Hybrid Protein Transports Experimental Drug for Lysosomal Storage Diseases Across the Blood-brain Barrier

Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Examples of macromolecules transported include IgA, transferrin, and insulin. While transcytosis is most commonly observed in cells of an epithelium, the process is also present elsewhere. Pharmaceutical companies are currently exploring the use of transcytosis as a mechanism for transporting therapeutic drugs across the BBB. Exploiting the body’s own transport mechanism can help to overcome the high selectivity of the BBB which typically blocks the uptake of most therapeutic antibodies into the brain and CNS.

ApoE is 299 amino acids long and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of apoE, while neurons preferentially express the receptors for apoE.

Investigators at Cincinnati Children's Hospital Medical Center (Ohio, USA) attached apoE to the lysosomal enzyme, alpha-L-iduronidase (IDUA) to create two experimental compounds IDUAe1 and IDUAe2, which, during in vitro screening, exhibited desirable receptor-mediated binding, endocytosis, and transendothelial transport as well as appropriate lysosomal enzyme trafficking and biological function.

The attached enzyme IDUA hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I).

The investigators used the hybrid molecules to treat a mouse model of MPS I. Results published in the February 4, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) revealed that following injections of IDUAe1 into the tail veins of the mice, IDUA activities were obtained and IDUAe1 protein was detected in neurons and astrocytes throughout the brain. The therapeutic potential was demonstrated by normalization of brain glycosaminoglycan and beta-hexosaminidase in the MPS I mice five months after moderate yet sustained delivery of the drug.

"This study provides a noninvasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders," said senior author Dr. Dao Pan, associate professor of pediatrics at Cincinnati Children's Hospital Medical Center. "Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson's and Alzheimer's."

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Cincinnati Children's Hospital Medical Center