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SPNS2 inhibitors as renal fibrosis therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK136371-01A1
Agency Tracking Number: R41DK136371
Amount: $301,373.00
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): 2023-09-08
Award End Date (Contract End Date): 2024-08-31
Small Business Information
Blacksburg, VA 24060-1839
United States
DUNS: 081332474
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (540) 231-5742
Business Contact
Phone: (540) 278-4743
Research Institution
BOX 400195
United States

 Nonprofit College or University

Fibrosis is an aberrant wound healing process characterized by progressive accumulation of extracellular
matrix that ultimately destroys organ function. Progressive fibrosis is inherent to chronic kidney disease (CKD),
which often leads to end-stage renal disease. Although patients can be maintained by hemodialysis while
awaiting transplantation, their’s and their care-giver’s quality of life are significantly degraded. Furthermore, the
costs incurred by the Nation’s health system are enormous. An ideal medicine would reverse fibrosis and re-
establish pristine kidney function, but even the more modest goal of slowing fibrotic progression (and thereby
delaying the need for hemodialysis or transplant) remains beyond therapeutic reach. Thus, new strategies for
developing experimental therapies are needed.Recent studies indicated that local sphingosine 1-phosphate (S1P) signaling in kidney pericytes
enhances the inflammatory response by recruiting cytokines and chemokines on activation of S1P1 receptor.
The resulting inflammatory cascade promotes fibrosis. Thus, interdicting at the point of synthesis and transport
of S1P or antagonism of S1P1 receptor can ameliorate the resultant fibrosis. The solute S1P transporter Spns2
is responsible for the extracellular release of S1P in pericytes (but not kidney tubular epithelial cells). The S1P
export inhibitors can reduce inflammation and fibrosis. Indeed, in mouse models of kidney fibrosis (unilateral
ischemia/reperfusion injury and folic acid toxicity), genetic deletion of Spns2 or inhibition with small molecules
significantly reduced renal fibrosis as compared to control animals. Taken together, the strong preliminary
evidence suggests that Spns2 inhibitors could be therapeutically useful anti-fibrotic agents. Flux Therapeutics
has the first-in class Spns2 inhibitors reported and is apparently the only team with such inhibitors, which uniquely
positions the company to move Spns2 inhibitors towards the clinic. To achieve this goal, we will winnow the three
best compounds from three different scaffolds through rigorous ADME-tox, counter screen, and pharmacokinetic
studies to identify a lead compound in Aim 1. In Aim 2, the lead Spns2 inhibitor will be validated for efficacy in
three different mouse models of kidney fibrosis. This program will afford a drug-like compound that validates
Spns2 as an anti-fibrotic drug target.

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

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