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Schwann cell gene therapies in sight

Gene Therapy volume 28, pages 618–619 (2021)Cite this article

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Only a decade ago, the drug development pipeline for inherited peripheral neuropathies was largely empty. Patients were left with few options and a depressing outlook for themselves and their children. Today, while physicians still do not have approved drugs in hand, a number of encouraging developments, chiefly in the genetic therapy field, spread cautious optimism. Once considered an impossible target for therapies, lower motoneurons, with their cell bodies located in the ventral horn of the spinal cord, have emerged as a highly promising cell population for different gene therapy approaches. Foremost, treatment of spinal muscular atrophy type I is now well-established with several genetic therapy products on the market. The same lower motoneurons give rise to peripheral nerve axons. These are involved in many genetically defined diseases, affecting peripheral nerves in a length-dependent manner. Creating gene therapies for peripheral nerve disorders should therefore, in principle, benefit from the experience gathered by FDA-approved motoneuron therapies. In reality, the targeting of peripheral nerves poses several specific challenges that were impressively addressed in a study by Kagiava et al. [1] in this issue.

Inherited peripheral neuropathies, often referred to as Charcot–Marie–Tooth disease (CMT), comprise over 100 genetically defined Mendelian disorders. Collectively, CMT represents one of the most common inherited diseases in the field of neurology with a prevalence of 1–1250 to 1–2500 [2]. By some estimates, the majority of these patients have the demyelinating form, with a primary pathophysiology in Schwann cells [3]. Schwann cells surround axons that run in peripheral nerves and create a highly specialized anatomical structure called the myelin sheath. The myelin sheath, in its most extreme form, represents a stack of densely layered membranes around axons, which are essential for high signal conduction velocity in all motor and some sensory nerve fibers. While we arguably do not fully understand the many functions of Schwann cells, it is clear that they maintain the integrity of the very long peripheral axons. When Schwann cells degenerate, such as in CMT type 1, peripheral nerve fibers are demyelinated, axons are damaged, and a dying-back process is activated known as Wallerian degeneration. Physiological regenerative attempts are usually limited and lead to irregularly layered myelin sheaths observable as “onion bulbs” in histological sections.

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  1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA

    Stephan Züchner

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Züchner, S. Schwann cell gene therapies in sight. Gene Ther 28, 618–619 (2021). https://doi.org/10.1038/s41434-021-00264-8

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