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Selection and preclinical validation of a lead candidate liver-directed AAV-FVIII expression cassette

Award Number: R43HL132725
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2018

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Selection and preclinical validation of a lead candidate liver-directed AAV-FVIII expression cassette - ¿ DESCRIPTION (provided by applicant): The development of transformative therapeutics, including the possibility of a cure though gene therapy, continues to be the major research and development activity in the commercial hemophilia space. For example, there are several company-sponsored ongoing clinical trials of recombinant adeno-associated viral (rAAV) encoding coagulation factor IX (FIX) for the treatment of hemophilia A. Furthermore as a result of these trials, there now exists extensive safety and initial efficacy data for multiple rAAV-FIX products. However, progress in the translation of this approach to hemophilia A has been hampered by significant hurdles including the size, complexity, immunogenicity, instability and biosynthetic inefficiency of coagulation factor VIII (FVIII) in comparison to FIX. Now through the identification of 1) liver-specific transcriptional regulatory modules (LTRMs) that are smaller tha existing enhancer-promoters combinations and 2) a liver-enhanced codon- optimization algorithm used to engineer the coagulation factor VIII (FVIII) transgene, we have been able to design rAAV vectors encoding FVIII with genome sizes under 5,000 nucleotides that have unprecedented potency. The proposed milestones of the current project are 1) to characterize and select a lead candidate LTRM optimized for FVIII mRNA and transgene product output, rAAV vector manufacture yield and rAAV product consistency, and 2) to identify a lead candidate AAV-FVIII transgene. These proof of concept studies will be performed using the preclinical murine model of hemophilia A. The data obtained should facilitate the selection and preclinical validation of a lead candidate liver-directed AAV-FVIII expression cassette combining these novel technologies exclusively available to Expression Therapeutics (ET). Therefore, ET is in an opportunistic position to capitalize on the ongoing rAAV-FIX/hemophilia B clinical findings and incorporate preclinical R&D and clinical protocol development strategies into this high priority rAAV-FVIII project. This existing clinical gene therapy knowledge combined with our hemophilia A experience and innovative technologies should enable ET to overcome the major hurdles facing commercialization of liver-directed rAAV-FVIII therapy for hemophilia A.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	EXPRESSION THERAPEUTICS LLC	1860 MONTREAL RD	TUCKER	GA	30084	DEKALB	USA	Cardiovascular Diseases Research	000	1	6/27/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $224,223 )
2016	2016	EXPRESSION THERAPEUTICS	2205 Corp Plz Pkwy SE	Smyrna	GA	30080	COBB	USA	Cardiovascular Diseases Research	000	1	8/3/2016	NEW	$224,223
														Subtotal = $224,223

Grand Total All Awards = $224,223

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Selection and preclinical validation of a lead candidate liver-directed AAV-FVIII expression cassette

Award Number: R43HL132725

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2018

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