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Once hailed as the solution to delivering gene therapies, adeno-associated virus (AAV) vectors have seen their star dim in recent years. Initially touted for its potential to treat a number of genetic disorders, the dwindle in research has now become apparent. The latest biopharma to scale back on AAV research is Vertex Pharmaceuticals, in a blow to the technological space.
The multinational biopharma slashing all AAV research was revealed in an article by Endpoints News. This is bound to impact its collaborations with gene therapy company Affinia Therapeutics and tRNA therapeutics developer Tevard Biosciences, both of which rely on AAV vector development to create their medicines.
But how significant is this pullback on AAV research?
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AAV research: pioneering gene therapeutics
AAVs are non-enveloped viruses, which are also known as naked viruses, as they lack an outer layer that is typical of a virus. Instead, they have a capsid – a protein shell – that packages the DNA of the virus.
These viruses were discovered rather accidentally by scientists who were making adenovirus preparations back in 1965. As the viral DNA in AAVs is encased within, the idea to engineer them to deliver medicines came about. Three decades after their discovery, an AAV vector was first used in a person who had cystic fibrosis, a genetic disorder that causes the buildup of mucus in the body.
Then came the approval of Glybera, the first-ever gene therapy to be cleared by the European Union (EU) in 2012. In Glybera, the gene was carried by an AAV vector to treat a rare genetic condition called hereditary lipoprotein lipase deficiency, wherein the body lacks an enzyme responsible for breaking down fats in the blood. However, excitement around the therapy was undercut five years later when its developer uniQure pulled it out of the market, citing hefty cost and lack of demand.
But its regulatory nod cleared the way for other AAV gene therapies to hit the market, many of which are curative. These include Luxturna for Leber’s congenital amaurosis, a rare, inherited eye disease, Zolgensma for spinal muscular atrophy – a neurodegenerative disorder that affects the spinal cord – Elevidys for the muscle-wasting disease Duchenne muscular dystrophy (DMD), and Hemgenix and Roctavian for the rare blood disorders hemophilia B and A, respectively.
Vertex breaks off partnerships with Affinia Therapeutics and Tevard Biosciences
However, it looks like maybe AAV gene therapies have had their day in the sun. Vertex had vowed to discover AAVs to better treat DMD and cystic fibrosis with Affinia in a $1.6 billion deal back in 2020, but last week Affinia told Endpoints that it has regained the rights to the DMD vectors. Vertex had already returned the rights to the cystic fibrosis-targeting vectors in 2022.
As Vertex retreats from the space, this affects Tevard Biosciences as well, which it began a collaboration with to advance tRNA therapies for DMD two years ago. tRNA therapies treat genetic conditions by targeting the mutations that disrupt protein synthesis. tRNAs are typically engineered to bypass and even correct mutations. In DMD, where a genetic mutation leads to the lack of production of the protein dystrophin required for healthy muscle development, engineered tRNAs aim to restore protein synthesis by correcting the mutation.
While various tRNA therapy developers rely on lipid nanoparticles (LNPs) as vehicles for their medicines, Tevard’s pipeline leans on AAVs to deliver these therapies. And especially in the case of DMD, AAVs are the better choice, as LNPs are not readily taken up by the body’s muscles, according to Tevard.
Late last year, Tevard was notified that Vertex was backing out from the DMD deal, among many others. And this month, it received the rights back to its tRNA program. Still, Tevard is holding out hope for the program as it gears up to present its findings to support its tRNA therapy at the American Society of Gene and Cell Therapy (ASGCT) summit in New Orleans this week.
Big pharmas retreat AAV space as safety signals arise
Meanwhile, while much has not been disclosed about the move, Vertex’s own CRISPR research for genetic diseases – which has lagged behind in recent years – has been canned. This comes after the biopharma severed ties with Massachusetts-based Verve Therapeutics and gave back the rights to the latter’s gene editing program for liver disease. Verve has an LNP-based gene editing pipeline.
Vertex’s withdrawal from the scene is part of a retirement by big pharmas from AAV research and development (R&D). Japanese multinational pharmaceutical Takeda let go of its preclinical program for AAV gene therapies two years ago. While much wasn’t revealed about its decision at the time, it was predicted that out of its 10 gene therapy deals it signed from 2020 to 2022, its AAV-specific partnerships with Massachusetts-based Selecta Biosciences and California-based Codexis would be in jeopardy.
The same year, pharma giant Biogen axed its preclinical AAV gene therapy program to cut costs amid rising safety concerns surrounding AAVs.
Philippe Chambon, founder and chief executive officer (CEO) of French biotech EG 427, explained that the safety profile of vectors is key to drug delivery.
“Pharma is pulling away from AAV-based gene therapies because of several challenges preventing their effective and cost-effective use beyond rare diseases,” said Chambon. “To unleash the real potential of gene therapy as a significant drug modality, it must be able to address diseases beyond the rare disease field and tackle chronic indications.”
Moreover, the only way to address chronic conditions is to overcome the “main roadblocks seen with AAV-based therapies,” according to Chambon. “These include improving the safety profile with less immunogenic, and whenever possible, local approaches. Better tolerability is also a must, so that re-dosable treatments can be developed to avoid the one-and-done paradigm that raises not only therapeutic regimen issues but also medico-economic concerns.”
Pfizer drops Beqvez, Roche gives up on gene therapy unit
Aside from Takeda and Biogen in 2023, more recently, Pfizer and Roche have scrapped AAV R&D. Pfizer ended the rollout of its AAV-based gene therapy Beqvez, which was approved by the U.S. Food and Drug Administration (FDA) to treat hemophilia B a year ago. It cited the limited interest in gene therapies for the bleeding disorder in February.
As for the Swiss pharma giant Roche, its AAV-focused gene therapy unit Spark Therapeutics in Philadelphia has been the subject of major restructuring. More than half of the staff were laid off, leaving 310 employees absorbed back into Roche. It is believed that this was to evade potential losses, as the company announced in March that there were no “significant future synergistic benefits” of having Spark around.
AAVs limited by payload size and manufacturing costs
Chambon thinks that AAVs have waning demand partly because of their small payload size. In fact, AAVs have a packaging capacity of about 4.7Kb, compared to other viral and non-viral vectors with much higher payloads. Some others can carry more than one gene.
“Payload size matters to achieve better control of therapeutic DNA expression and incorporate the full sequences of large proteins,” said Chambon, who added that developing an efficient AAV microdystrophin – a shorter version of the dystrophin protein used in gene therapy for DMD – took many years and may still need to be improved. “Also, we are seeing dual- and triple-AAV combos being tried to circumvent the payload size issue, but these are not the solution as they inherently face lower efficiency and require higher doses.”
Moreover, manufacturing AAV vectors is complex, and so scaling up is expensive, explained Chambon. Therefore, the hunt for better AAVs, and even vectors beyond AAV, is long overdue.
Beyond AAV research: searching for better drug delivery methods
For example, Affinia is committed to bringing its AAVs to the forefront despite Vertex’s disinterest. It is designing capsids that “better target tissues and cells that are the desired sites of efficacy while avoiding sites of toxicity.” This is achieved by re-engineering AAV9 by integrating short peptides into the AAV genetic sequence. To improve payload capacity, it looks to collaborate with fellow biopharmas as well as academic institutions as it also seeks to license its capsids to other biotechs.
Meanwhile, Chambon’s company EG 427 has based its genetic medicines pipeline on non-replicative Herpes simplex virus-1 (HSV-1) vectors. These carry a larger genetic payload of more than 30kb – compared to other viral vectors. They have also been found to curb immune responses, maintaining a safe profile so far.
“We believe this approach provides an alternative that has already demonstrated safety clinically, offers the possibility to re-dose, easier to scale manufacturing cost-effectively, and possesses an inherently large payload capacity at least six times bigger than AAV. Other companies, in particular Krystal Bio, have shown clinically that HSV-based vectors are safely re-dosable,” said Chambon.
As the search for alternatives to current AAVs continues, this is unlikely to dampen gene therapy research as a whole, especially now that FDA Commissioner Marty Makary announced plans in April to expedite rare disease drug approvals, much of which comprise gene therapies anyway. But where exactly the drug delivery space is headed in the next few years, we will have to wait and see.
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