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Development of Pirenzepine for HIV SN

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41NS105177-01
Agency Tracking Number: R41NS105177
Amount: $466,421.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 101
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-09-28
Award End Date (Contract End Date): 2019-08-31
Small Business Information
4685 CONVOY ST #210
San Diego, CA 92111-2339
United States
DUNS: 078868444
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ANDREW MIZISIN
 (858) 336-9084
 amizisin@winsantor.com
Business Contact
 STANLEY KIM
Phone: (858) 336-8094
Email: skim@winsantor.com
Research Institution
 UNIVERSITY OF CALIFORNIA SAN DIEGO
 
9500 Gilman Drive, Mail Code 0934
LA JOLLA, CA 92093-0934
United States

 Nonprofit College or University
Abstract

PROJECT SUMMARY
Over million people worldwide including million people in the USA are HIV positive HIV associated
sensory neuropathy HIV SN is the most frequent neurological manifestation of HIV and is characterized as a
distal symmetrical predominantly sensory polyneuropathy HIV SN may represent clinically indistinguishable
neuropathies with distinct pathogenesis a distal axonal degeneration caused by interaction of sensory neurons
with HIV associated proteins such as gp and Tat and also an anti retroviral therapy ART induced toxic
neuropathy ART may also potentiate the HIV SN induced by HIV proteins Recent studies have implicated
mitochondrial dysfunction in the pathogenesis of HIV SN and disruption of neuronal mitochondrial biogenesis
and quality control biogenesis mitophagy axis occurs in HIV SN patients There is no current treatment that
targets a pathological process underlying HIV SN but the emerging appreciation of the role of mitochondrial
dysfunction in the underlying pathogenesis provides a potential therapeutic approach The academic founders
of WinSanTor recently reported that neurite outgrowth from peripheral sensory neurons is under a cholinergic
constraint mechanism mediated by type muscarinic receptors M R Stimulation of the M R restrains
mitochondrial function thereby limiting neuronal energy supply and neurite growth Conversely inhibition of M R
activates AMP activated protein kinase AMPK with subsequent enhancement of mitochondrial bioenergetic
function and neurite regeneration M R inhibition also prevents and reverses indices of distal degenerative
neuropathy in animal models of diabetic and chemotherapy induced neuropathy These promising findings
suggest that the therapeutic efficacy of M R antagonists has the potential to extend across diverse peripheral
neuropathies in which mitochondrial function is compromised We have recently found that mouse models that
overexpress HIV associated proteins exhibit mitochondrial dysfunction and develop symptoms of neuropathy
Further
reduced neurite outgrowth from sensory neurons exposed to the HIV protein gp in vitro was
prevented by treatment with the M R antagonist pirenzepine while loss of corneal nerves induced by delivery
of gp to the eye of normal mice was both prevented and reversed by concurrent topical application of
a M R
antagonist Based on these results the goal of this Phase I STTR project is to evaluate efficacy of pirenzepine
against neuropathy in mice expressing HIV Tat protein evaluate efficacy of pirenzepine against neuropathy
in mice expressing HIV gp protein with concurrent ART therapy Successful completion of this Phase I
project will support further pre clinical development of pirenzepine as a novel therapeutic for treatment of HIV
SN In Phase II we will further define the safety toxicology profiles of pirenzepine to support filing of an IND
application with the FDA PROJECT NARRATIVE
HIV associated sensory neuropathy HIV SN is the most frequent neurological manifestation of HIV disease
and the available therapies are limited to minimizing discomfort rather than treating nerve damage WinSanTor
is developing a novel therapeutic approach for HIV SN based on their discovery of a cholinergic mechanism that
regulates cellular energy supply in sensory neurons and on the recent insights into the pathophysiological
processes in HIV SN induced by HIV proteins and antiretroviral therapy ART

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

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