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Improving CNS Gene Delivery Systems for AD/ADRD Therapy Development


Fast- Track proposals will be accepted. Direct-to-Phase II proposals will be accepted for companies that have already demonstrated feasibility and rigorously achieved the deliverables in described for Phase Number of anticipated awards: 2 to 5 Budget (total costs, per award): Phase I: $500,000 for 12 months; Phase II: $2,500,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: To improve, diversify, and reinvigorate the AD/ADRD drug development pipeline, the NIA has spearheaded several innovative programs including the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP- AD), aimed at identifying the next generation of therapeutic targets. These target discovery programs have identified and made publicly available more than 500 novel candidate targets (to view the list of targets and supporting evidence see the open-source platform Agora) . Detailed assessment of these nascent targets using a standard biopharma target tractability evaluation has revealed that a significant number of them have low small-molecule druggability. Therefore, an expanded tool- kit of therapeutic modalities to include traditional biotherapeutics (i.e. genome editing, gene silencing, and proteins) will be required to integrate many of the next generation targets into drug discovery campaigns. This contract focuses on gene therapy, which has the advantage over protein therapy to target specific cells for gene transduction leading to production or deduction of proteins precisely where therapy is needed. For gene delivery, adeno-associated virus (AAV)-vectors are widely used gene delivery vectors for gene therapy due to features such as tissue tropism, potential of gene transfer to non-dividing cells, and long-term expression. However, vectors have several challenges including low biodistribution and brain delivery, high immunogenicity, and limited payload size. Therefore, this contract proposal focuses on gene delivery system optimization to be used for AD/ADRD gene therapy development. Project goals: Drug delivery systems are engineered technologies to help with the transport of therapeutic agents to a therapeutic target. This can involve movement through the circulatory system and further through cells of the blood-brain-barrier (BBB). The BBB is the biggest limiting hurdle to deliver a drug to the brain, and this is especially true in the case of gene delivery. The current mode of administration that is typically used for brain delivery for gene therapy is the highly invasive intrathecal administration, while other methods such as intravenous injection would provide less physical burden on the patients. AAV-vectors are currently known as the most advanced gene delivery vector and are used to transduce therapeutic genes to the CNS site for treatment of neurodegenerative disorders. Many AAV serotypes have been developed using capsid modification strategies, but each serotype has various limitations associated with brain delivery, cell-type targeting, immunogenicity, biodistribution, and payload size. Novel gene delivery systems can strive to overcome these challenges by providing safer and more flexible routes to gene delivery. By engineering new delivery vehicles using novel biomaterials or delivery modalities, gene therapy can have enhanced stability and bioavailability, decreased immunogenicity, increased brain delivery, and improved cell-type targeting. Novel delivery vehicles can include (but are not limited Page 98 to) nanoparticles, liposomes, micelles, and Trojan horse approaches; examples of novel delivery modalities can include ultrasound, electroporation, and implantable pumps. The short-term goals of this contract proposal are development of a gene delivery system and proof of concept in vivo testing for Phase I, and long-term goals are further development leading to IND submission to the FDA for Phase II. Phase I Activities and Expected Deliverables: • Details concerning special formulations or technologies (i.e., slow release, liposomes, nanoparticles, etc.). • Perform in vitro efficacy studies in the relevant cell line(s) • In vivo study results that include assessment of pharmacokinetics and bioavailability at the relevant site of action. • Rigorous evidence that the agent is blood-brain-barrier penetrant. • Immunogenicity evaluations • Evaluation of metabolism. Phase II Activities and Expected Deliverables: • PK evaluations in species relevant for toxicology or human dose-prediction • Efficacy of gene therapy in a disease-relevant model • Testing delivery to target cells in a large animal species, as appropriate • Preliminary safety such as safety pharmacology and/or dose-range finding toxicology • IND-enabling toxicology, with toxicokinetics, if applicable • Tumorigenicity evaluations • Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working cell banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for INDenabling pharmacology/toxicology tests, as appropriate • IND document preparation and/or pre-IND meeting • GMP manufacturing of material for phase I clinical testing, if applicable
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