Gene therapy is revolutionizing treatment perspectives for patients affected with monogenic disorders. Gene therapies using antisense oligonucleotides (ASOs), for example, have been approved for patients with Duchenne muscular dystrophy (DMD), the most common lethal monogenic disorder worldwide. The growing success of these therapies has prompted research teams to further develop and refine the safety and efficacy of ASOs and adeno-associated viral vectors (AAVs), and are increasingly looking for alternative testing platforms.
Human induced pluripotent stem cells (iPSCs) can be differentiated into any cell type, to model disease-linked phenotypes while retaining patient-specific genetic mutations, human serotype and intracellular environment. In this review, Marisa Cappella and colleagues outline major findings from more than 18 studies in which iPSCs were used for therapeutic tests of neuromuscular and motor neuron disorders, reinforcing their value as reliable testing platforms for gene therapy.
Strategies using ASOs aim to increase their ability to rescue disease phenotypes and test novel chemistries and molecular technologies. Animal models for DMD and other neuromuscular disorders, though, often show minimal clinical disease phenotype, hampering the development and optimization process. Studies with iPSC-cardiomyocytes from DMD patients showed their capacity to test ASOs based on gene correction and rescue of disease hallmarks, helping select therapies with enhanced efficacy in humans.
AAV-mediated therapies have also become a reality since the approval of a treatment for severe spinal muscular atrophy (SMA). Yet there is a need to expedite the translational path from bench to clinic. Characteristics like AAV serotype or cell specificity, which are not preserved across species, can be best selected by testing in a human context. Several studies have used iPSC-derived cardiomyocytes, neurons, or glial cells to show delivery methods in differentiated iPSCs and identified the most efficient serotypes for each cell type. These results set the bases for the use of iPSC technology as a system to select therapeutic candidates that best translate to the clinic.
Taken together, the studies compiled in this review highlight the versatility of iPSC technology to model genetic diseases, their ability to recapitulate main hallmarks of important neuromuscular and motor neuron disorders and their capability to provide translational information that brings better gene therapies to patients.
AAV vectors and ASOs can be used to efficiently modify gene expression of patient-derived skeletal muscle or central nervous system cells, facilitating studies for neurological and neuromuscular diseases.
The specificity of ASOs and AAVs can be best selected with human iPSC-derived cells to expedite the translational path from bench to clinic.
Patient-specific approaches can be further refined by using iPSCs for potency assays of approved gene therapies.
 Cappella M, Elouej S, Biferi MG. The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders. Front Cell Dev Biol. 2021;9. doi:10.3389/FCELL.2021.662837