Emerging Gene Correction Strategies for Muscular Dystrophies: Scientific Progress and Regulatory Impact

Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

International Journal of Molecular Sciences ◽

10.3390/ijms22179630 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9630

Author(s):

Elena Abati ◽

Emanuele Sclarandi ◽

Giacomo Pietro Comi ◽

Valeria Parente ◽

Stefania Corti

Keyword(s):

Drug Testing ◽

Premature Death ◽

In Vitro Models ◽

Muscular Dystrophies ◽

Progressive Degeneration ◽

Induced Pluripotent ◽

Muscle Models ◽

Correction Strategies ◽

Pathogenic Process

Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments are urgently needed. From this perspective, it is particularly important to establish reliable in vitro models of human muscle that allow the recapitulation of disease features as well as the screening of genetic and pharmacological therapies. We herein review and discuss advances in the development of in vitro muscle models obtained from human induced pluripotent stem cells, which appear to be capable of reproducing the lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential. In addition, these platforms have been used to assess genetic correction strategies such as gene silencing, gene transfer and genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as well as to evaluate novel small molecules aimed at ameliorating muscle degeneration. Furthermore, we discuss the challenges related to in vitro drug testing and provide a critical view of potential therapeutic developments to foster the future clinical translation of preclinical muscular dystrophy studies.

Download Full-text

iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies

Cells ◽

10.3390/cells8010020 ◽

2019 ◽

Vol 8 (1) ◽

pp. 20 ◽

Cited By ~ 16

Author(s):

Jose L. Ortiz-Vitali ◽

Radbod Darabi

Keyword(s):

Drug Screening ◽

Disease Modeling ◽

Exon Skipping ◽

Short Review ◽

Zinc Finger Nucleases ◽

Muscular Dystrophies ◽

Gene Correction ◽

Transcription Activator ◽

Degenerative Disorders ◽

Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are the foundation of modern stem cell-based regenerative medicine, especially in the case of degenerative disorders, such as muscular dystrophies (MDs). Since their introduction in 2006, many studies have used iPSCs for disease modeling and identification of involved mechanisms, drug screening, as well as gene correction studies. In the case of muscular dystrophies, these studies commenced in 2008 and continue to address important issues, such as defining the main pathologic mechanisms in different types of MDs, drug screening to improve skeletal/cardiac muscle cell survival and to slow down disease progression, and evaluation of the efficiency of different gene correction approaches, such as exon skipping, Transcription activator-like effector nucleases (TALENs), Zinc finger nucleases (ZFNs) and RNA-guided endonuclease Cas9 (CRISPR/Cas9). In the current short review, we have summarized chronological progress of these studies and their key findings along with a perspective on the future road to successful iPSC-based cell therapy for MDs and the potential hurdles in this field.

Download Full-text

Replications can cause distorted belief in scientific progress

Behavioral and Brain Sciences ◽

10.1017/s0140525x18000584 ◽

2018 ◽

Vol 41 ◽

Cited By ~ 2

Author(s):

Michał Białek

Keyword(s):

Real World ◽

Scientific Progress ◽

The Public ◽

Psychological Science

AbstractIf we want psychological science to have a meaningful real-world impact, it has to be trusted by the public. Scientific progress is noisy; accordingly, replications sometimes fail even for true findings. We need to communicate the acceptability of uncertainty to the public and our peers, to prevent psychology from being perceived as having nothing to say about reality.

Download Full-text

Scientific progress is like doing a puzzle, not building a wall

Behavioral and Brain Sciences ◽

10.1017/s0140525x18000900 ◽

2018 ◽

Vol 41 ◽

Author(s):

Alexa M. Tullett ◽

Simine Vazire

Keyword(s):

Scientific Progress ◽

Original Research ◽

Jigsaw Puzzle ◽

Replication Research

AbstractWe contest the “building a wall” analogy of scientific progress. We argue that this analogy unfairly privileges original research (which is perceived as laying bricks and, therefore, constructive) over replication research (which is perceived as testing and removing bricks and, therefore, destructive). We propose an alternative analogy for scientific progress: solving a jigsaw puzzle.

Download Full-text