Advances in Cell and Gene Therapy and the Evolving AAV Landscape in 2025 H1

The cell and gene therapy (CGT) sector is experiencing unprecedented growth in 2025, marked by an expanding clinical pipeline, key regulatory milestones, and innovative technological breakthroughs. According to reports from the Alliance for Regenerative Medicine (ARM) and the American Society of Gene & Cell Therapy (ASGCT) in collaboration with Citeline, the global landscape includes 1,905 ongoing clinical trials in the first half of the year, with significant activity across North America (844 trials), Europe (453), and Asia-Pacific (750) (Figure 1). This surge is driven by advancements in gene editing, RNA therapies, and cell-based approaches, targeting a wide array of diseases from rare genetic disorders to common conditions like cancer and neurological ailments. Investment in the sector reached $5 billion in H1 2025, though start-up funding has slowed. At the heart of many developments lies the adeno-associated virus (AAV) platform, which continues to dominate gene delivery. This article combines these reports to explore the trends, with a particular emphasis on the role of AAV in propelling the field forward.

Figure 1. ARM CGT H1 2025 Sector Data

Landmark Approvals

The second quarter of 2025 delivered several watershed regulatory decisions:

• Abeona’s Zevaskyn was cleared by the FDA as the first cell-based gene therapy for recessive dystrophic epidermolysis bullosa, a rare and devastating skin disorder.
• Belief BioMed’s BBM-H901, an AAV-delivered treatment for hemophilia B, became the first gene therapy of its kind approved in China, a milestone for the country’s regulatory landscape.
• Moderna’s mNexspike, a lower-dose COVID-19 mRNA vaccine, won U.S. approval, expanding the footprint of mRNA-based medicines.

Globally, there are now 36 approved gene therapies, 71 non-genetically modified cell therapies, and 36 RNA therapies, highlighting the growing maturity of the field. Both the U.S. and Europe are projected to grant another five to six CGT approvals before the year closes.

Figure 2. Approved gene, cell, and RNA therapies

Clinical Pipeline and Development Trends

The CGT pipeline is robust and diverse, encompassing 4,469 therapies from preclinical stages to pre-registration, as per ASGCT-Citeline data. Gene therapies, including genetically modified cell therapies like CAR-T, account for 49% (2,210 assets), while non-genetically modified cell therapies make up 22% (962), and RNA therapies comprise 29% (1,297). Clinical-stage asset-indications have risen to 679, a 5.3% increase from Q1 2025, indicating a shift toward more advanced testing (Figure 2).

Figure 3. Pipeline overview of gene, cell, and RNA therapies

An increase in the number of gene therapy programs was seen at all stages of pipeline development. In gene therapy, programs have increased at all phases: preclinical (1,461), Phase I (361), Phase II (330), Phase III (45), and pre-registration (13) (Figure 4).

Figure 4. Gene therapy pipeline: quarterly comparison

When examining the entire pipeline, from preclinical stages through to pre-registration, oncology and rare diseases continue to be the leading areas for gene therapy development. Notably, gene therapy development for rare diseases is most active within oncology, making up 52% of the rare disease gene therapy pipeline. This proportion has remained consistent over the past quarter (Figure 5). Non-genetically modified cell therapies show similar patterns, with 280 targeting rare diseases (64% non-oncology) and a total pipeline of 962 assets. RNA therapies, led by mRNA and RNAi modalities, have 419 aimed at rare diseases, with non-oncology at 75%.

Figure 5. The most targeted therapeutic areas in the gene therapy pipeline

Neurological disorders are emerging as a major frontier, building on H1 momentum. Several gene therapy programs received key regulatory clearances and clinical milestones:

• MavriX Bio: The FDA cleared the company’s first-in-human Phase 1 study for an AAV gene therapy to treat Angelman syndrome. This is a significant step forward for a disease that currently has no FDA-approved treatments, and the therapy aims to restore function of the critical UBE3A gene.
• MeiraGTx: The company’s AAV gene therapy for Parkinson’s disease was granted Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA. This designation is intended to expedite the development and review of therapies that address serious conditions, signaling the potential of this treatment to meet a critical unmet medical need.
• AviadoBio: In a milestone for dementia research, AviadoBio dosed the first patients in a gene therapy trial to treat frontotemporal dementia. The goal is to develop one of the first potential cures for this type of dementia.

Several notable breakthroughs were also highlighted. Taysha Gene Therapies announced positive data for its Rett syndrome treatment, gaining alignment from the FDA for further trials. NeuroGene’s innovative program was selected for the FDA’s START Pilot Program, a key initiative designed to accelerate the development and review of novel, high-impact therapies. Additionally, novel approaches were given the green light, including Capsida’s gene therapy for epilepsy, which utilizes a next-generation capsid engineered to penetrate the blood-brain barrier and improve drug delivery directly to the brain. Innovations include Ensoma’s in-vivo hematopoietic stem cell therapy for chronic granulomatous disease and Epicrispr’s epigenetic editing for muscular dystrophy. A remarkable case is Baby KJ’s in-vivo gene editing for CPS1 deficiency, developed in just six months, showcasing the potential for rapid, personalized treatments in ultra-rare conditions.

Policy and regulatory advancements are facilitating progress. The European Commission’s Life Sciences strategy aims to boost ATMP competitiveness through centers of excellence and multi-country trials. In the US, the FDA’s platform technology designations—for Sarepta’s viral vector in muscular dystrophy. Oncology saw gains in solid tumors, with data from Candel Therapeutics’ viral immunotherapy for prostate cancer and Penn Medicine’s CAR-T for glioblastoma. Heart disease and diabetes also advanced, with Verve Therapeutics’ base editing reducing LDL-C by 53% and Vertex’s stem cell therapy eliminating insulin needs in most Type 1 diabetes patients.

Spotlight on AAV Clinical Trials and Pipeline

AAV vectors are pivotal in gene therapy, offering efficient delivery with relatively low immunogenicity. Over the past decade, the number of AAV clinical trials has grown rapidly. According to a review by Richard Jude Samulski et al. in Molecular Therapy, analysis of clinicaltrials.gov data through January 27, 2025, shows 343 AAV trials, a 34% increase from 255 in mid-2022. The most pronounced acceleration occurred in phase 1 trials, which increased by 49%, and phase 1/2 trials, which rose by 33%. In contrast, phase 3 studies only expanded by 18%, and just a single phase 4 trial has been registered, highlighting that most AAV programs are still early in development (Figure 6).

AAV gene therapy development is strongly focused on a handful of indications. Despite the existence of up to 8,000 rare diseases, only about 80 distinct conditions are currently addressed by ongoing trials. Hemophilia A and B continue to dominate as the leading targets, followed closely by muscular dystrophies, retinitis pigmentosa, and both wet and dry forms of age-related macular degeneration (AMD). Central nervous system disorders like Parkinson’s disease and ocular diseases such as Leber congenital amaurosis (LCA) additionally maintain substantial developmental momentum. However, the “one gene, one disease” ideal for monogenic recessive disorders has proven challenging in practice, often due to incomplete symptom resolution or overlooked unchanged parameters in models.

Tissue targeting focuses on ocular (26%), CNS (21%), and liver (18%) sites, unchanged from recent years, suggesting persistent organ-specific challenges like liver toxicity. The core targeted tissues for AAV gene therapy are the eye (26% of trials), central nervous system (21%), and liver (18%). These proportions remained consistent compared to analyses from previous years, indicating a main strategic focus despite broadening scientific discovery. Administration routes are selected based on anatomical and biological suitability: intravenous (vascular) delivery remains dominant, accompanied by ocular-field routes (subretinal, intravitreal, suprachoroidal) and brain-targeted methods (intracerebroventricular, intraparenchymal, intrathecal). A small but growing subset of trials utilizes dual routes—such as combining vascular and intracerebroventricular injections, which may necessitate distinct capsids and double resource investment. Trials also increasingly incorporate insights about host protein interactions in different biological environments, which can modulate the effectiveness of vector delivery and transgene expression.

Figure 6. Description of AAV clinical trials. (A) Distribution of clinical trials utilizing AAV by the phase of development. (B) Breakdown of clinical trials utilizing AAV by disease. (C) Distribution of clinical trials utilizing AAV based on the targeted tissues/organs. (D) Distribution of the routes of administration across AAV clinical trials.

In terms of vector choice, AAV2 remains the most used capsid in clinical trials, comprising 24% of all trials. It is followed by AAV9 at 16% and AAV8 at 13%. However, the deployment of engineered and novel capsids is accelerating. As of 2025, 39 trials utilize 15 unique customized capsids, up from 20 trials with 10 engineered capsids in 2022. The rationale is to circumvent pre-existing immunity, enhance tissue specificity, and improve vector performance. Notably, 32 trials have not publicly disclosed the capsid used, suggesting increased competitive sensitivity around vector design (Figure 7).

Figure 7. Distribution of AAV capsid utilization across 340 clinical trials

Navigating Safety and Biological Hurdles

The clinical advancement of AAV therapies is not without significant safety considerations. A primary concern is dose-dependent hepatotoxicity, observed in 20% to 90% of patients across trials. The severity ranges from asymptomatic liver enzyme elevations at lower doses to acute liver failure and even death at very high doses (e.g., 1.3e14 – 3.5e14 vg/kg), particularly in pediatric populations. The management of this toxicity with steroids has become a standard, though not always foolproof, practice.

Other serious adverse events include thrombotic microangiopathy (TMA), observed across several trials using high doses of AAV9 capsid, and specific neurotoxicity noted in trials for amyotrophic lateral sclerosis (ALS) and Batten disease. Furthermore, there is a growing appreciation for the potential risks of transgene overexpression (e.g., leading to thrombosis in hemophilia trials) and the unintended consequences of vector optimization strategies, such as codon optimization, which may disrupt co-translational protein folding and lead to toxic protein aggregation.

Future Directions: Innovation Beyond the Vector

The field is responding to these challenges with continued innovation. The use of engineered capsids is on a substantial upswing, with 39 trials now utilizing 15 unique novel capsids, compared to just 20 trials two years prior. Regulatory agencies are also adapting; the FDA’s granting of one of the first ‘platform technology designations’ for a viral vector signals a move toward streamlining the development pathway for validated delivery systems.

The future of AAV gene therapy will likely depend on a multi-faceted approach: continued technical innovation to improve safety profiles, smarter clinical trial designs fit for rare disease populations, and the exploration of sustainable commercial and reimbursement models that balance innovation with accessibility. As over 300 trials (e.g., managing liver toxicity, etc.) continue to generate data, the shared learning on managing toxicity and optimizing efficacy will be a critical driver in ultimately fulfilling the long-held promise of gene therapy for a broader range of patients.

The second quarter of 2025 confirms that the cell and gene therapy sector is maturing. It is moving beyond pure technical optimism into a more complex phase where clinical success must be matched by commercial viability, sustainable safety profiles, and ethical delivery to patients in need. The coming years will be defined by how well the industry navigates this challenging but necessary evolution.

References:

1. ARM Q2 2025 Sector Snapshot
2. ASGCT Q2 2025 Gene, Cell, & RNA Therapy Landscape Report
3. Lester Suarez-Amaran et al., AAV vector development, back to the future. Mol Ther. 2025 May 7;33(5):1903-1936.