AAV gene therapy / Capsida Biotherap, Eli Lilly - LARVOL DELTA

AAV gene therapy for GBA1 related diseases. (PubMed, Mol Ther) - "By comparing human GCase levels in AAV-treated NHP brains to healthy human donor brains, we demonstrate that AAV.GMU01 SS3-GBA1 replenishes the GCase deficit seen in GBA-PD patients, thus, restoring GCase to near-physiological levels Importantly, AAV.GMU01 SS3-GBA1 is well-tolerated with no adverse findings. Collectively, we establish a therapeutic strategy for the treatment of Gaucher Disease and GBA-associated Parkinson's Disease with a single gene therapy product."

Journal • CNS Disorders • Gaucher Disease • Gene Therapies • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Rare Diseases • GBA1

Nonclinical toxicity study duration in AAV gene therapy development: Evidence from industry survey supports adequacy of short-term assessments. (PubMed, Mol Ther Methods Clin Dev) - "These findings aligned with regulatory reviews of approved AAV products (e.g., Zolgensma, Luxturna, Roctavian) that consistently demonstrated the adequacy of ≤3-month studies for approved and marketed products. The outcome of this survey supports a risk-based, science-driven approach to in vivo study duration, emphasizing that shorter-term studies are generally sufficient for identifying relevant toxicities associated with AAV-based gene therapies. Embracing this approach can reduce animal use, accelerate development timelines, and support harmonized regulatory expectations for AAV gene therapy products."

Journal • Gene Therapies

Systemic Gene Therapy CAP-002 Demonstrates Potential for Disease-Modifying Treatment of Seizures and Motor and Cognitive Deficits of STXBP1-DEE Using an Engineered, CNS-Targeted AAV (ASGCT 2025) - "These results demonstrate that AAV gene therapy, if able to achieve wide-spread biodistribution and supplementation of STXBP1 protein in neurons across the brain, has the potential to be disease-modifying and provide a long-lasting treatment for STXBP1 encephalopathy. Based on these data and the well-tolerated efficacy profile of CAP-002, Capsida's STXBP1 program is targeting a 1H 2025 IND filing with the goal of achieving a disease-modifying treatment for patients suffering from STXBP1 encephalopathy. Disease Focus of Abstract:Central Nervous System Disorders"

Gene therapy • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Mental Retardation • Psychiatry • XBP1

Development of a Perfusion Process for AAV Production Using High-Throughput Bioreactor Systems (ASGCT 2025) - "Reduction of cost of goods (COGs) is essential for AAV gene therapy due to low process yield...Through this development work, the volumetric AAV titers were increased three-fold at pilot scale, relative to the legacy batch process. Disease Focus of Abstract:None"

Gene Therapies • Infectious Disease

AAV gene therapy for GBA-PD and Gaucher Disease (ASGCT 2025) - "By restoring GBA1 protein levels to physiological levels and enabling effective lipid clearance across both CNS and peripheral tissues, this strategy offers a transformative approach to treating lysosomal dysfunction in these genetically defined populations. Disease Focus of Abstract:Parkinson's Disease"

Gene therapy • CNS Disorders • Gaucher Disease • Gene Therapies • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Rare Diseases • GBA1

Intra-Ocular Delivery of the Bacterial Protease IdeS in Non-Human Primates: A Potential Strategy to Circumvent Pre-existing Immunity to Enable Successful AAV Gene Transfer to the Eye (ASGCT 2025) - "Preclinical studies in non-human primates (NHPs) have shown that nAbs can negatively impact AAV transduction following intravitreal injection (IVT) of an AAV gene therapy vector, leading to reduced transgene expression...These data demonstrate that intravitreal delivery of IdeS can improve the efficiency of AAV gene transfer in the presence of pre-existing immunity and suggest a potential safe and effective strategy for addressing this challenge in the clinic. Disease Focus of Abstract:Ophthalmic Diseases"

Gene Therapies • Ophthalmology

Generative AI Discovers GMU037, a Dual-Fitness Capsid with Simultaneous Superior NHP Ophthalmic Transduction and High Production Yield (ASGCT 2025) - "AAV gene therapy has made great progress in addressing previously intractable diseases...Intriguingly, both properties are associated with a novel mutation, suggesting that our GenAI dual-fitness engine could accelerate discovery of complex first-principles of AAV biology. Disease Focus of Abstract:None"

Gene Therapies • Ophthalmology

CAP-003, a CNS-Targeted IV-delivered AAV Gene Therapy, Safely Increases Brain GCase in NHPs to Level Supporting Potential Normalization of Activity in PD-GBA Patients (ASGCT 2025) - "Targeting a 1H 2025 IND filing, CAP-003 is being advanced with the goal of achieving disease modifying clinical benefit for patients with PD-GBA through a convenient single dose intravenous administration. Disease Focus of Abstract:Parkinson's Disease"

Clinical • Gene therapy • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease • GBA • GBA1

Systemic AAV Gene Therapy with Next Generation Engineered Capsid Demonstrates Expression Levels Supporting Potential Therapeutic Benefit for CNS, Cardiac, and Sensory Symptoms in Friedreich's Ataxia (ASGCT 2025) - "Together, these data demonstrate that CAP-004 has the potential to become a best-in-class targeted gene therapy for the treatment of FA by providing therapeutic benefit for CNS and sensory manifestations of the disease that are not targeted by other approaches in addition to impacting cardiac symptoms with a single intervention. Disease Focus of Abstract:Inherited Neurological Disorders"

Biomarker • Gene therapy • Ataxia • Friedreich ataxia • Gene Therapies • Movement Disorders • FXN

A Platform for Engineered Cross-Correction of AAV-Expressed Transgenes (ASGCT 2025) - "A limitation of many AAV gene therapy approaches is insufficient transduction of target cells and tissues to achieve the necessary therapeutic effect...Together, these results highlight the exciting potential of engineered cross-correction to overcome AAV transduction limitations across a range of indications. Disease Focus of Abstract:Central Nervous System Disorders"

Ataxia • Friedreich ataxia • Gaucher Disease • Gene Therapies • Genetic Disorders • Metabolic Disorders • Movement Disorders • Solid Tumor

Systemic AAV Gene Therapy Using a CNS-targeted Engineered Capsid Significantly Increases GCase Activity to Support the Potential Treatment of PD-GBA (AAN 2025) - "Objective:Capsida has developed a next-generation gene therapy candidate (CAP-003) for administration as a single intravenous (IV) infusion to Parkinson's disease patients with GBA1 mutations (PD-GBA).Background:Parkinson's disease (PD) is the second most common neurodegenerative disorder in the United States with no approved disease modifying treatments to date. Targeting a 1H 2025 IND filing, CAP-003 is being advanced with the goal of achieving disease modifying clinical benefit for patients with PD-GBA through a convenient single dose IV administration."

Gene therapy • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease • GBA • GBA1

2024 White paper on recent issues in bioanalysis: Impact of LDT in US and IVDR in EU; AI/ML for High Parameter Flow Cytometry; The rise of Olink Technology; CDx for AAV Gene Therapies; Integrative Bioanalysis by Multiple Platforms; Super Sensitive ADA/NAb LBA (PART 2A - Recommendations on Advanced Strategies for Biomarkers, IVD/CDx Assays (BAV), Cell Based Assays (CBA), and Ligand-Binding... (PubMed, Bioanalysis) - "This publication (Part 2) covers in the Part 2A the recommendations on Biomarkers/BAV, IVD/CDx, LBA and Cell-Based Assays and in Part 2B the Regulatory Inputs on these topics. Part 1 (Mass Spectrometry Assays and Regulated Bioanalysis/BMV) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 17 of Bioanalysis, issues 5 and 3 (2025), respectively."

Biomarker assay • Journal • Gene Therapies

Systemic Gene Therapy with Engineered AAV Demonstrates Preclinical Efficacy and Safety Supporting a Disease-Modifying Treatment for STXBP1 Developmental and Epileptic Encephalopathy (AES 2024) - "We also utilized non-human primates (NHPs) to assess the DNA and RNA biodistribution and safety of an engineered AAV vector designed to cross the blood-brain barrier after IV administration and deliver the therapeutic gene extensively across the brain. Our findings indicate that STXBP1 supplementation through AAV gene therapy reversed disease phenotypes in a dose-dependent manner across key behavioral domains, including robust and long-lasting correction of cognition and motor deficits and correction of myoclonic and spike-wave discharge seizures, with effects observed up to one-year post-treatment. These studies demonstrate potential for a first- and best-in-class, disease-modifying gene therapy for genetic epilepsy due to STXBP1 mutations. The CAP-002 gene therapy achieved levels of STXBP1 protein expression brain-wide in NHPs that were sufficient to produce meaningful and sustained phenotypic correction in the mouse model, highlighting the potential for significant..."

Gene therapy • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Mental Retardation • Psychiatry • XBP1

Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors. (PubMed, Toxicol Pathol) - "However, a differential toxicity profile associated with systemic AAV administration exists between humans and nonhuman primates (NHPs), in which certain toxicities reported in humans are yet to be observed in NHPs, and vice versa. This review aims to explore the recent literature on systemic rAAV toxicities, focusing on dose levels, the role of the complement activation pathway, endothelial injury, TMA, hepatotoxicity, and the bidirectional translational safety profiles from both human and animal studies."

Gene therapy • Journal • Cardiovascular • Gene Therapies • Hepatology • Inflammation

Systemic AAV gene therapy with CNS-targeted engineered capsids achieves significant GCase activity increases in the primate brain to support the potential treatment of PD-GBA (Neuroscience 2024) - "Parkinson’s disease (PD) is the second most common neurodegenerative disorder with an estimated prevalence of over 1.2 million people in the United States by 2030 and no approved disease modifying treatments today. Importantly, these levels of GCase supplementation are achieved at doses that are well tolerated and without any clinical pathology or immunogenicity findings, including a lack of histopathology in the liver and dorsal root ganglia, that are associated with higher-dose systemic gene therapies. Taken together, CAP-003 is being advanced with the ultimate goal of achieving disease modifying clinical benefit for patients with PD-GBA through a convenient single dose IV administration."

Gene therapy • Late-breaking abstract • CNS Disorders • Parkinson's Disease • GBA

PHASE 1/2 OPEN-LABEL STUDY DESIGN TO EVALUATE SAFETY, TOLERABILITY, AND EFFICACY OF SAR444836, AN AAV-MEDIATED GENE TRANSFER IN PKU PATIENTS (SSIEM 2024) - P1/2 | "Background: Patients with phenylketonuria (PKU) require lifelong treatment with dietary Phenylalanine (Phe) restriction, tetrahydrobiopterin (BH4), and/or PEGylated phenylalanine ammonia lyase (Pegvaliase). Discussion/Conclusion Targeting the unmet need in the treatment of PKU, this innovative trial will investigate whether AAV gene therapy can provide a substantial treatment advantage over existing therapy. NCT number: NCT05972629 Palavras-chave : Phenylketonuria, Safety, Efficacy, Study design, AAV-mediated gene transfer"

Clinical • P1/2 data • Gene Therapies • Metabolic Disorders • Phenylketonuria • Rare Diseases

GUAAVA: Generation of Ultra-Manufacturable Adeno-Associated Viruses by Artificial Intelligence (ASGCT 2024) - "In summary, we have established GUAAVA, a generative AI-based platform and used it to improve the manufacturability of AAV capsids which can increase the economic viability of AAV gene therapies. This generative model framework is extensible; with proper training data, it can apply to other critical features of AAV gene therapies, such as immunogenicity or tissue tropism, bringing AAV-based genomic medicines to a wider patient population."

Gene Therapies • Rare Diseases

Systemic AAV Gene Therapy with CNS-Targeted Engineered Capsids Achieves Significant GCase Activity Increases in the Primate Brain to Support the Potential Treatment of GBA-PD (ASGCT 2024) - "Importantly, these levels of GCase supplementation throughout the brain can be achieved at doses that are well tolerated, without any of the clinical pathology, immunogenicity or histopathological findings associated with higher dose systemic gene therapies. With the above profile, CAP-003 is being developed with the aim of achieving meaningful, disease-modifying clinical benefit for patients with GBA-PD through a convenient, single-dose, intravenous administration."

Gene therapy • CNS Disorders • Cognitive Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease • Psychiatry • Sleep Disorder • Solid Tumor

AAV Gene Therapy Corrects Neurological Phenotypes with Clinically Relevant Doses in a Mouse Model of STXBP1-Related Developmental and Epileptic Encephalopathy (ASGCT 2024) - "Importantly, our candidate, CAP-002, which consists of an engineered AAV capsid that is a product of our high-throughput, non-human primate (NHP)-based AAV engineering platform packaging the human STXBP1 gene, can effectively cross the blood-brain barrier in NHPs and achieve a brain-wide distribution at levels expected to provide therapeutic benefit. Thus, gene replacement achieving widespread neuronal transduction by engineered capsids has the potential to be a promising gene therapy for STXBP1-related developmental and epileptic encephalopathy."

Gene therapy • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Mental Retardation • Pediatrics • Psychiatry • CLSPN, • XBP1

CAP-002: Systemic AAV Gene Therapy with Next Generation Capsids for Treatment of STXBP1 Encephalopathy (ASGCT 2024) - "This breakthrough profile of brain transduction, coupled with significant de-targeting of the liver compared to AAV9, allows CAP-002 to be delivered at lower doses than historically used with systemically delivered gene therapies, providing a greater therapeutic window for mitigating potential toxicities and pathology associated with high-dose intervention. This well-tolerated efficacy profile is expected to provide a disease-modifying solution and achieve meaningful prospect of direct benefit for patients suffering from STXBP1 encephalopathy."

Gene therapy • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Mental Retardation • XBP1

Capsida Biotherapeutics to Present New Data on its Wholly Owned Gene Therapy Programs in Genetic Epilepsy and Parkinson's Disease at the Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) (PRNewswire) - "Capsida Biotherapeutics...announced eight presentations - three oral presentations and five poster presentations - at the American Society of Gene & Cell Therapy (ASGCT) 2024 Annual Meeting....The oral presentation on Capsida's wholly owned Parkinson's disease associated with GBA mutations (PD-GBA) program showcases development candidate data demonstrating high levels of GCase supplementation throughout the brain at well-tolerated doses, while simultaneously detargeting the liver....Data will describe the dose-dependent rescue of key phenotypic defects in adult STXBP1 haploinsufficient mice following intravenous (IV) administration of a next-generation adeno-associated virus (AAV) gene therapy that achieves brain-wide neuronal expression."

Preclinical • CNS Disorders • Parkinson's Disease

Biodistribution and safety of a single rAAV3B-AAT vector for silencing and replacement of alpha-1 antitrypsin in Cynomolgus macaques. (PubMed, Mol Ther Methods Clin Dev) - "In this nondeficient model, we did not find downregulation of endogenous AAT. However, the dual-function vector did serve as a potentially "liver-sparing" alternative for high-dose liver-mediated AAT gene replacement in the context of underlying liver disease."

Journal • Alpha-1 Antitrypsin Deficiency • Gene Therapies • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies. (PubMed, Toxicol Pathol) - "Reports should describe findings at these sites, any TA relationship, and the criteria used for assigning severity grades. Contextualizing adversity of ganglia findings can require a weight-of-evidence approach because morphologic changes of variable severity occur in ganglia but often are not accompanied by observable overt in-life functional alterations detectable by conventional behavioral and neurological testing techniques."

Journal • Gene Therapies • Oncology • Pain

Prediction of Adeno-Associated Virus Manufacturability by Machine Learning (ASGCT 2023) - "In the future, this model could be used as an in-silico screen for AAV capsids to reduce the time necessary for in-vitro experiments. With this work, we aim to establish an ML-based platform to increase manufacturability of clinical AAV capsids to make AAV gene therapies economically viable for patients."

Machine learning • Gene Therapies • Rare Diseases

A Computational Framework to Detect ITR Deletion for rAAV Vectors (ASGCT 2023) - "We also establish the need to triangulate analyses from multiple variant calling tools to conclusively confirm deletions in the ITR sequences. Identifying mutations in complex genomic regions can save substantial costs down the line and lead to more reproducible results in manufacturing AAV gene therapies."

Gene Therapies