TY - JOUR
T1 - Treating late-onset Tay Sachs disease
T2 - Brain delivery with a dual trojan horse protein
AU - Osher, Esther
AU - Anis, Yossi
AU - Singer-Shapiro, Ruth
AU - Urshanski, Nataly
AU - Unger, Tamar
AU - Albeck, Shira
AU - Bogin, Oren
AU - Weisinger, Gary
AU - Kohen, Fortune
AU - Valevski, Avi
AU - Fattal-Valevski, Aviva
AU - Sagi, Liora
AU - Weitman, Michal
AU - Shenberger, Yulia
AU - Sagiv, Nadav
AU - Navon, Ruth
AU - Wilchek, Meir
AU - Stern, Naftali
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/9/12
Y1 - 2024/9/12
N2 - 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 decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, 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 approximately 40% within 6 weeks, when injected intravenously (IV) 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, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.
AB - 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 decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, 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 approximately 40% within 6 weeks, when injected intravenously (IV) 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, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.
KW - GM2 ganglioside
KW - HEXA
KW - HEXB
KW - HexA
KW - blood-brain barrier
KW - enzyme replacement therapy
KW - late-onset Tay-Sachs
KW - lysosomal disease
KW - β-hexosaminidase A
UR - http://www.scopus.com/inward/record.url?scp=85200517527&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2024.101300
DO - 10.1016/j.omtm.2024.101300
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 39211733
AN - SCOPUS:85200517527
SN - 2329-0501
VL - 32
JO - Molecular Therapy Methods and Clinical Development
JF - Molecular Therapy Methods and Clinical Development
IS - 3
M1 - 101300
ER -
