Adeno-associated virus (AAV) vectors were once heralded as the answer to delivering gene therapies, but in recent years, their prominence has diminished. It was first hailed as having the ability to treat several hereditary illnesses, but the decline in research has already been recognized. Vertex Pharmaceuticals is the most recent biopharma to reduce its investment in AAV research, which is a setback for the technology industry.
Endpoints News reported that the international biopharma was cutting off all AAV research. This will undoubtedly affect its partnerships with Tevard Biosciences, a producer of tRNA therapies, and Affinia therapies, a gene therapy business that depends on the production of AAV vectors to produce its medications. – Vertex drops AAV gene therapy research –
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History of AAV-Based Gene Therapy
Because they don’t have the usual outer covering of a virus, AAVs are often referred to as naked viruses or non-enveloped viruses. Rather, they have a capsid, which is a protein shell that encases the virus’s DNA.
In 1965, while preparing adenovirus preparations, scientists made the relatively unintentional discovery of these viruses. The concept of engineering AAVs to deliver medications emerged because of the encapsulated viral DNA. An AAV vector was initially utilized in a patient with cystic fibrosis, a hereditary condition that results in the accumulation of mucus in the body, thirty years after it was discovered.
Then, in 2012, the European Union (EU) approved Glybera, the first gene therapy ever approved. In Glybera, the gene was delivered via an AAV vector to treat hereditary lipoprotein lipase deficiency, a rare genetic disorder in which the body is deficient in an enzyme that breaks down blood lipids. Five years later, however, the enthusiasm surrounding the therapy was dashed when its creator, UniQure, removed it off the market due to high costs and low demand.
However, its regulatory approval made it possible for further AAV gene therapies—many of which are curative—to be released into the market. These include Elevidys for the muscle-wasting disease Duchenne muscular dystrophy (DMD), Luxturna for the rare, inherited eye disease Leber’s congenital amaurosis, Zolgensma for spinal muscular atrophy, a neurodegenerative condition affecting the spinal cord, and Hemgenix and Roctavian for the rare blood disorders hemophilia B and A, respectively.
Vertex breaks off partnerships with Affinia Therapeutics and Tevard Biosciences
But it appears that AAV gene treatments may have had their moment. In a $1.6 billion agreement with Affinia back in 2020, Vertex had promised to find AAVs to better treat DMD and cystic fibrosis. However, Affinia informed Endpoints last week that it had reclaimed the rights to the DMD vectors. In 2022, Vertex had already given up the rights to the vectors that target cystic fibrosis.
Among other things, Tevard was informed late last year that Vertex was pulling out of the DMD contract. Additionally, it regained the rights to its tRNA program this month. As the group prepares to deliver its data to support its tRNA therapy at the American Society of Gene and Cell Therapy (ASGCT) congress in New Orleans this week, Tevard is optimistic about the program.
Risks of AAV-Based Gene Therapies
Big pharmaceutical companies are retiring from AAV research and development (R&D), which includes Vertex’s exit from the scene. Two years ago, the Japanese multinational pharmaceutical company Takeda terminated its preclinical research for AAV gene treatments. Although not much was known at the time, it was anticipated that its AAV-specific alliances with California-based Codexis and Massachusetts-based Selecta Biosciences, two of the ten gene therapy agreements it had signed between 2020 and 2022, would be in doubt.
In order to save money in the face of growing AAV safety concerns, pharmaceutical behemoth Biogen discontinued its preclinical AAV gene therapy research that same year.
The safety profile of vectors is crucial for medicine delivery, according to Philippe Chambon, founder and CEO of the French biotech company EG 427.
“AAV-based gene therapies are losing favor with pharmaceutical companies due to a number of issues that hinder their efficient and economical application outside of rare diseases,” Chambon stated. “Gene therapy needs to be able to treat chronic indications and diseases outside of the rare disease field in order to reach its full potential as a significant drug modality.”
Furthermore, Chambon says that overcoming the “main roadblocks seen with AAV-based therapies” is the only method to treat chronic illnesses. These include using less immunogenic and, whenever feasible, local methods to improve the safety profile. In order to produce re-dosable medicines and avoid the one-and-done paradigm, which raises medico-economic and therapeutic regimen challenges, better tolerability is also essential.
Roche abandons the gene therapy unit and Pfizer discontinues Beqvez
More recently, Pfizer and Roche have abandoned AAV R&D, with the exception of Takeda and Biogen in 2023. Beqvez, an AAV-based gene therapy that was approved by the U.S. Food and Drug Administration (FDA) to treat hemophilia B, was discontinued by Pfizer a year ago. In February, it mentioned the lack of interest in gene therapy for the bleeding condition.
The massive Swiss pharmaceutical company Roche has undergone significant restructuring at its Philadelphia-based AAV-focused gene therapy division, Spark Therapeutics. Over half of the employees were let go, leaving 310 who were reintegrated within Roche. Since the firm declared in March that there were no “significant future synergistic benefits” of having Spark around, it is thought that this was done to avoid any losses.
AAVs are constrained by manufacturing costs and payload size
According to Chambon, the tiny payload capacity of AAVs is one reason for their declining demand. AAVs can actually carry far larger payloads than other viral and non-viral vectors, with a packing capacity of roughly 4.7Kb. Others may possess multiple genes.
Chambon stated that it took years to develop an effective AAV microdystrophin, a condensed form of the dystrophin protein used in gene therapy for DMD, and that it might still require improvement. “Payload size matters to achieve better control of therapeutic DNA expression and incorporate the full sequences of large proteins,” Chambon said. Additionally, dual- and triple-AAV combos are being attempted to get around the payload size problem, but they are not the answer because they require greater dosages and have lesser efficiency by nature.
Furthermore, scaling up is costly due to the complexity of manufacturing AAV vectors, Chambon explained. The search for improved AAVs and perhaps vectors other than AAV is therefore long overdue.
Beyond AAV research: looking for more effective ways to deliver drugs
For instance, despite Vertex Pharmaceuticals’ lack of interest, Affinia Therapeutics is dedicated to making its AAVs more widely known. In order to “better target tissues and cells that are the desired sites of efficacy while avoiding sites of toxicity,” capsids are being designed. Short peptides are incorporated into the AAV genetic code in order to re-engineer AAV9. As it looks to license its capsids to other biotechs, it also looks to work with university institutions and other biopharmas to increase payload capacity.
In the meantime, non-replicative Herpes simplex virus-1 (HSV-1) vectors have served as the foundation for Chambon’s business EG 427’s genetic medication pipeline. When compared to other viral vectors, these carry a bigger genetic payload of almost 30 kb. They have so far maintained a safe profile by also being discovered to suppress immunological responses.
“We think this strategy offers a substitute that has previously shown clinical safety, allows for re-dosing, makes it simpler to scale production economically, and has a payload capacity that is at least six times larger than AAV. HSV-based vectors have been scientifically demonstrated to be safely re-dosable by other businesses, most notably Krystal Bio,” Chambon noted.
Given that FDA Commissioner Marty Makary announced efforts in April to speed rare disease drug approvals—many of which use gene therapies anyway—this is unlikely to slow down gene therapy research overall as the hunt for alternatives to existing AAVs continues. However, we will have to wait and see where the medicine delivery industry is going in the coming years.
Explore more: Full-Length Dystrophin May Be Possible for DMD Treatment
