Project Summary:
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).