A novel gene editing system to treat both Tay–Sachs and Sandhoff diseases

Li Ou, Michael J. Przybilla, Alexandru Flaviu Tăbăran, Paula Overn, M. Gerard O’Sullivan, Xuntian Jiang, Rohini Sidhu, Pamela J. Kell, Daniel S. Ory, Chester B. Whitley

Research output: Contribution to journalArticle

Abstract

The GM2-gangliosidoses are neurological diseases causing premature death, thus developing effective treatment protocols is urgent. GM2-gangliosidoses result from deficiency of a lysosomal enzyme β-hexosaminidase (Hex) and subsequent accumulation of GM2 gangliosides. Genetic changes in HEXA, encoding the Hex α subunit, or HEXB, encoding the Hex β subunit, causes Tay–Sachs disease and Sandhoff disease, respectively. Previous studies have showed that a modified human Hex µ subunit (HEXM) can treat both Tay–Sachs and Sandhoff diseases by forming a homodimer to degrade GM2 gangliosides. To this end, we applied this HEXM subunit in our PS813 gene editing system to treat neonatal Sandhoff mice. Through AAV delivery of the CRISPR system, a promoterless HEXM cDNA will be integrated into the albumin safe harbor locus, and lysosomal enzyme will be expressed and secreted from edited hepatocytes. 4 months after the i.v. of AAV vectors, plasma MUGS and MUG activities reached up to 144- and 17-fold of wild-type levels (n = 10, p < 0.0001), respectively. More importantly, MUGS and MUG activities in the brain also increased significantly compared with untreated Sandhoff mice (p < 0.001). Further, HPLC-MS/MS analysis showed that GM2 gangliosides in multiple tissues, except the brain, of treated mice were reduced to normal levels. Rotarod analysis showed that coordination and motor memory of treated mice were improved (p < 0.05). Histological analysis of H&E stained tissues showed reduced cellular vacuolation in the brain and liver of treated Sandhoff mice. These results demonstrate the potential of developing a treatment of in vivo genome editing for Tay–Sachs and Sandhoff patients.

Original languageEnglish (US)
JournalGene therapy
DOIs
StateAccepted/In press - Jan 1 2020

Fingerprint

Sandhoff Disease
Hexosaminidases
G(M2) Ganglioside
GM2 Gangliosidosis
Brain
Clustered Regularly Interspaced Short Palindromic Repeats
Premature Mortality
Enzymes
Clinical Protocols
Hepatocytes
Albumins
Complementary DNA
High Pressure Liquid Chromatography
Gene Editing
Liver

Cite this

Ou, L., Przybilla, M. J., Tăbăran, A. F., Overn, P., O’Sullivan, M. G., Jiang, X., ... Whitley, C. B. (Accepted/In press). A novel gene editing system to treat both Tay–Sachs and Sandhoff diseases. Gene therapy. https://doi.org/10.1038/s41434-019-0120-5

A novel gene editing system to treat both Tay–Sachs and Sandhoff diseases. / Ou, Li; Przybilla, Michael J.; Tăbăran, Alexandru Flaviu; Overn, Paula; O’Sullivan, M. Gerard; Jiang, Xuntian; Sidhu, Rohini; Kell, Pamela J.; Ory, Daniel S.; Whitley, Chester B.

In: Gene therapy, 01.01.2020.

Research output: Contribution to journalArticle

Ou, L, Przybilla, MJ, Tăbăran, AF, Overn, P, O’Sullivan, MG, Jiang, X, Sidhu, R, Kell, PJ, Ory, DS & Whitley, CB 2020, 'A novel gene editing system to treat both Tay–Sachs and Sandhoff diseases', Gene therapy. https://doi.org/10.1038/s41434-019-0120-5
Ou, Li ; Przybilla, Michael J. ; Tăbăran, Alexandru Flaviu ; Overn, Paula ; O’Sullivan, M. Gerard ; Jiang, Xuntian ; Sidhu, Rohini ; Kell, Pamela J. ; Ory, Daniel S. ; Whitley, Chester B. / A novel gene editing system to treat both Tay–Sachs and Sandhoff diseases. In: Gene therapy. 2020.
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