The Fall of AAV: From Star Vector to Pharma’s ‘Discarded Tool’

From Star Vector to Pharma's "Abandoned Child," AAV (Adeno-Associated Virus) Is Experiencing an Unprecedented Winter.

Safety Issues Emerge: Sarepta’s AAV Gene Therapy Elevidys Suspended by FDA Following Patient Death, Capsida Biotherapeutics’ AAV-Related Clinical Trial Also Halted Due to Death of Pediatric Patient.

Coupled with the "astronomical cost" issue, the commercialization progress has been slow to take off. In the past year, signs of retreat in the AAV gene therapy field have grown increasingly strong: In February this year, Pfizer announced the termination of its last AAV project, Beqvez; in May, Vertex Pharmaceuticals clearly stated that it would no longer use AAV as a delivery mechanism for gene therapy projects; at the end of September, Biogen even announced the complete clearance of all its AAV pipelines.

The once highly popular AAV sector is now suddenly filled with an atmosphere of retreat and danger, presenting a stark contrast to the booming scene just a few years ago.

As a once-celebrated vector, AAV has successfully facilitated the emergence of a series of epoch-making gene therapies, attracting bets from countless biotechs and large pharmaceutical companies.

However, with the deepening of clinical research and the acceleration of commercial implementation, the hidden dangers of AAV have become increasingly apparent: high-dose toxicity, uncontrollable immune responses, exorbitant costs... The AAV vector is gradually falling from its pedestal, even being "shunned" and abandoned by major pharmaceutical companies.

The plight is far more brutal than imagined. From being the highly sought-after "golden tool" to a delivery system now questioned and even abandoned, what lies ahead for the future of AAV vectors?

/ 01 / Three Major Flaws

At the initial stage of gene therapy's rudimentary development, while other delivery systems still had many immature factors, AAV quickly stood out with its characteristics—structural stability, long-lasting expression, and low immunogenicity—becoming an undisputed star vector.

However, as the industry moves into deeper waters, these once dazzling highlights have all turned into insurmountable "hard injuries."

First, AAV vectors have the defect of being too small in capacity. The natural AAV vector can only carry about 4.7kb of genetic material, which seems insufficient when facing the treatment needs of many diseases.

A typical example is Duchenne muscular dystrophy (DMD), where the related pathogenic gene is too large to be fully loaded into an AAV vector. To overcome this challenge, researchers have had to adopt a "split-and-reassemble" strategy, dividing the target gene into multiple fragments that are separately loaded into AAV vectors, and then achieving complete gene expression through in vivo reassembly.

The currently approved Elevidys for the treatment of DMD delivers a functional micro-DMD gene to achieve therapeutic effects. However, the clinical efficacy of this approach is not ideal: although the truncated protein can partially restore function, the effect is far from sufficient to replace the full-length protein.

In May this year, Johnson & Johnson's bota-vec Phase 3 trial for the treatment of X-linked retinitis pigmentosa (XLRP) failed, which also reflects the insufficient functionality of its truncated RPGR protein when facing complex pathogenic mechanisms.

Secondly, the immune response poses another significant challenge for AAV vectors.

After AAV enters the human body, it may activate the innate immune system, triggering inflammatory responses mediated by neutrophils, natural killer cells, and macrophages, which could potentially lead to a cytokine storm in severe cases; involvement of the complement system may result in thrombotic microangiopathy.

Moreover, AAV may also stimulate B cells to produce antibodies, which can inhibit the transfection efficiency of the viral vector while exacerbating inflammatory responses; CD8 T cells, on the other hand, directly kill cells transfected by AAV, leading to loss of transgene expression and tissue damage, which in turn causes severe adverse events such as lethal hepatotoxicity, dorsal root ganglion toxicity, and myocarditis.

More troubling is the widespread presence of neutralizing antibodies against AAV in the population, an innate immune characteristic that presents multiple obstacles to the application of AAV gene therapy.

On one hand, a large number of patients are directly excluded (unable to enroll), and those who do enroll may also experience reduced efficacy or failure; on the other hand, due to the presence of neutralizing antibodies, AAV gene therapy can hardly be administered repeatedly. For patients who require multiple treatments to maintain efficacy or whose conditions relapse, a single treatment must be an “all-in” approach. This leads to the need for injecting more viral vectors to effectively deliver the therapeutic gene to the target cells and achieve the desired effect.

Once patients face a single AAV injection dose exceeding 1010vg (copy number), it undoubtedly significantly increases the risk of acute immune reactions.

Moreover, the high price is also an insurmountable gap for AAV vectors.

The biological characteristics of AAV vectors are complex, requiring multi-step production and purification processes, making it difficult to achieve efficient large-scale production. Moreover, batch-to-batch variability, low vector yield, and the need for ultra-pure products to meet regulatory standards all contribute to long production cycles and high product costs.

The most直观的结果就是，目前上市的AAV基因治疗药物定价都在百万美元级别，甚至Hemgenix、Upstaza和Elevidys均突破了300万美元。

Even with the rare disease treatment capability of "one-shot cure," such an astronomical price also greatly limits accessibility. Because no country's health system in the world can afford it, including the United States, which is also quite troubled.

For gene therapy companies, the process of exploring生产工艺 requires a significant amount of capital. Additionally, the high cost of viral production places most of them under substantial financial pressure and operational risk.

/ 02 /AAV Retreat

If the issues of capacity and immunity are daunting, the consecutive clinical failures and commercial setbacks have become the straw that breaks the industry's confidence.

Rocket Pharmaceuticals' RP-A501, a drug for treating Danon disease, saw the death of a patient due to a fatal acute systemic infection in Phase 2 clinical trials; Neurogene’s NGN-40, a therapy for Rett syndrome, also reported a patient death related to a rare hyperinflammatory syndrome complication associated with AAV overexposure; In July this year, Capsida Biotherapeutics’ CAP-002 also experienced a fatality during early-stage trials.

The successive safety incidents have plunged the entire AAV gene therapy industry into a trust crisis, prompting people to reevaluate the safety boundaries of AAV gene therapy.

It has been clearly established that some safety incidents are caused by off-target effects. Research shows that AAV vectors do not always reach their intended targets, with high-risk off-target organs such as the liver being particularly vulnerable. Not long after Elevidys was approved for marketing, three patients died of acute liver failure, which not only led to the FDA halting its sales but also raised significant public concerns about the safety of AAV gene therapy.

Previously, Novartis' Zolgensma and Astellas' AT132, both AAV drugs, were also suspended in clinical trials due to liver toxicity issues.

The Dilemma of Gene Therapy: Far More Brutal Than Imagined

Even MNCs with mature commercialization systems cannot provide clear answers. After Pfizer's Beqvez was launched, not a single person used it, and Roche’s Luxturna sales plummeted. The company also frankly stated, “The future revenue and synergies of its subsidiary Spark cannot cover its book value.”

With no sign of profitability and continuous questioning about safety issues, it has directly triggered a large-scale industry retreat: At the end of September, Biogen announced the halt of all gene therapy projects using AAV capsids, redirecting resources to areas more likely to achieve good efficacy.

Prior to this, industry giants such as Roche, Takeda, and Vertex Pharmaceuticals also successively exited the AAV research and development field within a year; Pfizer completely withdrew from the gene therapy sector and cleared its related pipeline in February.

At the same time, the attitude of the capital market towards the AAV sector has also returned to rationality from the previous feverish pursuit. Many biotech companies with AAV gene therapy as their core business are facing financing difficulties, and the AAV winter is bitterly cold.

This is in stark contrast to around 2018, when big pharmaceutical companies unanimously "scrambled" for gene therapy assets.

/ 03 / Where to Go in the Future

In the entire track filled with chilling currents, there are still sparks of resilience shining brightly.

In August this year, Kriya Therapeutics completed a $320 million Series D financing round during an industry downturn to advance the development of its gene therapy pipeline. Since its establishment in October 2019, Kriya has raised over $900 million in cumulative financing.

On September 24, uniQure announced breakthrough results from the pivotal Phase 1/2 clinical trial of its gene therapy AMT-130 for Huntington's disease: at 36 months, patients in the high-dose group showed a significant 75% slowing of disease progression, meeting the primary endpoint. Driven by this positive data, uniQure's stock price surged nearly 248% at the close of trading the following day.

On October 7, Affinia Therapeutics announced the completion of a $40 million Series C financing round to develop novel AAV gene therapies for treating devastating cardiovascular and neurological diseases.

However, faced with the constraints of reality, should we retreat or persevere? The crossroads for AAV has already unfolded.

The industry is actively seeking new paths for the "post-AAV" era: LNP (lipid nanoparticles, validated by mRNA vaccines and supporting repeated dosing), polymeric nanoparticles, VLPs (virus-like particles), and other next-generation delivery tools are rapidly emerging.

Among them, the LNP delivery system has demonstrated its delivery capability through the successful application of the COVID-19 mRNA vaccine; moreover, LNPs can carry larger nucleic acid molecules and support repeated dosing. The nanoparticle delivery system has also made significant progress in the field of gene delivery due to its small size and excellent biocompatibility.

Giant companies that have retreated from the AAV sector, such as Vertex Pharmaceuticals and Takeda, have also successively increased their investment in novel non-viral vectors. This may imply that in the coming years, the proportion of AAV in gene therapy R&D pipelines will significantly decrease, while the share of non-viral delivery technologies is expected to rise substantially.

Of course, the strategic adjustment does not announce that AAV is "outdated". It is still the most clinically verified and widely used vector. Some pharmaceutical companies are still actively exploring various strategies to optimize the performance of AAV vectors, and uniQure is a typical example. Its established gene therapy platform focuses on the treatment of liver and CNS diseases.

uniQure's logic is clear: AAV can achieve persistent gene expression in non-dividing cells, and in these therapeutic areas, AAV still has significant advantages. At the same time, its vector optimization (core capsid) is crucial, as the capsid not only affects the tissue specificity of the vector but is also directly related to immunogenicity. According to uniQure's official website, the AAV5 capsid it uses is safer and more tolerable for a longer duration, effectively overcoming safety risks posed by neutralizing antibodies.

In addition, the optimization of drug delivery methods can also enhance the therapeutic effects of AAV vectors: uniQure's AMT-130 achieves local administration through stereotactic brain injection, maximizing the utilization efficiency of the vector.

There are still companies in China that are persisting in exploration. Public data shows that the R&D of AAV gene therapies in China is experiencing a surge, with over 50 AAV gene therapy IND applications approved. The preliminary success of uniQure, as well as the persistence and exploration of companies both in and outside of China, also suggests to us that optimizing vectors (especially capsids), focusing on applicable fields, and innovating drug delivery methods may allow AAV to regain vitality in specific areas.

Clearly, both the AAV vector, which has exposed many problems, and the non-viral vectors currently being explored are driving the progress of gene therapy forward.

In this changing situation, some companies choose to leave the field to avoid the risks associated with gene therapy, while others are accumulating strength beneath the surface, waiting for spring. The industry's collective reflection and breakthrough point to a consensus:

The prospect of gene therapy remains promising, but AAV is no longer the only answer.

       Title: The Disparaged AAV Viral Delivery System