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Pharmacological induction of KLF2 and reversal of endothelial dysfunction for the treatment of hypertension

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43HL164171-01
Agency Tracking Number: R43HL164171
Amount: $317,243.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-272
Solicitation Year: 2020
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-05-01
Award End Date (Contract End Date): 2023-04-30
Small Business Information
Watertown, MA 02472
United States
DUNS: 078493775
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (617) 398-7784
Business Contact
Phone: (617) 398-7784
Research Institution

There is a clear unmet need for new differentiated anti-hypertensive therapies, as high blood pressure and its
pathological sequelae remain significant burdens to human health despite several classes of approved drugs.
The vascular endothelium is a dynamic interface that regulates vasotone, inflammation, hemostasis and vascular
remodeling. Dysfunction of the vascular endothelium, including vasoconstriction, impaired vasoreactivity,
inflammation, thrombosis and loss of vascular quiescence, is a key driver of many vascular diseases. Riparian
Pharmaceuticals recently discovered novel small molecules that target endothelial dysfunction by activating the
endothelial Krüppel-like factor 2 (KLF2) pathway, a key node of vasoprotection. The transcription factor KLF2 is
an upstream regulator of critical vasodilatory, anti-inflammatory, anti-coagulatory and homeostatic genes. KLF2
promotes vasodilation and endothelial function by several mediators but a principal mechanism is the
transactivation of the endothelial nitric oxide synthase (eNOS) gene. eNOS and its product NO are widely
appreciated key components of vascular function having vasodilatory, anti-coagulatory and anti-inflammatory
effects. We believe KLF2 induction is a promising new therapeutic approach to the widely studied but persistent
challenge of reduced NO bioavailability in hypertension. We have extensively studied the pharmacology of our
first-in-class KLF2-inducing therapeutic program. In this project, we plan to validate our therapeutic hypothesis
in established hypertensive rat models. We hypothesize that KLF2 and eNOS induction by our lead candidate
will promote a vasoprotective phenotype, improve endothelial function and lower blood pressure in normotensive
and hypertensive animals. Success here will advance this program into IND-enabling studies and clinical
evaluation of a new therapeutic approach to hypertension.

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

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