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ENZYME REPLACEMENT THERAPY OF THE BRAIN IN MUCOPOLYSACCHARIDOSIS TYPE II

Award Number: R43NS067707
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2011
PERIOD OF PERFORMANCE END DATE: 07/31/2011

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ENZYME REPLACEMENT THERAPY OF THE BRAIN IN MUCOPOLYSACCHARIDOSIS TYPE II - DESCRIPTION (provided by applicant): Type II Mucopolysaccharidosis (MPS), also known as Hunter's syndrome, is an genetic disease that affects the lysosomal enzyme, iduronate-2-sulfatase (IDS). Consequently, patients with MPS-II develop extensive lysosomal storage product accumulation in tissues, including the brain. Children develop multiple brain disorders including mental retardation and hydrocephalus. The current therapy for MPS-II is Enzyme Replacement Therapy (ERT) with the recombinant human protein. However, ERT does not treat the brain of MPS-II, because IDS does not cross the blood-brain barrier (BBB). The present work will re-engineer human IDS to enable transport across the BBB, using molecular Trojan horse technology. A molecular Trojan horse is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, such as the human insulin receptor (HIR). The human IDS is fused to the heavy chain of the HIRMAb to create a new chemical entity, called the HIRMAb-IDS fusion protein. Preliminary studies show the HIRMAb-IDS fusion protein retains high IDS enzyme activity and high binding for the HIR. The present work will engineer a tandem vector for electroporation of host cells for development of a permantently transfected cell line to enable commercial production of the new fusion protein. The fusion protein will be purified with 2 columns and validated with HIR binding assays, IDS enzyme activity, Western blotting, and other biochemical assays. The biological activity of the HIRMAb-IDS fusion protein will be verified with assays in MPS-II fibroblasts that measure fusion protein uptake, cell IDS enzyme activity, and clearance of glycosoaminoglycans. These phase I studies will enable future phase II studies that test the safety, efficacy, and pharmacokinetics in animals prior to human testing. PUBLIC HEALTH RELEVANCE: Mucopolysacchridosis Type II, or Hunter's Syndrome, patients develop severe brain abrormalities, owing to the genetic defect in the gene encoding the lysosomal enzyme, iduronate-2-sulphatase (IDS). Enzyme replacement therapy (ERT) is not effective for the brain, because the IDS do not cross the blood-brain barrier (BBB). This research will develop a new treatment for the brain in patients with Hunter's Syndrome, which involves the re-engineering of human IDS as a fusion protein that crosses the human BBB.


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: 2011 ( Subtotal = $111,214 )
2011	2011	ARMAGEN TECHNOLOGIES INC	914 COLORADO BOULEVARD	LOS ANGELES	CA	90401		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/17/2011	NEW	$111,214
														Subtotal = $111,214

Grand Total All Awards = $111,214

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ENZYME REPLACEMENT THERAPY OF THE BRAIN IN MUCOPOLYSACCHARIDOSIS TYPE II

Award Number: R43NS067707

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2011

PERIOD OF PERFORMANCE END DATE: 07/31/2011

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