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In Vivo Studies of a Novel HDAC Inhibitor for Treating Hemoglobin Disorders

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42HL136068-02
Agency Tracking Number: R42HL136068
Amount: $499,220.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-04
Award End Date (Contract End Date): 2021-08-31
Small Business Information
4605 VALLEY RIDGE CT, Fort Collins, CO, 80526-6500
DUNS: 078526138
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (706) 721-6893
Business Contact
Phone: (303) 895-8216
Research Institution
 1120 15TH STREET
AUGUSTA, GA, 30912-0004
 Nonprofit college or university
PROJECT SUMMARY Thehemoglobinopathies are prevalent genetic blood diseases with few treatment optionsIt is estimate thatof the worldandapos s population carries an abnormal hemoglobin gene withinfants born annually with a severe life threatening hemoglobinopathyDrug mediated induction of normalbut developmentally silencedfetal hemoglobinHbFexpression reduces anemia and ameliorates clinical severity in thehemoglobinopathiesHistone deacetylaseHDACandare components of the NURD repressor complexwhich promotes silencing of the fetalglobin genes in adult erythroid cellsPrior generation HDAC inhibitors increase HbF in patients withhemoglobinopathiesbut had limitations for pharmaceutical application and or required titration to reduce anti proliferative effectsCetya has generated a library of high potency HDAC inhibitorsone of whichCThas demonstrated efficacy in inducing HbF expression inthalassemia and sickle cell erythroid progenitors and in theYAC mouse model that contains the normal humanglobin gene locus without significant anti proliferative effectsWe will test the central hypothesis that CThas a sufficiently wide margin of activitywithout significant inhibition of erythroid cell growthto be developed as a new agent for treatment ofhemoglobinopathiesWe propose to conduct studies to evaluate CTin theYAC model to optimize dose and scheduleand then confirm efficacy in the Townes sickle cell disease mouse modelCetya will scale the CTmanufacturing process and produce sufficient quantities to support the murine studies and oral formulation developmentThe goal of this project is to develop the new high potency HDAC inhibitor CTfor an IND and clinical therapeuticsTo test our hypothesis the following aims will be completedAimTest the hypothesis that CTinduces HbF expression in the preclinicalYAC and Townes sickle cell disease mouse models through epigenetic histone modificationsAimScale the manufacturing processes and produce sufficient quantities of CTto conduct IND enabling studies required for a Phase I clinical studyAimDevelop an oral dosage formulation of CTsuitable for human administrationThe expected outcome of this Phaseproject is to develop CTas an oral effective HbF inducerOur experimental approach rests on the scientifically validated concept of the inhibition of sickle hemoglobin polymerization by HbF and red blood cell sickling by reversing a well known epigeneticglobin gene silencing mechanismDevelopment of the potent HDAC inhibitor CTwill impact the field and addresses an unmet need for additional disease modifying therapy forhemoglobinopathies PROJECT NARRATIVE This proposal will build on findings obtained in our Phase I grantutilizing transgenic mouse models to determine the optimal dose and schedule for a future clinical study in patientsThe manufacturing process for the compoundCTwill be optimized at Cetyaand then manufacturing scaled for animal studies and formulation for oral dosage in human trialsUpon completion of the proposed activities in this PhasegrantIND enabling studies will be performed and CTadvanced rapidly into clinical trials!

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

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