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Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology of the human disease, and sometimes accurately recreate the genetic perturbations found in patients. Ideally, models achieve both, but this is not always possible; nonetheless, such models are informative. Here we describe two animal models of inherited peripheral neuropathy: mice with a mutation in tyrosyl tRNA‐synthetase, YarsE196K, modeling dominant intermediate Charcot‐Marie‐Tooth disease type C (diCMTC), and mice with a mutation in serine palmitoyltransferase long chain 1, Sptlc1C133W, modeling hereditary sensory and autonomic neuropathy type 1 (HSAN1). YarsE196K mice develop disease‐relevant phenotypes including reduced motor performance and reduced nerve conduction velocities by 4 months of age. Peripheral motor axons are reduced in size, but there is no reduction in axon number and plasma neurofilament light chain levels are not increased. Unlike the dominant human mutations, the YarsE196K mice only show these phenotypes as homozygotes, or as compound heterozygotes with a null allele, and no phenotype is observed in E196K or null heterozygotes. The Sptlc1C133W mice carry a knockin allele and show the anticipated increase in 1‐deoxysphingolipids in circulation and in a variety of tissues. They also have mild behavioral defects consistent with HSAN1, but do not show neurophysiological defects or axon loss in peripheral nerves or in the epidermis of the hind paw or tail. Thus, despite the biochemical phenotype, the Sptlc1C133W mice do not show a strong neuropathy phenotype. Surprisingly, these mice were lethal as homozygotes, but the heterozygous genotype studied corresponds to the dominant genetics seen in humans. Thus, YarsE196K homozygous mice have a relevant phenotype, but imprecisely reproduce the human genetics, whereas the Sptlc1C133W mice precisely reproduce the human genetics, but do not recreate the disease phenotype. Despite these shortcomings, both models are informative and will be useful for future research. [ABSTRACT FROM AUTHOR]

• We describe gene replacement, knockdown, and splicing gene therapy approaches. • We highlight successful gene therapy approaches for neuromuscular diseases. • We provide candidate disorders to be the next targets for gene therapy. Nearly one-hundred loci in the human genome have been associated with different forms of Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Despite this wealth of gene targets, treatment options are still extremely limited, and clear "druggable" pathways are not obvious for many of these mutations. However, recent advances in gene therapies are beginning to circumvent this challenge. Each type of CMT is a monogenic disorder, and the cellular targets are usually well-defined and typically include peripheral neurons or Schwann cells. In addition, the genetic mechanism is often also clear, with loss-of-function mutations requiring restoration of gene expression, and gain-of-function or dominant-negative mutations requiring silencing of the mutant allele. These factors combine to make CMT a good target for developing genetic therapies. Here we will review the state of relatively established gene therapy approaches, including viral vector-mediated gene replacement and antisense oligonucleotides for exon skipping, altering splicing, and gene knockdown. We will also describe earlier stage approaches for allele-specific knockdown and CRIPSR/Cas9 gene editing. We will next describe how these various approaches have been deployed in clinical and preclinical studies. Finally, we will evaluate various forms of CMT as candidates for gene therapy based on the current understanding of their genetics, cellular/tissue targets, validated animal models, and availability of patient populations and natural history data. [ABSTRACT FROM AUTHOR]