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A Novel Therapeutic that Harnesses Microtubules to Promote Cavernous Nerve Regeneration after Radical Prostatectomy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42DK117684-02A1
Agency Tracking Number: R42DK117684
Amount: $1,686,452.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: 300
Solicitation Number: PA20-265
Timeline
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-21
Award End Date (Contract End Date): 2023-08-31
Small Business Information
105 SYLVAR ST
Santa Cruz, CA 95060-3728
United States
DUNS: 079613572
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 LISA BAKER
 (646) 209-2712
 lisa@microcures.com
Business Contact
 DAVID SHARP
Phone: (914) 462-2241
Email: david@microcures.com
Research Institution
 ALBERT EINSTEIN COLLEGE OF MEDICINE
 
1300 MORRIS PARK AVENUE
BRONX, NY 10461-1900
United States

 Nonprofit College or University
Abstract

Radical prostatectomy (RP) is a commonly used treatment option for localized prostate cancer, which carries a
high risk for development of erectile dysfunction (ED) because of cavernous nerve (CN) injury. Even newer,
nerve-sparing, robotic procedures do not convincingly improve erectile function (EF) outcomes after RP. In
addition, ED resulting from RP is often refractory to treatment by orally administered phosphodiesterase type 5
inhibitors (PDE5i) leaving patients with poor treatment options that are invasive, associated with side-effects,
have limited efficacy, and treat symptoms rather than being curative. There is a real and urgent need to
identify new therapeutic strategies to treat ED associated with RP.
As a consequence of CN injury there is decreased neuronal nitric oxide (NO) release in corporal tissue, the
primary activator of the molecular pathways leading to an erection. Lower levels of NO release lead to a failure
in mechanisms that facilitate cavernosal oxygenation, resulting in fibrosis and cavernosal smooth muscle
apoptosis, which then act as potentially irreversible barriers to recovery of EF, even after CN regeneration. Since
EF is impacted within 48 hours of CN injury, a strategy called “penile rehabilitation” such as oral PDE5i
administration, is initiated as early as possible after RP with the goal of raising basal corporal blood flow and
preserving penile architecture until there is functional CN regeneration.
Based on the central role that CN injury plays in the development of ED following RP, our novel treatment
strategy uses siRNA technology to target expression of a newly discovered microtubule regulator, Fidgetin-like
2 (FL2) to enhance CN regeneration. Preliminary and published studies suggest FL2 is a negative regulator of
axon growth and wound repair; in Phase I studies a novel lead therapeutic formulation (a “wafer” releasing FL2-
siRNA; SiFi2) was identified that when administered to rats undergoing bilateral CN transection resulted in visible
CN regeneration and improved erectile function. Compared to other pre-clinical strategies under investigation
for CN regeneration, SiFi2 is exceptionally fast and effective in promoting CN regeneration, inducing reformation
of nerve tissue across a gap of several millimeters, and resulting in significant improvement in erectile function
as early as two weeks following transection. However, this and other preclinical strategies being explored for
CN regeneration may fail to recover optimal EF because irreversible changes may occur in penile architecture
during the time it takes for nerve regeneration. Therefore, we will explore a two-pronged approach enhancing
nerve regeneration and mitigating corporal tissue damage while the nerve is healing.
The goal for this Phase II proposal is to initiate steps towards an Investigational New Drug application (IND)
filing, over three specific aims: (1) evaluate the ability of orally administered PDE5i to enhance SiFi2 treatment;
(2) initiate a GMP start-up program at a contract manufacturing organization (CMO); and (3) evaluate toxicity of
SiFi2 produced at the CMO.Radical prostatectomy (RP), a commonly used treatment option for localized prostate cancer, often results in
erectile dysfunction (ED) and, unfortunately, no orally or topically administered therapeutics exist which reliably
restore erectile function in these afflicted men. Phase I studies have shown that when siRNA targeting the newly
discovered microtubule regulator, Fidgetin-like 2 (FL2-siRNA-wafer; SiFi2), is administered to rats that
underwent CN transection, visible CN regeneration and improved erectile function outcomes as early as two
weeks post-transection were observed; these effects were both faster and more effective than other pre-clinical
strategies. The goal for this Phase II proposal is to initiate steps towards an Investigational New Drug application
(IND) filing, over three specific aims: (1) evaluate the ability of the commonly prescribed, orally administered
phosphodiesterase type 5 inhibitors (PDE5i) to enhance SiFi2 treatment; (2) initiate a good manufacturing
process (GMP) start-up program at drug substance and drug product contract manufacturing organizations
(CMO); and (3) evaluate toxicity of the CMO generated SiFi2.

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

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