Therapeutic Strategy to slow progression of calcific aortic valve stenosis

  • Miller, Jordan D, (PI)
  • Schaff, Hartzell V. (PI)
  • Schaff, Hartzell V. (PI)
  • Enriquez-Sarano, Maurice (PI)
  • Schaff, Hartzell V. (PI)
  • Schaff, Hartzell V (CoPI)

Project: Research project

Description

Hemodynamically significant calcific aortic valve stenosis (CAVS) affects 3% of the population
over age 65, and patients with even moderate aortic valve stenosis (peak velocity of 3-4 m/sec)
have a 5 year event-free survival of less than 40%. Presently, there are no effective treatments
to slow progression of aortic valve calcification, and aortic valve replacement is the only available
treatment for advanced CAVS. Thus, major aims of our research program include: 1) the use of
integrative approaches to identify mechanisms contributing to initiation and progression of CAVS,
and 2) the use of integrative approaches to identify therapeutic interventions that slow
progression of CAVS without negatively impacting other organ systems/tissues in vivo (e.g.,
skeletal ossification). In the present UH2/UH3 application (submitted in response to the NIH-
Industry Pilot Project: Discovering New Therapeutic Uses for Existing Molecules), we propose
that a Sanofi compound is a novel pharmacotherapy that can slow progression CAVS. During the
UH2 phase of the grant, we aim to provide key proof-of-concept data that this compound: 1) is
well tolerated by patients with mild to moderate CAVS, 2) slows progression of CAVS in a robust
mouse model of valvular calcification and stenosis, 3) reduces osteogenic signaling in human
aortic valve interstitial cells in vitro, and 4) attenuates osteogenic signaling in valves from patients
with severe CAVS. Upon meeting appropriate milestones during the UH2 phase of the grant, we
will rapidly move towards the UH3 phase of the grant, where we will examine the effects of
chronic administration of the compound on accumulation of aortic valve calcium, progression of
aortic valve and ventricular dysfunction, and inflammatory cytokine levels in patients with mild to
moderate CAVS. Collectively, we believe the proposed studies have a high likelihood of not only
providing new insight into fundamental mechanisms regulating gene expression in CAVS, but are
also likely to identify the compound as a novel therapeutic agent to slow progression of CAVS in
humans.
StatusFinished
Effective start/end date6/18/135/31/16

Funding

  • National Institutes of Health: $367,324.00
  • National Institutes of Health: $163,310.00
  • National Institutes of Health: $681,374.00
  • National Institutes of Health: $969,945.00
  • National Institutes of Health: $987,837.00

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Aortic Valve Stenosis
Organized Financing
Therapeutics
Aortic Valve
Calcification of Aortic Valve
Ventricular Dysfunction
Therapeutic Uses
Osteogenesis
Disease-Free Survival
Industry
Pathologic Constriction
Cytokines
Calcium

ASJC

  • Medicine(all)