Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids

Author(s):Show less -

Trujillo, Cleber A. ^[1] ; Adams, Jason W. ^{[1, 2, 3]} ; Negraes, Priscilla D. ^{[1, 4]} ; Carromeu, Cassiano ^{[1, 4]} ; Tejwani, Leon ^{[1, 5]} ; Acab, Allan ^[1] ; Tsuda, Ben ^{[2, 6]} ; Thomas, Charles A. ^[1] ; Sodhi, Neha ^[4] ; Fichter, Katherine M. ^[4] ; Romero, Sarah ^[4] ; Zanella, Fabian ^[4] ; Sejnowski, Terrence J. ^{[7, 6, 8]} ; Ulrich, Henning ^[9] ; Muotri, Alysson R. ^{[1, 3]}

Affiliation

^[1] Univ Calif San Diego, Sch Med, Dept Pediat, Rady Childrens Hosp, Dept Cellular & Mol Med, La Jolla, CA 92093 - USA

^[2] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 - USA

^[3] Univ Calif San Diego, Ctr Acad Res & Training Anthropogeny, La Jolla, CA 92093 - USA

^[4] StemoniX Inc, Maple Grove, MN - USA

^[5] Yale Sch Med, Interdept Neurosci Program, New Haven, CT - USA

^[6] Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 - USA

^[7] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 - USA

^[8] Univ Calif San Diego, Inst Neural Computat, La Jolla, CA 92093 - USA

^[9] Univ Sao Paulo, Dept Bioquim, Inst Quim, Sao Paulo - Brazil

• Document type: Journal article
• Source: EMBO MOLECULAR MEDICINE; v. 13, n. 1 DEC 2020.
• Web of Science Citations: 1

Abstract

Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology. (AU)

• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants