Journal
PHARMACEUTICALS
Volume 14, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/ph14060565
Keywords
human pluripotent stem cells; motor neuron diseases; gene editing; neurodegeneration; axonopathy; amyotrophic lateral sclerosis; spinal muscular atrophy; gene therapy; antisense oligonucleotides; viral vectors
Categories
Funding
- Spastic Paraplegia Foundation
- National Institute of Health [R21NS109837, R01NS118066]
- Blazer Foundation
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Recent advancements in iPSC technology and gene editing tools have enabled the generation of motor neuron disease models for dissecting pathogenic mechanisms and exploring potential therapeutics. Targeted gene therapies including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing have been developed to address the critical role of genes in motor neuron diseases.
Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.
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