Metachromatic Leukodystrophy or MLD, is a genetic disease that affects the lysosomal enzyme, arylsulfatase A (ASA). People born with MLD develop extensive lysosomal storage product accumulation in tissues, including the brain. Children with MLD develop multiple brain disorders including mental retardation and hydrocephalus early in life. The current therapy in clinical trials for MLD is Enzyme Replacement Therapy (ERT) with the recombinant human enzyme, ASA. However, ERT does not treat the brain of MLD, because ASA does not cross the blood-brain barrier (BBB). The present work will continue work on the development of a new treatment of the brain of MLD, which is a genetically engineered IgG-enzyme fusion protein. The ASA enzyme is fused to a BBB molecular Trojan horse, which is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, the human insulin receptor (HIR). The human ASA is fused to the heavy chain of the HIRMAb to create a new biological entity, the HIRMAb-ASA fusion protein named AGT-183. Phase I studies show the HIRMAb-ASA fusion protein could be engineered and expressed by stably transfected host cells. The fusion protein retained high affinity binding to the HIR, retained high ASA enzyme activity, was triaged to the lysosomal compartment of MLD fibroblasts, and rapidly penetrated the BBB in rhesus monkeys after intravenous administration. The proposed phase II work will develop a manufacturing plan that can be replicated for future GMP manufacturing. The AGT-183 produced in phase II will be evaluated for safety, toxicology and pharmacokinetics in Rhesus monkeys. The completion of this work will enable entry of the AGT-183 drug development program into GLP toxicology and GMP manufacturing required for submission of an IND to begin treatment of the brain in patients with MLD.

Public Health Relevance

People born with the genetic disorder called Metachromatic Leukodystrophy, or MLD, develop severe abnormalities of the brain, owing to the inherited defect in the gene encoding the lysosomal enzyme, arylsulfatase A (ASA). Enzyme replacement therapy is not effective for the brain, because the ASA does not cross the blood-brain barrier (BBB). This research will develop a new treatment for the brain in patients with MLD, which involves the re-engineering of human ASA as a fusion protein that crosses the human BBB.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44HD074272-02
Application #
8521564
Study Section
Special Emphasis Panel (ZRG1-ETTN-M (11))
Program Officer
Oster-Granite, Mary Lou
Project Start
2012-08-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$416,309
Indirect Cost
Name
Armagen Technologies, Inc.
Department
Type
DUNS #
137142589
City
Calabasas
State
CA
Country
United States
Zip Code
91302