid so that it is covered in ligands specific for neurons in the brain, or photoreceptors in the retina, or cells in the liver (and so on).
“Our ALIGATER technology is very versatile – theoretically we can use it to create a gene therapy for any type of cell in the body. We have in vivo data from animal models, including Non-Human Primates, demonstrating the superiority of our vectors in biodistribution and cell targeting, and since our technology uses just a single step to bind the ligands to the viral vectors, it is easy chemistry to perform at a large scale.”
Q: So you can use this technology to create new viral vectors, but can you also use it to alter existing ones?
Rodolphe Clerval: “Yes, that’s the other big advantage of the ALIGATER platform: we can use it to redecorate too! Say for example your company has already developed a gene therapy product using AAV, but you’re not entirely happy with the vector. Normally, you would have to go through the whole process of changing your entire capsid, which can take up to three years. This is hugely disruptive. Using the ALIGATER platform, we can instead redecorate the existing AAV, eliminating the need to screen for new capsids and saving a lot of time and hassle. This makes our platform very attractive for external partners.
“This is really the only technology currently available that can be used to improve viral capsids, generating a better gene therapy product from one that already exists.” – Rodolphe Clerval
“We have in fact recently signed three collaborations with Nasdaq-listed gene therapy companies. These companies came to us with their existing AAV products, complete with the transgene payloads. In just a few weeks, we were able to modify the capsids without otherwise changing the product. This is really the only technology currently available that can be used to improve viral capsids, generating a better gene therapy product from one that already exists.”
Q: Do you also have your own pipeline of candidate therapies, in addition to the ALIGATER platform?
Rodolphe Clerval: “We do. The most advanced candidate in our pipeline is a Phase I/II legacy program from the early days of the company – a product created using traditional AAV to treat an ocular disorder. Our other programs were created using the ALIGATER capsid technology and our own payloads and are advancing through preclinical studies.
“We’re very excited about these programs, which are all targeting neurodegenerative diseases at a really fundamental, preventative level. The hallmark of many neurodegenerative disorders is that you have an aggregation of proteins that occurs in the brain, leading to cell deterioration and death. Many companies have tried to target those protein aggregates with antibodies, to varying degrees of success. We have decided to take a different route by going upstream of the problem to stop aggregates forming in the first place.
“This is our approach: harnessing our ALIGATER capsid technology to create gene therapies that can precisely target neurons at a low dose, restoring their natural cell cleaning mechanism to prevent protein aggregation and cell death.” – Rodolphe Clerval
“There is a natural pathway in all of our cells called the Autophagy Lysosomal Pathway (ALP), which is the cleaning mechanism cells use to degrade proteins and rid themselves of plaques. In neurodegenerative disorders, this mechanism is dysfunctional, leading to the buildup of these toxic protein plaques, which in turn leads to the death of neurons. In some disorders, ALP dysfunction is caused by a mutation of a single gene, like the GBA1 gene in Parkinson’s Disease. In others, we’re not entirely sure why the mechanism isn’t working, but there is a master regulator of the pathway called TFEB that can be used like a master switch to restore the cell cleaning function.
“So this is our approach: harnessing our ALIGATER capsid technology to create gene therapies that can precisely target neurons at a low dose, restoring their natural cell cleaning mechanism to prevent protein aggregation and cell death. In Parkinson’s Disease we are doing this by targeting GBA1 in the deep structure of the brain – we’re expecting this program to be in the clinic by 2025. In non-genetically defined diseases like ALS and MSA we are targeting the master regulator TFEB, which may well be the future for gene therapy in neurodegenerative disorders.”
Read this article to find out more about the inspiring potential of gene therapy in neurology!
Q: Most gene therapies approved so far have been for diseases with a single target gene. Are your efforts to target non-genetically defined diseases a next-gen approach?
Rodolphe Clerval: “All gene therapies approved so far have indeed targeted monogenic diseases – relatively low hanging fruit where the issue was clearly caused by a single faulty gene. But over the last ten years or so, we’ve started seeing a few companies like ours entering the non-monogenetic space. Gene therapy has achieved a certain level of maturity, including in terms of vector technology, which is making this possible. This is where we really see a chance for widespread impact: in these big, non-genetically defined patient populations where the disorders aren’t caused by a simple genetic mutation, but millions of people can still benefit from gene therapy. I think this kind of strategy may well form a significant part of the future of the field.”
