Ex Vivo Hematopoietic Stem Cell Gene Therapy: Broad Applications and Therapeutic Potential 

The keynote speaker, Masayuki Kai, PhD, Kyowa Kirin, Inc. VP, Head of Research, presented on the 2024 FDA approved Lenmeldy™, a hematopoietic stem cell gene therapy (HSC-GT) for Metachromatic Leukodystrophy (MLD) that is an asset of their subsidiary Orchard Therapeutics. His talk also highlighted the features of HSC-GT products that Kyowa Kirin believes make them good treatment candidates for non-monogenic cancers, infectious disease, bone disease, and autoimmune diseases.

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GTI Director, Stephanie Cherqui, PhD, UC San Diego Department of Pediatrics, showed how her lab has capitalized on their clinical results that ex-vivo lentiviral-modified HSCs can rescue cells affected by the multisystemic degenerative lysosomal disease cystinosis. They are testing a similar approach in lysosomal disorders, Mucopolysaccharidosis IIIC and Danon disease. Exploiting the differentiation potential of HSCs to develop into microglial cells and macrophages, they have expanded applications of gene modified HSCs to Friedreich’s ataxia and Alzheimer’s disease (AD).

AAV-Mediated Gene Therapy: Challenges, Innovations and Clinical Applications

Farah Sheikh, PhD, UC San Diego Department of Medicine, provided an overview of her translational work with AAV vectors on a disease characterized by structurally compromised heart cells and heart rhythm abnormalities known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)​. A product for human administration is currently being tested in a Phase ½ trial by Lexeo Therapeutics.

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Brian Head, PhD, UC San Diego Department of Anesthesiology, provided compelling preliminary evidence that the protein caveolin, which has important roles in neuronal signaling and neuroprotection, may be a good molecular target for degenerative CNS diseases and restore functional neuroplasticity. In vivo experiments that explored AAV-mediated delivery via various routes reveal extended survival and improved motor function and memory recall.

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Loren Looger, PhD, UC San Diego Department of Neurosciences is designing improved AAVs de novo. This customization is intended to help to get past the current drawbacks of naturally evolved serotypes of AAV. These include low payload size capacity, existing immunity due to previous exposure, and poor retrograde trafficking to cell types like dopaminergic neurons.

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Nayla Mamoud, MD, Novartis Pharmaceuticals Corporation, Executive Medical Director, NeuroMuscular, described in detail the technical considerations and data that supported market approval of Novartis’ AAV gene therapy for spinal muscular atrophy (SMA), Zolgensma®. The talk covered AAV9 vector design that included a continuous promoter for sustained protein expression, and a scAAV ITR for increased double-stranded transgene transcription speed. Production aspects as well as preclinical and clinical data were discussed.

Testing Gene Therapies in Induced Pluripotent Stem Cell Models

Alysson Muotri, PhD, UC San Diego Department of Pediatrics, is developing an AAV5 gene therapy approach for the rare and progressive neurological disorder Rett Syndrome (RTT) that mediates RTT astrocyte rescue in vitro and in vivo. This method aims to target astrocytes and achieve a balanced expression of MeCP2, which is important for normal neuron/synapse function, thus improving safety compared to other gene therapy products. MeCP2 AAV5 has been shown to increase survival and overall health in vivo.

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Angels Almenar-Queralt, PhD, UC San Diego Department of Pediatrics, proposes to establish proof of concept for enhanced microglial anti-amyloid and neuroprotective capacities of an AD-protective CD33 gene variant in HSPC transplantation. Both hiPSC models and CRISPR-editing tools are being used in vitro to test the potential functional advantage of this approach.

Session 4: Resources & Support for the Development of Gene Therapy Strategies for Rare Diseases

The afternoon panelists Nancy Stack, Director of the Cystinosis Research Foundation,  Rodica Stan, PhD, NIH, NCATS Senior Scientific Project Manager, and Lisa Kadyk, PhD, CIRM Associate Director, Therapeutics Development, answered questions about the importance of engaging with patient advocacy groups; the NIH National Center for Advancing Translational Sciences’ real-world experience with development of an AAV gene therapy platform for rare diseases; and CIRM strategies for addressing unmet medical needs.

Session 5: Therapeutic Advances in RNA Technologies for the Treatment of Rare and Ultra-Rare Diseases

 

Nicole Coufal, MD, PhD, UC San Diego Department of Pediatrics, presented a case study for the clinical utility of rapid whole genome sequencing to identify pathogenic genetic variants for ultra rare disease, and the application of commercial AI technology (from Creyon Bio) to engineer an optimal allele-selective ASO. She outlined the challenges of developing an investigator-initiated trial and finding the optimal dose for an infant with TNPO2 who presented with severe developmental delay and refractory epilepsy.

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Gene Yeo, PhD, MBA, UC San Diego Department of Cell and Molecular Medicine, described a novel RNA targeted zinc finger protein (ZFP) platform for binding to and modifying RNA with unprecedented specificity and selectivity​. In vivo and in vitro evidence of disease biomarker reversal and mitigated neurodegeneration was presented in models for a common amyotrophic lateral sclerosis (ALS) called C9-ALS.

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Holly Kordasiewicz, PhD, Ionis Pharmaceuticals, Inc. Vice President Neurology Research, described the advances in medicinal chemistry that have driven the evolution of Ionis antisense drugs. The 2023 FDA approval of their intrathecally administered ASO, tofersen (Qalsody®), for the treatment of SOD1 ALS has been followed by other technological improvements currently in testing. For instance, MsPA ASO backbones have been shown to stabilize molecule to metabolism and increases duration. Ionis is also tackling systemic delivery to CNS.