Overall goal: This phase 1 SBIR application requests support to perform a large-scale screen for highly active siRNA?s targeting all hTau isoforms, as well as 4RTau specific candidates as a first step in developing novel therapeutics for Tauopathies. An essential part of the proposed drug discovery and lead characterization work is the use of DTx Pharma?s novel lipid conjugation technology to enable safe and effective delivery of bioactive siRNA into neuronal cells in vivo. Initial animal work is focused on in vivo delivery, target engagement in hTau transgenic mTauKO animals, and early safety assessments to select candidate siRNAs to advance into disease model proof of concept experiments and IND enabling work in a subsequent phase 2 application. The timeline for these experiments is 6 months. Company Thesis and Background: DTx Pharma is a San Diego-based startup developing a new technology for efficient delivery of nucleic acid medicines?direct conjugation of novel lipid structures (proprietary) to siRNA or antisense. The expertise of the founding team includes oligo therapeutics (Ionis, Regulus, Arcturus), large pharma (Pfizer, J&J, Astra-Zeneca) and neurodegenerative disease (CurePSP, Tau Consortium). DTx has identified novel lipid motifs that solve the fundamental problem of cellular uptake for siRNA?creating molecules that are essentially ?self-transfecting?. The lead lipid motif works with any siRNA tested and appears to be a universal delivery reagent?allowing efficient uptake into a wide array of cultured mammalian cell types. In vivo?the most extensive data comes from ocular administration where prolonged, safe and durable knockdown of several targets has been demonstrated in the retina. Initial experiments using intraventricular injection for CNS application have also been encouraging, demonstrating significant knockdown in multiple anatomic regions. Here, DTx requests support to continue to develop this novel siRNA delivery technology as a new modality to tackle neurodegenerative diseases characterized by protein accumulation?with hTau mRNA/protein being the first target. Successful deployment of DTx delivery technology to achieve gene knockdown in the CNS would have a significant impact on the direction of the company, and if successful, would open an avenue for the broader pharma community to use siRNA?s safely and effectively against validated CNS targets?where there is enormous unmet medical need. Hypothesis to be tested: The underlying hypothesis is that reducing Tau protein levels in neurons of patients with PSP, CBD, AD and other Tauopathies will slow or prevent disease progression. This proposal covers initial steps and tests feasibility of developing a new modality to achieve therapeutic reduction of Tau expression. In this phase 1 application, specific lipid structures designed at DTx Pharma, will be directly conjugated to the ?passenger? strand of siRNA?s, to improve cellular uptake and in vivo PK/PD properties such that siRNA-mediated therapeutic gene knockdown becomes feasible in the CNS (in this application, by targeting expression of Tau).
Genetics, pathology and protein biochemistry all identify abnormalities in the Tau gene/protein as being a cause of brain degeneration in rare diseases such as Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Chronic Traumatic Encephalopathy (CTE) and in the much more common Alzheimer?s Disease (AD). These observations have suggested to many scientists and clinicians that reducing Tau protein in brain might slow or prevent neurodegeneration. This proposed study will generate and test DTx Pharma?s proprietary lipid-modified siRNAs targeting human Tau mRNA, thereby reducing production of Tau protein, with the goal of identifying and advancing a new drug candidate suitable for development as a treatment for the Tau- mediated disorders listed above.