For the past decade, adeno-associated viruses (AAVs) have been the undisputed stars of modern gene therapy. Their safety, tissue versatility, and ability to sustain long-term gene expression made them the vector of choice for treating rare genetic disorders once considered untreatable. Since 2012, eight AAV-based therapies have received approval, covering a range of conditions including inherited retinal dystrophy, spinal muscular atrophy, hemophilia B, and Duchenne muscular dystrophy.
But that story is beginning to change. After a period of extraordinary growth and promise, the AAV field is now experiencing significant setbacks. In September 2025, Biogen officially discontinued all gene therapy programs using AAV capsids, following similar moves by Vertex Pharmaceuticals, Pfizer, and Takeda.
Once hailed as the gold standard for in vivo gene delivery, AAV is now under heightened scrutiny in a more disciplined environment. The question facing the field today is no longer whether AAV works; it’s whether it can remain viable as the foundation for the next generation of gene therapies.
The real-world limits of AAV therapies
The most immediate challenge facing AAV gene therapies is their high cost. Treatments such as Luxturna, Zolgensma, and Hemgenix rank among the most expensive therapies in the world, with price tags of approximately $850,000, $2.1 million, and $3.5 million per dose, respectively. From the companies’ perspective, these prices reflect not just the potential clinical benefit but also the substantial risks, costs, and uncertainties inherent in developing such complex therapies.
However, these costs often contrast sharply with the uncertain durability of clinical benefit. While some studies have shown long-term transgene expression — up to 10 years in humans — loss of expression has also been observed in both animal models and clinical trials. Durability is influenced by multiple factors including immune responses, promoter silencing, and loss of episomal DNA, meaning that therapeutic effects can diminish over time and may necessitate additional interventions or alternative treatments. This challenge is compounded by the fact that AAV gene therapies cannot be reliably re-dosed due to immune responses.
Even when AAV therapies achieve clinical success, adoption can be slow. In 2022, the FDA approved Hemgenix from CSL Behring as the first gene therapy for hemophilia B, followed shortly by BioMarin’s Roctavian for hemophilia A. Despite their strong efficacy and the potential for a single-dose treatment rather than ongoing infusions, uptake of both therapies has remained limited.
Reflecting these challenges, Pfizer ended its partnership with Sangamo Therapeutics in December 2024, which had been developing an investigational gene therapy for adults with moderately severe to severe hemophilia A. This decision came despite positive topline results from the Phase 3 AFFINE trial, and previous indications that biologics license application and marketing authorization application submissions were expected in early 2025. In parallel, Pfizer also announced in February 2025 that it would no longer commercialize Beqvez (fidanacogene elaparvovec), its FDA-approved gene therapy for hemophilia B, citing little interest from patients and doctors.
More recently, biological and safety risks have also come into sharper focus. Systemic AAV delivery has been linked to liver toxicity, immune reactions, and, in rare cases, patient deaths. For instance, in 2025, Sarepta Therapeutics reported that three patients with muscular dystrophy died of acute liver failure following treatment with AAV gene therapies. This led to all of Sarepta’s clinical trials for gene therapy products being put on hold, and shipping of its FDA-approved product, Elevidys, was suspended.
At a similar time, several cell and gene therapies were stalled at the FDA due to shortcomings in manufacturing readiness. As these therapies move from proof-of-concept to mainstream development, regulators are demanding higher-quality and more detailed data on process performance and product characterization.
“Early on, many believed AAV therapies were ‘one-and-done,’ with minimal integration risk. But as long-term data have emerged, regulators now expect more evidence on durability, redosing potential, and immunogenicity. Today, agencies like the FDA and EMA are emphasizing not just clinical outcomes, but also the molecular integrity and consistency of the vector itself,” Alan Griffith told DDN, Head of Contract Development and Manufacturing Organization Global Operations at VectorBuilder.
Emerging alternatives to AAVs
Several companies are now pivoting toward alternative platforms. Vertex Pharmaceuticals, for example, recently discontinued internal AAV research and now plans to leverage lipid nanoparticle (LNP) technology through a collaboration with Orna Therapeutics for sickle cell disease and transfusion-dependent beta thalassemia.
LNPs could become a leading alternative to AAVs since they can deliver genetic material without the same immunogenicity and durability concerns. Unlike viral vectors, LNPs are non-viral carriers that can be re-dosed, offer flexible payload capacity, and are relatively straightforward to manufacture and scale. They also eliminate the risk of insertional mutagenesis associated with genome integration, while providing tunable delivery to specific tissues through lipid composition and chemical modification.
Similarly, Sarepta Therapeutics has announced a strategic pivot to focus primarily on its siRNA platform, which enables tissue-targeted gene silencing and the potential for chronic, repeat dosing without triggering strong immune responses. The pipeline includes investigational treatments for facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1 (DM1), spinocerebellar ataxia type 2, idiopathic pulmonary fibrosis, and Huntington’s disease.
Another emerging platform is Krystal Biotech’s non-replicating herpes simplex virus type 1 (HSV-1) vector, which received the FDA’s second platform technology designation after the agency revoked the first designation previously granted to Sarepta’s AAV platform. Unlike AAV, HSV-1 offers a higher payload capacity and immune evasion potential. Krystal’s platform is already used in Vyjuvek, a topical gel approved for dystrophic epidermolysis bullosa, and is being evaluated in KB801, an eye-drop therapy for neurotrophic keratitis.
AAVs are not dead
What’s shifting is the recognition that we need better control over the cost of goods, manufacturing consistency, and immunogenicity before AAV reaches its full commercial potential. Startups and platform companies that can solve these issues will define the next chapter of AAV.
- Alan Griffith, VectorBuilder
Despite these challenges, AAVs remain far from obsolete. For over a decade, they have been the dominant platform, thanks to their broad tissue tropism, strong safety profile, and versatile manufacturing potential.
Griffith explained, “AAV hasn’t lost its scientific validity. It remains one of the most effective delivery systems ever developed. What’s shifting is the recognition that we need better control over the cost of goods, manufacturing consistency, and immunogenicity before AAV reaches its full commercial potential. Startups and platform companies that can solve these issues will define the next chapter of AAV.”
Novartis, for example, is continuing to advance its AAV therapy, Zolgensma, for spinal muscular atrophy, with clinical trials aimed at an older population. Additionally, Novartis announced a $1.1 billion acquisition of gene therapy platform company Kate Therapeutics, which develops technology that could improve how these treatments work.
Regulatory support also remains in place for some indications. For instance, in September, the FDA granted fast-track designation to Sanofi’s SAR446268 for DM1, and in August 2025 lifted the clinical hold on Rocket Pharmaceuticals’ pivotal Phase 2 trial of RP-A501 for Danon disease, allowing the study to resume with optimized dosing and an improved immunomodulatory regimen.
The field is increasingly moving toward precision, targeting tissues to reduce systemic risk, focusing on validated biology, and pursuing indications with clear clinical endpoints. But with persistent challenges such as high costs, limited patient uptake, durability concerns, and safety risks, combined with shifting investments from Big Pharma, only time will tell whether AAVs will be improved, supplemented by new platforms, or eventually replaced altogether.
