Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein

Abstract

Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal β –hexosaminidase A (HexA). We report that 1) recombinant HEXA alone increased HexA activity and reduced GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein comprised of HEXA linked to two blood brain barrier (BBB) entry elements, a transferrin receptor binding sequence and G-CSF, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by ∼40% within 6 weeks , when injected intravenously to adult TS mutant mice mimicking the slow course of late onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, reduce the accumulation of GM2 and improve muscle strength, thereby providing potential treatment for late-onset TS.