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RECOMBINANT ENZYME FUSION PROTEIN FOR LYSOSOMAL STORAGE DISORDERS

Award Number: R44HD052303
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2007
PERIOD OF PERFORMANCE END DATE: 02/28/2009

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RECOMBINANT ENZYME FUSION PROTEIN FOR LYSOSOMAL STORAGE DISORDERS - DESCRIPTION (provided by applicant): Zhang, Yun Abstract There are over 40 lysosomal storage disorders, and most of these diseases affect adversely the central nervous system (CNS). The mainstay of treatment is enzyme replacement therapy (ERT). However, ERT is not effective for the brain, because the enzymes do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. Without treatment of the CNS, the young patients are destined to progressive neurodegeneration and death. The limiting factor in the future treatment of these diseases is the transport of the enzyme across the BBB. Bypass of the BBB with direct injection into the brain is not effective, because only a small part of the brain is treated with a trans-cranial delivery system. Conversely, virtually all cells of the brain can be treated with a trans-vascular delivery system that enables the enzyme to cross the BBB following intravenous administration. A new approach to the BBB delivery of large molecules such as enzymes is the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the missing recombinant enzyme is fused to a BBB molecular Trojan horse. The latter is a genetically engineered protein that is able to cross the human BBB by receptor- mediated transcytosis on endogenous BBB peptide transport systems. Pre-clinical studies show that a large enzyme with a molecular weight >100,000 Daltons, can be delivered to brain via transport across the BBB, following attachment to a BBB receptor-specific Trojan horse. The present work will produce a novel fusion gene encoding a lysosomal enzyme and a genetically engineered molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-180. The fusion gene will be incorporated in a eukaryotic expression vector followed by permanent transfection of cells. These phase II studies will enable production of a master cell bank and development of the purification and downstream processing of the fusion protein. Fusion proteins comprised of BBB targeting antibodies and recombinant enzymes could be therapeutic in the treatment of the brain in human lysosomal storage disorders. 1 Zhang, Yun Project Narrative Lysosomal storage disorders are serious inborn errors of metabolism, and about 75% of the ~40 lysosomal storage disorders affect the brain. The mainstay of treatment is Enzyme Replacement Therapy (ERT). However, ERT is ineffective in the brain, because the enzymes do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) retain high lysosomal enzyme activity. This novel drug, designated AGT-180, will be a model for the treatment of the brain for multiple genetic diseases. 1


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: 2008 ( Subtotal = $456,597 )
2008	2008	ARMAGEN TECHNOLOGIES INC	914 COLORADO BOULEVARD	LOS ANGELES	CA	90401		USA	Child Health and Human Development Extramural Research	000	3	3/4/2008	NON-COMPETING CONTINUATION	$456,597
														Subtotal = $456,597

Issue Date FY: 2007 ( Subtotal = $357,386 )
2007	2007	ARMAGEN TECHNOLOGIES INC	914 COLORADO BOULEVARD	LOS ANGELES	CA	90401		USA	Child Health and Human Development Extramural Research	000	2	4/19/2007	COMPETING CONTINUATION	$357,386
														Subtotal = $357,386

Grand Total All Awards = $813,983

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RECOMBINANT ENZYME FUSION PROTEIN FOR LYSOSOMAL STORAGE DISORDERS

Award Number: R44HD052303

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2007

PERIOD OF PERFORMANCE END DATE: 02/28/2009

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