Author: Dempsey, Graham T ; Legakis, Helen ; Upadhyay, Hansini ; Brown, Duncan ; Ambrosi, Christina ; Kopin, Alan ; Nalbach, Karsten ; Joshi, Vaibhav ; Behrends, Christian ; Dhandapani, Aishwarya ; Cinquino, Stefania ; Harikrishnan, Karthiayani ; Williams, Luis A ; Douville, Julie ; Black, Lauren ; Sato, Ai ; Agrawal, Sudhir ; Ryan, Steven J ; Tseng, Wei Chou ; Gerber, David J ; Delaney-Busch, Nathaniel ; Galluzzi, Lorenzo ; Lewarch, Caitlin ; Elder, Amy ; Meier, Joshua ; Baru, Valeriya ; Mahimkar, Gauri ; Yu, Timothy W ; Shah, Himali ; Margulies, David ; Rajendran, Sakthi H

Mutations in the TECPR2 gene are the cause of an ultra-rare neurological disorder characterized by intellectual disability, impaired speech, motor delay, and hypotonia evolving to spasticity, central sleep apnea, and premature death (SPG49 or HSAN9; OMIM: 615031). Little is known about the biological function of TECPR2, and there are currently no available disease-modifying therapies for this disease. Here we describe implementation of an antisense oligonucleotide (ASO) exon-skipping strategy targeting TECPR2 c.1319delT (p.Leu440Argfs∗19), a pathogenic variant that results in a premature stop codon within TECPR2 exon 8. We used patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons homozygous for the p.Leu440Argfs∗19 mutation to model the disease in vitro. Both patient-derived fibroblasts and neurons showed lack of TECPR2 protein expression. We designed and screened ASOs targeting sequences across the TECPR2 exon 8 region to identify molecules that induce exon 8 skipping and thereby remove the premature stop signal. TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids. Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts. To examine potential functional rescue induced by ASO-005-02, we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2. Finally, ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology. Broad distribution of ASO-005-02 and induction of TECPR2 exon 8 skipping was detected in multiple central nervous system (CNS) tissues, supporting the potential utility of this therapeutic strategy for a subset of patients suffering from this rare disease.

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Indication	Highest Phase	Country/Location	Organization	Date
Paraparesis, Spastic	Preclinical	US	Q-State Biosciences, Inc.	22 Jun 2022

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