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Intracerebroventricular Iduronidase Delivery to the Brain

Award Number: R43NS108853
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: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2019

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Intracerebroventricular Iduronidase Delivery to the Brain - PROJECT SUMMARY MPS I (Hurler Syndrome) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan, in various tissues. A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS I, a disease with good systemic effects, but no effect on the neurodegenerative process symptoms due to poor transport across the blood-brain barrier. Using iduronidase (IDUA) conjugated to guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS I (IDUA-/-). Furthermore, intranasal administration of GNeo-IDUA demonstrated that small amounts of enzyme were delivered to the brain and were able to reduce pathological glycosaminoglycans. The purpose of this grant is to assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS I mouse model using intracerebroventricular administration. Dose-dependent biodistribution of GNeo-IDUA and the effect on biochemical and histological pathology and behavior will be evaluated. Efficacy and safety will be assessed in single dose and 2-week dosing studies. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.


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: 2020 ( Subtotal = $0 )
2020	2018	TEGA THERAPEUTICS, INC.	3550 GENERAL ATOMICS CT STE G02-102	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/9/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $225,000 )
2018	2018	TEGA THERAPEUTICS INC	9500 GILMAN DR MC 0713	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/20/2018	NEW	$225,000
														Subtotal = $225,000

Grand Total All Awards = $225,000

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Intracerebroventricular Iduronidase Delivery to the Brain

Award Number: R43NS108853

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: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2019

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