Charcot-Marie-Tooth (CMT) is a heterogeneous group of disorders. Among them, CMT2A is relatively common; it is characterized by selective damage of motor neurons (MNs) and sensory neurons (SNs), which is clinically expressed by progressive muscle weakness and sensory loss in patients affected. Further signs and symptoms may characterize the disease. It is caused by missense mutations in Mitofusin 2 gene (MFN2) transmitted with autosomal dominant inheritance pattern. MFN2 encodes for the homonymous protein that is a GTPase protein expressed in the outer mitochondrial membrane (OMM) and mainly involved in the regulation of the mitochondrial network. MFN2 mutations seem to induce disease with a “dominant-negative” mechanism, where the expression of the wild-type MFN2 allele is negatively regulated by the mutant protein.
The establishment of induced pluripotent stem cells (iPSCs) from patient’s skin fibroblasts or other somatic cell sources may advance knowledge into pathophysiology and therapeutic targets. Mitochondrial content and its correlation to the rate of mitophagy, impairment of the mitochondrial transport along axons and susceptibility to apoptosis could be analysed in iPS-derived motor neuron cells.
Although no effective treatment exists, molecular silencing of mutant pathological protein, in combination with restoration of wild-type activity, represents a possible strategy for this disease, such as those based on a RNA interfering (RNAi)/gene therapy which at the same time would silence the mutated allele through shRNA and induce the expression of the native allele through a mutagenized copy of MFN2.
Validation of the RNAi/gene therapy in fibroblasts and induced pluripotent stem cells (iPSCs) derived from CMT2A patients might be a relevant strategy in this field.
Spinal muscular atrophy (SMA) is a neuromuscular disease, characterized by the progressive loss of motor neurons in the spinal cord, which leads to muscle weakness and atrophy. SMA remains the leading inherited cause of infant mortality. The condition is caused by the depletion of survival motor neuron (SMN) protein due to mutations in the SMN1 gene.
During the last decades the development of reliable cellular and animal models were instrumental for understanding the disease mechanisms and developing therapeutics in SMA.
Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, have opened up the possibility of generating a substantial amount of disease-specific cells, including motor neurons and glial cells implementing not only 2D, but also 3D platforms. Now drug molecules, antisense oligonucleotide, and gene therapy approaches, all of which had a major impact in cells and animal models of SMA, are used in clinic with positive results.
Nusinersen, an antisense oligonucleotide that modulates the splicing of the SMN2 mRNA, is the first therapy approved for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN showed positive results in survival and motor milestones achievement. Furthermore, other additional therapeutic options are in the pipeline, including modulation of SMN2 transcripts with small molecules, neuroprotective agents, and compounds that act on other peripheral targets. We discuss the challenges from implementing innovative models to understand novel mechanisms and to develop effective treatments for patients with SMA.
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