2025’s Most Impactful Cell and Gene Therapy Milestones

The year 2025 marked a pivotal period for cell and gene therapy (CGT), defined by the convergence of major scientific breakthroughs and sector-shaping challenges. Together, these advances and setbacks underscored both the transformative potential of CGT and the complexity of translating innovation into safe, scalable medicines.

The field achieved several landmark milestones, including regulatory approvals for novel therapies, initiation of high-impact clinical programs, and technological advances that expanded therapeutic boundaries. Notable firsts included the successful administration of a bespoke CRISPR base-editing therapy for a single infant, the first FDA approval of a nonprofit-developed lentiviral gene therapy, and five-year data demonstrating durable functional cure following a single gene therapy infusion for hemophilia. Additional clinical progress was seen in CAR-T therapies inducing deep remission in autoimmune diseases, AAV-mediated hearing restoration in congenitally deaf children, and next-generation base-editing platforms offering improved precision and safety.

At the same time, 2025 highlighted critical challenges testing the field’s maturity. A serious safety event associated with Sarepta’s DMD gene therapy Elevidys prompted a distribution pause, heightened regulatory scrutiny, and renewed focus on risk assessment in neuromuscular disorders. Clinical holds affecting Intellia’s in vivo CRISPR program and regulatory setbacks for uniQure’s Huntington’s disease candidate AMT-130 further illustrated the iterative nature of clinical translation.

This dual narrative—remarkable proof-of-concept achievements alongside real-world validation—defines the CGT landscape of 2025. Advances in personalized medicine, durability, and therapeutic scope were balanced by increased emphasis on safety, manufacturing robustness, and sustainable commercialization. From the N-of-1 cure for CPS1 deficiency to the evolving regulatory landscape for DMD therapies, 2025 reinforced both CGT’s disease-modifying power and the rigor required to deliver it reliably.

 Biggest Overall Progress: Personalized mRNA-Based CRISPR Therapy for CPS1 Deficiency

In 2025, a first-in-class personalized CRISPR adenine base-editing therapy was developed for an infant with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a lethal urea cycle disorder. The mRNA-based therapy, delivered via lipid nanoparticles, encoded a base editor and guide RNA to precisely correct the patient’s CPS1 mutation in hepatocytes without inducing double-strand DNA breaks. The first patient (KJ) was treated at CHOP/Penn Medicine in early 2025, demonstrating improved protein tolerance and reduced medication dependence by April. Results published in NEJM in May marked a historic N-of-1 milestone and prompted expansion of personalized gene-editing platforms to other ultra-rare diseases later in the year.

2. Telethon’s LVV Gene Therapy for Wiskott–Aldrich Syndrome: First FDA Approval

Waskyra (etuvetidigene autotemcel) became the first FDA-approved lentiviral vector (LVV) gene therapy for Wiskott–Aldrich syndrome, a life-threatening immunodeficiency. The ex vivo therapy uses a self-inactivating LVV to insert a functional WAS gene into autologous CD34+ hematopoietic stem cells, restoring immune and platelet function. Following a positive CHMP opinion in November, FDA approval was granted in December 2025 for patients lacking matched donors. Supported by durable efficacy in 27 patients, this marked the first nonprofit-led gene therapy approval and validated LVV platforms for immunodeficiency disorders.

3. Regeneron’s DB-OTO: Restoring Hearing with Dual-AAV Therapy

DB-OTO is a dual-vector AAV1 gene therapy for congenital deafness caused by otoferlin (OTOF) mutations. Using cochlea-targeted delivery, the therapy reconstitutes the large OTOF gene in inner hair cells to restore synaptic transmission. Phase 1/2 CHORD trial updates in February 2025 showed meaningful hearing improvement in 11 of 12 children, with three achieving normal hearing and no serious adverse events. Benefits were sustained through 24 weeks, supporting AAV’s utility in localized, non-systemic indications.

4. CSL Behring’s Hemgenix: Five-Year Durability in Hemophilia B

Hemgenix (etranacogene dezaparvovec) continued to set the benchmark for durable gene therapy in hemophilia B. The AAV5-based therapy delivers a hyperactive FIX-Padua variant to hepatocytes, enabling sustained clotting factor production. Five-year HOPE-B data published in NEJM showed stable FIX levels (~36%), a 90% reduction in bleeding rates, and 94% of patients remaining prophylaxis-free. These results addressed durability concerns and reinforced the viability of one-time gene therapy for hemophilia.

5. Beam Therapeutics’ BEAM-101: Non-Viral Base Editing for Sickle Cell Disease

BEAM-101 is an ex vivo adenine base-edited HSC therapy for severe sickle cell disease that avoids viral vectors. By editing HBG1/2 promoters to mimic hereditary persistence of fetal hemoglobin, the therapy increases HbF (>60%) and suppresses sickling HbS without DNA cleavage. By December 2025, the BEACON Phase 1/2 trial showed resolved anemia in all treated patients, leading to RMAT and Orphan Drug designations. With 31 patients treated, BEAM-101 advanced toward pivotal trials as a potentially safer alternative to nuclease-based editing.

6. Encoded Therapeutics’ ETX101: Gene Regulation in Dravet Syndrome

ETX101 is an AAV9-based gene regulation therapy designed to upregulate SCN1A expression in inhibitory interneurons for Dravet syndrome. Delivered under a GABAergic promoter, the therapy restores NaV1.1 function without off-target overexpression. Phase 1/2 POLARIS data demonstrated a 78% median seizure reduction and developmental gains at the lead dose, with favorable tolerability. These results secured Breakthrough Therapy Designation and supported study expansion, with a pivotal trial planned for 2026.

7. Novartis’ Intrathecal Zolgensma: Expanding SMA Treatment

In 2025, the intrathecal formulation of Zolgensma (Itvisma) achieved a major milestone for spinal muscular atrophy. Using AAV9-mediated SMN1 delivery directly to the CNS, the Phase 3 STEER trial met its primary endpoint in patients aged 2–18 with Type 2 SMA. FDA approval in November expanded gene therapy access to older SMA patients, supported by consistent efficacy and a manageable safety profile across multiple trials.

8. uniQure’s AMT-130 for Huntington’s Disease: Breakthrough Momentum with Regulatory Headwinds

AMT-130 is an investigational AAV5-based gene therapy for Huntington’s disease, delivered via intrastriatal injection. The therapy uses a microRNA cassette to non-allele-specifically silence huntingtin (HTT) mRNA, reducing toxic protein accumulation without permanent genome editing. In April 2025, AMT-130 received Breakthrough Therapy Designation based on interim data showing slowed disease progression and reduced neurofilament light chain levels. However, late-year regulatory challenges delayed BLA plans, underscoring the complexity of CNS gene therapy development. A Type A FDA meeting is scheduled for January 2026 to clarify requirements for a potential accelerated approval pathway as EXPLOR-HD trials continue.

9. CAR-T Therapies for Autoimmune Diseases – Major Expansion from Oncology with Promising Data in Lupus and Beyond

In 2025, a diverse class of CAR-T therapies expanded into autoimmune indications such as lupus, myasthenia gravis, and rheumatoid arthritis, led by clinical-stage candidates like Cartesian’s mRNA-based Descartes-08 and Kyverna’s CD19-targeted KYV-101. The field evolved significantly as emerging models like CAR-Tregs for atherosclerosis began using regulatory T cells to modulate inflammation rather than focusing solely on cytotoxicity. This progress is bolstered by off-the-shelf options like Fate’s FT819 and next-generation in vivo approaches from Orbital and MagicRNA, which utilize circular RNA and lipid nanoparticles (LNPs) to reprogram immune cells directly within the body. These innovative in vivo delivery methods are gaining significant momentum as they begin to bypass the complex requirements of external cell manufacturing entirely.

Clinical progress marked a boom in 2025 with multiple FDA designations and data readouts, including Cartesian’s Descartes-08 showing positive Phase 2 lupus data (November 2025) with deep B-cell depletion and symptom remission in most patients alongside plans for pivotal trial, Kyverna’s KYV-101 succeeding in stiff person syndrome (December 2025) with durable responses targeting first autoimmune approval in 2026 and priorities set early (January 2025), Cabaletta’s CABA-201 reporting promising results across diseases (June 2025) with high remission rates and pivotal plans, Fate’s FT819 gaining RMAT for lupus and Allogene’s AlloCAR T gaining Fast Track Designation for rheumatology/autoimmune indications (April 2025), acquisitions like AbbVie’s $2.1B Capstan buy (June 2025) fueling in vivo CAR-T, preclinical wins including Orbital’s circular RNA data (July 2025) and MagicRNA’s lupus clinical data (September 2025), setbacks like Caribou shelving its program (April 2025) contrasting with overall momentum, and CAR-Treg achieving 70% plaque reduction in atherosclerosis (November 2025) expanding to cardiovascular autoimmunity, with no full approvals yet but RMAT/Fast Track designations positioning 2026 as pivotal.

10. Accelerated Regulatory Designations in 2025: Breakthrough, Fast Track, and RMAT

 In 2025, multiple high-impact therapies received FDA Breakthrough Therapy Designation (BTD), Fast Track Designation (FTD), or Regenerative Medicine Advanced Therapy (RMAT) status, reflecting strong early clinical signals and urgent unmet medical needs. RMAT continued to play a central role in the CGT sector, offering benefits comparable to BTD—such as intensive FDA interaction and rolling BLA reviews—while addressing the unique challenges of regenerative therapies.

Key recipients included uniQure’s AMT-130 for Huntington’s disease, which received BTD in April 2025 based on evidence of slowed disease progression. In autoimmune disease, Adicet Bio’s allogeneic γδ CAR-T therapy ADI-001 received FTD for lupus nephritis following early Phase 1 data showing effective B-cell depletion. RMAT designations were also granted to Fate Therapeutics’ FT819 for systemic lupus erythematosus and Immix Biopharma’s BCMA-targeted CAR-T NXC-201 for relapsed/refractory AL amyloidosis, supported by high response rates and enabling rolling BLA submissions.

Ocular gene therapy saw notable acceleration as Atsena Therapeutics’ ATSN-201 for X-linked retinoschisis received both RMAT and FTD in April 2025, backed by Phase 1/2 data demonstrating improved retinal structure and vision. Outside CGT, Sanofi’s investigational mRNA vaccine for Chlamydia trachomatis secured FTD in March 2025, advancing plans for early-stage clinical trials.

Additional late-year designations highlighted expanding momentum in oncology and cardiovascular disease. Senti Bio’s logic-gated CAR-NK therapy SENTI-202 received RMAT in December 2025 following encouraging AML data, while Solid Biosciences’ SGT-003 for Duchenne muscular dystrophy obtained a UK Innovation Passport. Rocket Pharmaceuticals further strengthened its cardiovascular portfolio with RMAT designation for RP-A601 (PKP2-associated ACM) and FTD for RP-A701 (BAG3-related dilated cardiomyopathy), positioning both programs for accelerated clinical development.

11. Duchenne Muscular Dystrophy: High Activity with Mixed Outcomes

Duchenne muscular dystrophy (DMD) remained one of the most intensively pursued indications in cell and gene therapy in 2025, reflecting its severe unmet medical need. Multiple approaches—including AAV-mediated gene replacement and cell therapy—advanced during the year, while persistent challenges related to delivery, durability, immunogenicity, and safety became increasingly evident.

Sarepta Therapeutics’ Elevidys (delandistrogene moxeparvovec), an AAVrh74 micro-dystrophin gene therapy, continued to define the DMD landscape. In 2025, the Phase 3 EMBARK confirmatory trial failed to meet its primary functional endpoint, despite signals in secondary and subgroup analyses. More critically, a treatment-associated patient death prompted label updates, a temporary distribution pause, and intensified FDA scrutiny. These events underscored the risks of systemic AAV delivery in a fragile pediatric population and highlighted the tension between urgent access and long-term safety.

Next-generation AAV programs showed incremental progress. Solid Biosciences’ SGT-003, featuring an engineered capsid and optimized micro-dystrophin cassette, demonstrated early dystrophin expression with acceptable safety and received UK regulatory support for accelerated development. Similarly, REGENXBIO’s RGX-202 showed consistent dystrophin expression and functional stabilization in early cohorts, with pivotal data anticipated in 2026, reinforcing optimism around improved AAV design.

Beyond gene replacement, Capricor Therapeutics advanced deramiocel (CAP-1002), an allogeneic cell therapy targeting DMD-associated cardiomyopathy through paracrine and immunomodulatory mechanisms. Positive Phase 3 data in late 2025 demonstrated improvements in cardiac function, emphasizing the importance of addressing cardiac disease independently of skeletal muscle correction.

Overall, developments in 2025 highlighted both the promise and vulnerability of therapeutic progress in DMD, with advances tempered by renewed focus on safety, durability, and clinical relevance.

12. Heart Cluster: Gene Therapy Advances in Cardiomyopathies and Heart Failure

In 2025, cardiovascular gene therapy advanced from concept to clinical validation, driven by AAV-based programs targeting inherited cardiomyopathies and myocardial repair. The field adopted a dual strategy: correcting defined genetic defects to halt disease progression while exploring regenerative approaches to restore cardiac function. Despite ongoing delivery challenges, multiple programs demonstrated encouraging safety and early efficacy.

Tenaya Therapeutics emerged as a leader in arrhythmogenic right ventricular cardiomyopathy (ARVC) with TN-401, an AAV9-mediated PKP2 gene replacement therapy designed to restore desmosomal integrity and reduce arrhythmias. Progress in 2025 included a $52.5 million financing and positive Phase 1b MyPEAK-1 data showing favorable safety and reduced arrhythmia burden, supporting advancement toward pivotal studies in 2026.

Rocket Pharmaceuticals strategically refocused its pipeline on cardiovascular indications, deprioritizing other programs to concentrate on heart disease. Its AAV9-based portfolio includes RP-A501 for Danon disease, which saw its clinical hold lifted with Phase 2 trials planned for 2026, RP-A601 for PKP2-associated cardiomyopathy receiving RMAT designation, and RP-A701 for BAG3-related dilated cardiomyopathy securing IND clearance and Fast Track status. Together, these programs reflect growing regulatory confidence in cardiac gene therapy.

Beyond genetic correction, regenerative strategies gained momentum. Medley Therapeutics dosed the first patients in a Phase 1 trial of an AAV therapy aimed at promoting cardiomyocyte regeneration in heart failure. Supporting preclinical data reported in late 2025 further demonstrated reversal of cardiac dysfunction through targeted correction of contractile and electrical abnormalities.

Collectively, these developments indicate a maturing cardiovascular gene therapy field, increasingly capable of delivering durable clinical benefit in complex cardiac diseases.

13. Ocular Cluster: Maturing Retinal Gene Therapy and Commercial Readiness

Ocular gene therapy continued to mature in 2025, with the field shifting from early safety validation toward durable efficacy, regulatory acceleration, and commercial positioning. AAV-based therapies advanced across rare inherited retinal diseases (IRDs) and high-prevalence indications such as wet age-related macular degeneration (AMD), supported by multiple RMAT and Fast Track designations and reinforced by strategic industry partnerships.

Beacon Therapeutics strengthened its leadership in X-linked retinitis pigmentosa with AGTC-501, reporting durable 24-month efficacy data that supported RMAT designation. Atsena Therapeutics similarly advanced ATSN-201 for X-linked retinoschisis, securing both RMAT and Fast Track status. Complementing gene replacement approaches, Nanoscope Therapeutics demonstrated mutation-agnostic vision restoration in retinitis pigmentosa using its optogenetic therapy MCO-010, while Opus Genetics reported sustained one-year visual benefit with OPGx-LCA5 for Leber congenital amaurosis.

Ocugen made notable progress with its modifier gene therapy platform aimed at restoring retinal homeostasis. OCU400 (AAV-NR2E3) showed positive two-year Phase 1/2 data in retinitis pigmentosa, with sustained or improved visual function and no serious adverse events, supporting advancement of its Phase 3 liMeliGhT trial toward anticipated 2026 regulatory filings. Additional programs targeting Stargardt disease (OCU410ST) and geographic atrophy secondary to dry AMD (OCU410) reported favorable safety and lesion-growth reductions, positioning these candidates for late-stage development.

In wet AMD, Adverum Biotechnologies initiated Phase 3 development of Ixo-vec, an AAV “biofactory” therapy expressing aflibercept, a strategy further validated by an $85 million upfront partnership with Eli Lilly. REGENXBIO’s continued clinical progress with RGX-314 reinforced the competitive momentum in chronic retinal disease.

Collectively, 2025 marked a transition for ocular gene therapy from experimental promise to clinically and commercially viable platforms, supported by durable data, regulatory confidence, and sustained pharmaceutical investment.

Other Significant Milestones: Expanding AAV into New Frontiers

Beyond cardiac and ocular indications, 2025 marked meaningful expansion of AAV-based gene therapy into metabolic and neurodegenerative diseases. These advances spanned late-stage regulatory submissions and first-in-class clinical entries, underscoring the versatility of AAV platforms in addressing high unmet medical needs.

Ultragenyx reached a major regulatory milestone with DTX401 for glycogen storage disease type Ia (GSDIa), completing its FDA BLA submission in December 2025. The AAV8-based, liver-directed therapy delivers a functional G6PC gene to restore glucose metabolism, supported by Phase 3 data showing reduced reliance on cornstarch therapy. If approved, DTX401 could become the first AAV gene therapy for GSDIa in 2026.

In neurodegeneration, SineuGene advanced SNUG01 into global Phase 1 trials for amyotrophic lateral sclerosis (ALS) in March 2025. The therapy targets TRIM72, a membrane repair protein, and is designed to enhance cellular resilience in motor neurons and muscle tissue. This marks the first clinical evaluation of a TRIM72-based gene therapy, introducing a novel disease-modifying strategy for ALS.

Fractyl Health expanded AAV applications into metabolic disease with RJVA-001, submitting the first CTA module in Europe in May 2025. This pancreas-targeted AAV therapy delivers a GLP-1 transgene under a nutrient-responsive promoter, enabling physiologic, glucose-dependent hormone release. Supported by strong preclinical data presented at ASGCT, RJVA-001 is positioned to enter first-in-human trials as a potential long-term alternative to chronic GLP-1 injections.

 Conclusion

Taken together, 2025 stands as a defining inflection point for CGT—one that moved the field decisively from promise toward proof, while simultaneously exposing the realities of clinical, regulatory, and commercial execution at scale. Across modalities ranging from AAV gene replacement and lentiviral stem cell therapies to base editing, mRNA delivery, and in vivo immune reprogramming, the year delivered compelling evidence that CGT can provide durable, and in some cases curative, benefit across genetic, neurologic, cardiovascular, ocular, metabolic, and autoimmune diseases.

At the same time, 2025 reinforced that scientific success alone is insufficient. Safety events, regulatory recalibrations, and mixed late-stage outcomes—most notably in DMD and CNS-directed gene therapies—highlighted the need for more refined delivery strategies, better biomarkers of efficacy and risk, and realistic expectations around timelines and patient selection.

Importantly, the year demonstrated a clear evolution in strategy. The field is no longer defined solely by first-generation AAV or CRISPR tools, but by next-generation capsids, non-viral editing approaches, disease-responsive delivery systems, modular manufacturing, and platform-based development models. The rise of in vivo CAR-T, precision base editing, and targeted cardiac and ocular gene therapies signals a shift toward solutions that are not only effective, but scalable and economically viable.

In this sense, 2025 was less about isolated breakthroughs and more about consolidation—of lessons learned, of technological maturity, and of strategic clarity. As the field enters 2026, it does so with stronger clinical evidence, clearer regulatory pathways, and a deeper understanding of risk, positioning CGT not as experimental medicine, but as an increasingly reliable pillar of modern therapeutics.

Author: Jin Qiu

References:

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