Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a midlife onset hereditary disease affecting skeletal muscles. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INI) in patient's skeletal muscle cells. OPMD is caused by a mutation in the poly (A) binding protein nuclear 1 protein (PABPN1) gene, located on chromosome 14q. The normal PABPN1 gene has a (GCG)6 repeat encoding a polyalanine stretch at the 5' end, while in OPMD patients this repeat is expanded to (GCG)8-13. Currently there is no effective treatment for OPMD. In this review, we discuss our current treatment strategies for OPMD. We present three experimental therapeutic approaches: pharmacological, RNA replacement, and gene editing. Our scientific findings could ultimately lead to an effective therapy for OPMD patients.

RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

“…We previously developed a stable C2C12 cell model that is relevant to OPMD 6, 9. We sought to evaluate the silencing effects of hhRzs and miRNAs, with or without the opt-PABPN1, in this model.…”

“…Currently there is no effective treatment for OPMD. Since our publication of the first PABPN1 mutations in 1998, 4 several molecular mechanisms have been proposed to contribute to the pathogenesis of the disease, 6 including defects in the potential clearance pathway of the misfolded protein (i.e., chaperones and ubiquitin-proteasome pathway [UPP]), 7 alterations in histone acetylation,8, 9 perturbation in the Wnt signaling pathway, 10 and the role of protein’s structure 11, 12. Over the last few years, several potential treatment strategies have emerged targeting these mechanisms 8, 10, 13, 14, 15, 16, 17, 18, 19.…”

“…Over the last few years, several potential treatment strategies have emerged targeting these mechanisms 8, 10, 13, 14, 15, 16, 17, 18, 19. The strategies include drug,6, 8, 9, 10, 13, 14, 17, 18 cell, 19 and gene therapy 20 (Table S1). Although the role of protein aggregates in OPMD pathogenesis is controversial, drug therapies aiming to reduce misfolded aggregates have been proven effective in pre-clinical studies.…”

“…Although the role of protein aggregates in OPMD pathogenesis is controversial, drug therapies aiming to reduce misfolded aggregates have been proven effective in pre-clinical studies. For example, chaperone expression,7, 21 6-aminophenanthridine and guanabenz, 22 ADAPT-232 (Chisan), 6 cystamine, 16 doxycycline, 18 and trehalose 17 have shown phenotype improvement in cell, fly, and mouse models of OPMD. It is noteworthy to mention that disaccharide trehalose is under phase IIb clinical trial for OPMD patients (ClinicalTrials.gov: NCT02015481).…”

“…In a recent study, we developed RiboSoft software, which implements a comprehensive hammerhead ribozyme (hhRz) design procedure, and we were able to choose, assay, and validate four ribozymes targeting wild-type PABPN1 transcript: hhRz144, hhRz363, hhRz437, and hhRz867 31 . These four hhRzs were successfully tested in vitro (HEK293T) for their ability to cleave the targeted transcript 6, 31. Because these RNA molecules cannot distinguish between wild-type and mutant PABPN1 RNAs, we decided to develop an opt-PABPN1 that is resistant to cleavage by these RNA molecules.…”