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Bioengineered factor VIII gene therapy for hemophilia A

Award Number: R44HL114241
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2017

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Bioengineered factor VIII gene therapy for hemophilia A - DESCRIPTION (provided by applicant): The overall goal of this proposal is to conduct a gene therapy clinical trial incorporating genetically modified hematopoietic stem cells (HSCs) for persons with hemophilia A. In a series of recent studies, we have shown that the transplantation of genetically-engineered HSCs can restore factor VIII (fVIII) activity to curative levels in hemophilia A mice and that human HSCs are readily transduced with recombinant lentivector encoding a genetically-engineered fVIII transgene. Our gene therapy approach uses a bioengineered fVIII transgene designed at Emory University and contains critical high-expression sequences, which we have shown are necessary and sufficient to achieve therapeutic/curative fVIII expression levels. Using the bioengineered fVIII construct, designated ET-3, in preclinical murine studies we routinely observe normal fVIII activity levels (1 unit/ml) i mice engrafted with 1 - 5% genetically-modified hematopoietic cells. These engraftment levels are similar to those that have already been achieved in human HSC-based clinical gene therapy trials. In contrast, we and others have shown that similar strategies using fully human fVIII sequences do not achieve these robust fVIII activity levels in the hemophilia A mouse preclinical model. We have generated extensive preclinical data using the ET-3 transgene, which demonstrate proof-of-concept that HSCs genetically engineered with ET-3-encoding lentivector, coupled with a non-myeloablative transplant regimen, can be used to treat and possibly cure hemophilia A. In addition, a favorable pre-IND meeting was held that provided the necessary guidance needed to finalize our preclinical data package and vector manufacturing. We now propose to 1) generate late-stage preclinical data using clinical-grade (GMP) lentivector product, 2) complete the regulatory submissions necessary for approval to conduct a pilot gene therapy clinical trial and 3) recruit and treat 7 patients with hemophilia A in the proposed trial. Four organizations have partnered to accomplish these aims, including: i) Expression Therapeutics, LLC, a biotechnology company founded on the high expression fVIII technology, ii) Emory University, where the majority of the preclinical studies have been performed, iii) Children's Healthcare of Atlanta, a financial supporter of the Gene Therapy Program at Emory University and investor in Expression Therapeutics, and iv) Lentigen Corporation, a company dedicated to the successful clinical application of lentivectors. Lentigen will generate the clinical lentivecto product that will be used in the proposed studies including the clinical trial, and the trial will e conducted at Emory University by expert principal investigators with clinical expertise in stem cell transplantation and the treatment of hemophilia A. The chief milestone of the current Phase II SBIR proposal is the translation of the ET-3 gene therapy concept and project from the late-pre-clinical study phase into a first-in-man trial.


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: 2017 ( Subtotal = $0 )
2017	2015	EXPRESSION THERAPEUTICS LLC	1860 MONTREAL RD	TUCKER	GA	30084	DEKALB	USA	Blood Diseases and Resources Research	000	3	6/2/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $826,775 )
2015	2015	EXPRESSION THERAPEUTICS	2205 Corp Plz Pkwy SE	Smyrna	GA	30080	COBB	USA	Blood Diseases and Resources Research	000	3	5/4/2015	NON-COMPETING CONTINUATION	$826,775
														Subtotal = $826,775

Issue Date FY: 2014 ( Subtotal = $659,086 )
2014	2014	EXPRESSION THERAPEUTICS	2205 Corp Plz Pkwy SE	Smyrna	GA	30080	COBB	USA	Blood Diseases and Resources Research	000	2	4/23/2014	COMPETING CONTINUATION	$659,086
														Subtotal = $659,086

Grand Total All Awards = $1,485,861

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Bioengineered factor VIII gene therapy for hemophilia A

Award Number: R44HL114241

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2017

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