Advancing Gene-Targeted Therapies for Central Nervous System Disorders Proceedings of a Workshop (2019) / Chapter Skim
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6 Future Directions in the Development of Gene-Targeted Therapies
6 Future Directions in the Development of Gene-Targeted Therapies
Pages 45-58
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From page 45... ...
. • Nanocapsules composed of biodegradable polymers and containing the ribonucleoproteins needed for CRISPR/Cas9 genome editing can be targeted to specific cells to achieve rapid editing with low off-target effects (Gong)
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From page 46... ...
. • Highly penetrant genes associated with neurodevelopmental disorders may represent targets for gene therapy (Buxbaum)
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From page 47... ...
More recently, investigators have demonstrated efficient transduction in the central nervous system (CNS) using ceDNA constructs delivered directly to rat brain using c onvection-enhanced delivery.
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As part of the Somatic Cell Genome Editing Consortium established last year by the National Institutes of Health (NIH) , Gong and colleagues are developing nanoplatforms to deliver Cas9 protein/single guided RNA (sgRNA)
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. Now, in a parallel approach, they are applying directed evolution with deep sequencing to create variants that can achieve biodistribution to specific cell types such as endothelial cells in the vasculature or neurons.
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. DIVERSE EXPERTISE NEEDED TO TACKLE DELIVERY CHALLENGES Protein engineering and directed evolution have made significant impacts on the development of better vectors to deliver cargo to a specific cell type, said Suh.
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, represented by the dotted green line, shows the variation in light intensity over time; the corresponding output signal (green fluorescent protein, or GFP, expression) shows the desired sinusoidal oscillations, demonstrating the ability of light to accurately and precisely control gene expression.
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Developing Gene-Targeted Therapies of Psychiatric and Neurodevelopmental Disorders Although scientists have begun to tackle complex polygenic disorders with gene therapy, they have not yet begun to apply this therapeutic approach to psychiatric disorders, said Hyman. He asserted that the time has come to think about this challenge while recognizing that clinical applications are a long way off.
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From page 53... ...
examining 36,000 exomes from affected and unaffected individuals identified 102 genes that are strongly associated with autism, said Joseph Buxbaum, director of the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai in New York. Many of the gene mutations that have been identified are highly penetrant with serious deleterious impact and can be parsed into those that are autism specific and less autism specific, Buxbaum said.
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From page 54... ...
Taking PMS as one example, Buxbaum made the following points. Given that genetic testing can readily identify PMS; that it is thought to be fully penetrant with many potential biomarkers, rodent models, and even a primate model; and that there is an effective and engaged family foundation, Buxbaum suggested that this disorder may be an excellent target for gene therapy.
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POTENTIAL FOR PRE-COMPETITIVE COLLABORATION Henderson commented that, while it is important that each company create its own intellectual property around specific programs, the large number of variables associated with gene-targeted therapies remains a significant challenge for individual companies. He suggested exploring the potential of pre-competitive partnerships to establish reproducible baseline data for standardized preparations of widely used capsids in primate models, including routes of administration and safety issues.
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Story Landis noted that academic groups and patient groups may not be aware of what is needed to make a natural history study useful for those who are conducting clinical trials. Natural history studies are essential to developing compelling clinical trials, said Landis.
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FUTURE DIRECTIONS 57 ery to the correct brain regions and cell types, increasing the potency of antisense oligonucleotides and RNA interference chemistries, and designing bridging studies to accelerate moving from first generation to safer and more potent second generation vectors and other products. Innovations in these and other areas may help to increase the efficacy of treatments and applicability to a broader range of diseases and may also drive down costs and improve patient access to treatments, said S hihabuddin.
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