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Targeting Myosin to Treat Polycystic Kidney Disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK136452-01
Agency Tracking Number: R41DK136452
Amount: $298,326.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 400
Solicitation Number: PA22-178
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-04-12
Award End Date (Contract End Date): 2024-03-31
Small Business Information
1209 6TH AVE N STE 101
Seattle, WA 98109
United States
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 (857) 210-0606
Business Contact
Phone: (857) 210-0606
Research Institution
SEATTLE, WA 98195-9472
United States

 Nonprofit College or University

The goal of this proposal is to advance a new therapeutic approach targeting myosin for polycystic kidney
disease (PKD). PKD is a major life-threatening Mendelian disorder that affects 12,000,000 individuals,
representing a market opportunity of ~$1 billion. In PKD, tiny tubules in the kidneys, liver, and other organs
gradually expand into fluid-filled cysts, leading to organ failure. PKD is commonly inherited as a loss-of-function
mutation in PKD1 or PKD2, encoding polycystin-1 (PC1) or polycystin-2 (PC2), respectively. General treatment
involves managing complications of chronic kidney disease, controlling blood pressure, and preparing for renal
replacement therapy. Tolvaptan, a vasopressin receptor antagonist, is approved for use in rapidly progressing
cases, but its modest efficacy and occasionally severe side effects make it unsuitable for many PKD patients.
How cysts form mechanistically remains incompletely understood, which has hampered drug development. Thus
a compelling need and market exists for new treatments and targets to slow or reverse PKD.To better model human PKD and develop therapeutic strategies, we have invented PKD1-/- and PKD2-/- human
kidney organoids, which undergo PKD-specific cyst formation from tubules, reconstituting the disease phenotype
in a petri dish. Organoid studies reveal that PKD cyst formation is highly sensitive to the microenvironment, and
that blebbistatin, a myosin II inhibitor, greatly increases cystogenesis. Non-muscle myosin II (NMII), a known
target of blebbistatin that confers strength and shape to cells, is strongly expressed in tubular epithelia and
redistributed in organoid cysts. Conversely, in preliminary studies, we have discovered a myosin II activator that
reduces PKD cystogenesis, suggesting a novel therapeutic strategy. This compound has a well-established
safety and bioavailability profile in large animal studies. Based on our preliminary data and the literature, we
hypothesize that it directly activates NMII heavy chains to strengthen and stiffen the cytoskeleton of kidney
tubules, thus limiting their tendency to deform into cysts. The major goal of this proposal is to demonstrate this
mechanism of action as proof of concept for targeted drug development. This will be achieved in independent
aims using purified NMII in vitro and in phenotypic human and animal models.Aim #1: Demonstrate that our hit compound activates NMII in assays suitable for drug optimization.Aim #2. Elucidate the targetable function of NMII during PKD cyst formation in organoids and in vivo.
Completion of these two aims will connect the dots between our therapeutic hit compound, NMII, and PKD cyst
formation from the single molecule to organoid scale, elucidating a novel mechanism of action for treating cystic
disease. This will demonstrate proof of concept, further validate the therapeutic hit, and lay the groundwork for
deeper drug development efforts in Phase II (lead optimization and pre-clinical testing).

* Information listed above is at the time of submission. *

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