Gene Therapy: A Promising Future for Inherited Peripheral Neuropathy

peripheral neuropathy written in a notebook on white table
Gene therapy shows promise in the management of inherited peripheral neuropathy and the complex array of symptoms that patients experience. Gene therapy holds promise in the management of peripheral neuropathies and in significant improvement of quality of life for patients.

Peripheral neuropathy is an umbrella term for a number of conditions in which there is degeneration of peripheral nerves. There are over 150 different causes of peripheral neuropathy, including heredity, diabetes, autoimmune disorders, and chemotherapy. The leading cause is diabetes, with about 60-70% of people with diabetes developing the condition. Overall, it is estimated that almost 20 million people in the United States currently live with some form of peripheral neuropathy.1 

Limitations of currently available treatments

While not always life-threatening, peripheral neuropathies damage both sensory and motor nerves, leading to a complex array of symptoms that can significantly impact quality of life. Currently, management of neuropathy has two arms – palliative control of symptoms and addressing the root cause of the disease to prevent progression. Palliative treatment may include the use of specific medication for chronic neuropathic pain or mechanical aids for motor weakness.

Addressing the root cause of the disease depends on the disease itself, and may involve strict glucose control for diabetes or immunosuppressive medication for autoimmune diseases. In this regard, treatment of inherited peripheral neuropathy (IPN) poses a challenge as the cause is genetic. Today, treatment of IPN is based on modifying the cellular response to degeneration, rather than addressing the cause. “There is no clear mode of action,” explained Dr Young Bin Hong, Associate Professor of Biochemistry at Dong-A University, Korea. “While such drugs, especially small molecules, have advantage in the proof of safety, the disease-modifying efficacy is still questionable.” There is, therefore, a need to find drugs that address the cause of nerve degeneration and halt the process.

How gene therapy can transform management of peripheral neuropathy

Gene therapy introduces selected sections of DNA into the human body to dictate cellular functioning. The main feature of peripheral neuropathy is axonal degeneration. Therapeutic genes operate at the cellular level to suppress factors causing such degeneration and to induce an environment that is conducive to axonal growth and regeneration.  

In IPN, therapeutic genes can go one step further and target the underlying cause.  “IPN is essentially a genetic disease,” stressed Dr Hong. “The ultimate treatment option would be to ‘fix’ the abnormal copy of the target gene.” He added that gene therapy directly addresses the cause of the disease by preventing the mutant gene from expressing itself. Dr Hong and his team recently reviewed the various kinds of gene therapy available for IPN and their current status.2 They describe four key kinds of gene therapy:

  • Gene addition: The Neurotrophin-3 gene is known to influence proliferation and migration of Schwann cells, and release of neurotrophic factors, all of which aid in axonal growth. NT-3 has been shown to induce axonal regeneration in mouse models. A Phase I/IIa trial is currently evaluating the effect of the NT-3 gene in patients with Charcot-Marie-Tooth Neuropathy (CMT) type 1A ( Identifier: NCT03520751).
  • Gene replacement: This approach is suitable when the IPN is caused by a single defective gene. For instance, CMT type 4c is an autosomal recessive condition caused by a defective SH3TC2 gene. Studies in mouse models have shown that replacing this gene with the target gene improved myelination and motor behaviour.3 One of the first clinical trials for inherited peripheral neuropathy, which involves gene replacement, is still ongoing ( Identifier: NCT02362438). This trial aims to assess the efficacy of intrathecal administration of the GAN1 gene in patients with Giant Axonal Neuropathy. Previous studies in mouse models have proven the efficacy of the same gene/vector combination in restoring normal neuronal configurations.
  • Gene silencing: Defective genes can sometimes result in the development of mutant proteins that can cause demyelinating nerve injuries. In such cases, antagonist genes that ‘silence’ the defective genes may be employed. This method, when used in mouse models with CMT 1A, has shown improvement in locomotor coordination.4 
  • Gene editing: This therapy aims to modify the activity of the defective gene. CMT1A, for instance, is characterized by over-expression of the PMP22 protein. Therapeutic genes such as CRISPR/Cas9 can downregulate the expression of PMP22, normalizing its levels. This therapy may be more effective at disease onset or in the early stages, as it helps prevent axonal degeneration.

Outside of inherited causes, the main focus of gene therapy in this field has been for diabetic neuropathy. A recently published clinical trial evaluated the use of the therapeutic gene VM202 for diabetic neuropathy. This gene drives expression of Hepatocyte Growth Factor (HGF), which has potent neurotrophic and angiogenic activities. Patients who received VM202 experienced significant, long-lasting pain relief, as compared to patients who received a placebo.6 In-vitro studies have also shown the effectiveness of gene silencing in alleviating nerve injury caused by diabetic neuropathy.7

Challenges of gene therapy

One of the key concerns with gene therapy is the use of viral vectors, which carry the risk of virulence mediated immunotoxicity or genotoxicity. “Safety issues might be the primary consideration,” said Dr Hong. “In the past, gene therapy has usually been tried clinically for critical diseases that carry high lethality. From that perspective, peripheral neuropathy has a moderate phenotype.” One way to overcome safety concerns, he added, is to expand the use of nonviral, target specific delivery.

Another challenge appears to be the difficulty in establishing clinical efficacy. “Because the disease phenotype progresses very slowly, it is challenging to establish the primary outcome in clinical trials,” Dr Hong noted. He added, “Thus far, gene therapy has shown sufficient efficacy in animal experiments, which have had sufficient time to regenerate the peripheral neuropathy. However, the same timeframe – which can be a couple of years – may not be enough to demonstrate efficacy in human trials.”

The future of gene therapy

While research in gene therapy is steadily growing, this is yet to be translated into clinical practice. However, this is likely just a matter of time, as several clinical trials are already underway in patients. “Intriguingly, all the treatments under clinical evaluation apply different types of gene therapy,” said Dr Hong. He believes that the results of these trials, which are imminent, will be to establish both safety and efficacy, promising hope to the significant proportion of people waiting for a cure for peripheral neuropathy.


1. National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. Published 2020. Accessed March 29, 2021.,for%20all%20forms%20of%20neuropathy

2. Thenmozhi R, Lee JS, Park NY, Choi BO, Hong YB. Gene Therapy Options as New Treatment for Inherited Peripheral Neuropathy. Exp Neurobiol. 2020;29(3):177-188. doi:10.5607/en20004

3. Schiza N, Georgiou E, Kagiava A, et al. Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy. Brain. 2019;142(5):1227-1241. doi:10.1093/brain/awz064

4. Lee JS, Kwak G, Kim HJ, Park HT, Choi BO, Hong YB. miR-381 Attenuates Peripheral Neuropathic Phenotype Caused by Overexpression of PMP22. Exp Neurobiol. 2019;28(2):279-288. doi:10.5607/en.2019.28.2.279

5. Lee JS, Lee JY, Song DW, et al. Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice. Nucleic Acids Res. 2020;48(1):130-140. doi:10.1093/nar/gkz1070

6. Kessler JA, Shaibani A, Sang CN, et al. Gene therapy for diabetic peripheral neuropathy: A randomized, placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Clin Transl Sci. Published online January 19, 2021. doi:10.1111/cts.12977

7. Chen J, Li C, Liu W, Yan B, Hu X, Yang F. miRNA-155 silencing reduces sciatic nerve injury in diabetic peripheral neuropathy. J Mol Endocrinol. 2019;63(3):227-238. doi:10.1530/JME-19-0067