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In Vivo Editing for Hemophilia Gene Therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41TR001869-01A1
Agency Tracking Number: R41TR001869
Amount: $430,170.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 100
Solicitation Number: PA16-303
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-05-05
Award End Date (Contract End Date): 2019-08-31
Small Business Information
Gaithersburg, MD 20878-1353
United States
DUNS: 806729547
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (240) 632-5540
Business Contact
Phone: (240) 623-5501
Research Institution
Campus Box 1054 1 Brookings Drive
SAINT LOUIS, MO 63130-4862
United States

 Nonprofit College or University

Project Summary
The exceptional promise of gene therapy for hemophilia has been shown in recent studies that result in
long term correction of factor IX deficiency via hepatic transduction with an adeno associated vector AAV In
spite of this watershed event in the history of the gene therapy field there presently exist barriers to the fullest
implementation of hemophilia gene therapy The limited packaging capacity of AAV for larger gene constructs
practically confounds the use of this vector for factor VIII correction and vector related toxicities have been
noteworthy for the context of in vivo transduction of the liver We propose to develop a novel vector approach
that addresses these limitations Of note our recent strategies to retarget adenoviral vectors Ad have allowed
mitigation of vector associated liver toxicities and in vivo transduction of the pulmonary endothelium that has
demonstrated that this site can serve as a fully effective platform to reconstitute deficient serum proteins
Moreover new generation Ads with multiple deletions can be modified to incorporate an expanded range of
gene constructs and larger payloads relevant to gene therapy for the full spectrum of hemophilia disorders We
propose to utilize the CRISPR Cas system which is fully commensurate with Ad technology in conjunction
with our pulmonary endothelial targeted Ad to achieve stable incorporation of corrective hemophilia genes
within the pulmonary endothelium Our novel strategy thereby offers the potential for stable genetic correction
in a manner that circumvents potential vector associated toxicities for both factor IX and factor VIII hemophilia
Successful completion of the aims within this proof of feasibility Phase STTR will set the stage for the
application of corrective gene therapy for hemophilia to the widest context of patients and provide the rationale
for translational development of our highly novel approach into lead optimization and selection in Phase II Our
groups have unparalleled track records for successful bench to bed translation of novel gene therapy
strategies Our strategy to accomplish stable expression of deficient hemophilia factors deriving from a
pulmonary vascular source clearly represents a highly original approach In addition to circumventing the issue
of vector mediated hepatotoxicities the expanded packaging capacity of adenovirus vectors also feasibilizes
gene therapy for factor VIII as well as factor IX deficiency disorders To hasten translation of our approach we
will utilize adenoviral vectors derived from non human primate adenoviruses and will specifically use gorilla Ad
vectors GAd that address a pivotal human use barrier by circumventing preformed adenoviral immunity and
are show excellent performance characteristics in therapeutic applications The profile of efficacy studies
herein will constitute the rationale for translational development of this novel approach as well as a leap to
establishing the pulmonary endothelium as a source to provide secreted factors as an important strategy for
the range of inherited genetic disorders based upon deficient serum factors as well as other potential
therapeutic applications PROJECT NARRATIVE
Gene therapy for hemophilia has great promise We propose to develop a novel vector approach that
addresses the key limitations to current methods and utilizes the unique capacity to target pulmonary
endothelium for reconstituting deficient serum factors We will accomplish this by combining technologies from
Washington University and GenVec Inc In Phase I we will demonstrate the feasibility of the new platform
technology to efficiently deliver to pulmonary endothelium and achieve stable long term correction of factor VIII
deficient mice

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

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