Nerve Connect

Vol. 8, July 2023

2023 PNS Education Course – Featured Scientific Articles by Junior Members, Vol. 8, July 2023

Jul 26, 2023 | Nerve Connect

Navigating New Developments in the Pain Field

It’s an interesting time to be a basic scientist in pain!

By Asta Arendt-Tranholm, PhD, Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas

At the 2023 annual meeting of the Peripheral Nerve Society, I had the pleasure of attending a talk by Dr Grace Ji-eun Shin, an incoming assistant professor at Ohio State University. The topic was one which all of us will at some point have intimate experience with: Pain.

Pain serves as a vital protective mechanism, ensuring we remove our hands from a burning pot. In contrast, chronic pain is a leading cause of disability worldwide. Treatments for chronic pain are for many inadequate, highlighting the need for a better understanding of the underlying cause. The last decade has seen an explosion of new information within the field of pain research. Pain sensation is traditionally described as being conveyed by specialized nerve cells called nociceptors. These cells stretch all the way from our spinal cord to our fingertips, where they sense stimuli capable of damaging the body. Recent research, summarized by Dr Shin, suggests other cell types including skin-cells (keratinocytes), immune cells (macrophages), and Schwann cells, which traditionally provide support to nerve cells, may also play a key role in the initiation and maintenance of chronic pain.

So how do we ensure that our advanced understanding of basic mechanisms of pain translates to meaningful outputs in the clinic for pain patients? Dr Shin highlighted an increase in research looking directly at human cells, as well as animal models looking specifically at human pain mechanisms. “There are still lots of unanswered questions,” Dr Shin said, “but we have the best refined understanding of pain mechanisms at present.” These new paths are now being explored with the hope of finding novel treatments for chronic pain in humans.


Towards a Cure: Pioneering Research in CMT1X Therapy

How do you treat neuropathy caused by a faulty gene?

By George C. Murray, Graduate Candidate, Laboratory of Dr. Robert W. Burgess, The Jackson Laboratory, Graduate School of Biomedical Science and Engineering, The University of Maine

At PNS 2023, Dr. Alexia Kagiava of The Cyprus Institute of Neurology & Genetics discussed progress toward a gene therapy for X-linked Charcot-Marie-Tooth disease type 1 (CMT1X). CMT1X is a neuropathy caused by a faulty copy of the gene GJB1, also called a GJB1 variant. The disease leads to muscle weakness, loss of reflexes and loss of sensation. Dr. Kagiava’s team have developed a gene therapy that improved symptoms in mice with CMT1X but continue to grapple with specific variants that resist treatment.

The symptoms of CMT1X stem from any one of hundreds of different GJB1 variants. Mice lacking this gene cannot make Connexion32, a channel protein that allows axons — the cellular wiring of the nervous system — to communicate with Schwann cells. As a result, these mice have shrunken axons and show a progressive loss of myelin — the fatty insulation created by Schwann cells to insulate axons.

Dr. Kagiava shared how mice lacking the Gjb1 gene have impaired nerve signaling, mirroring effects of GJB1 variants in patients. Her team used a viral particle, called a lentivirus, to deliver a healthy copy of the human GJB1 gene into these mice in an approach called gene addition. This improved nerve function and strength, but wasn’t effective for mice with other CMT1X variants. In some cases, interaction between the faulty protein and healthy virally delivered therapeutic protein, called a dominant-negative effect, prevented symptom improvement.

In a forthcoming article Dr. Kagiava takes aim at these problematic Gjb1 variants using a different viral delivery method. “[Spinal] delivery of [adenovirus] resulted in improved functional and morphological outcomes,” said Dr. Kagiava, “providing a more translatable approach.”

A treatment for CMTX1 just got one step closer.