A potential gene therapy approach for long-term alleviation of neuropathic pain

Neuropathic pain is caused by a lesion or disease of the somatosensory system and affects 7–10% of the general population. Patients typically experience a distinct set of symptoms, such as burning and electrical-like sensations, and pain resulting from non-painful stimulations. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signaling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. To better management of neuropathic pain and develop personalized interventions there is a need to understand the pathophysiology of neuropathic pain.

Microglia are the principal immune cells in the central nervous system and they rapidly expand after peripheral nerve injury. Several studies demonstrated a complex molecular and cellular interaction between microglia and spinal dorsal horn neurons that can lead to the development of neuropathic pain after peripheral nerve injury. Injured neurons located in the dorsal root ganglia release signaling molecules such as colony-stimulating factor 1 (CSF1). CSF1 stimulates microgliosis in the dorsal horn of the spinal cord. At the onset of nerve injury, there is an increased expression and release of CSF1 along with a concomitant rise in CSF1 receptors.

Novel ways to inhibit CSF1 signaling pathway in the development of neuropathic pain forms the foundation of a new study by Svetlana Gushchina, Dr. Ping Yip, Dr. Glesni Parry, Dr. Haripriya Sivakumar, Dr. Jie Li, Dr. Min Liu, Dr. Xuenong Bo from the Queen Mary University of London. The researchers devised a molecular theory based on a three-pronged approach to alleviate neuropathic pain. The three-pronged model comprises microglia proliferation in spinal cord dorsal horn, macrophage accumulation in dorsal root ganglia (DRG) and the injured peripheral nerve. The key objective of this study was to alleviate neuropathic pain without affecting microglia, macrophages, and dendritic cells in other parts of the central and peripheral nervous systems, and other organs. The original research article is now published in the journal Glia.

Using an animal model of neuropathic pain, the authors intrathecally injected an adeno-associated viral vector (AAV) expressing a soluble non-functional CSF-1 receptor (sCSF1R). The idea is that the sCSF1R is released from AAV-transduced cells and acts as a decoy receptor, to reduce the CSF1 binding to its native functional receptors on the microglia and macrophages, hence preventing their proliferation.  The research team revealed that the overexpression of sCSF1R in DRG neurons resulted in suppression of microgliosis in the dorsal horn of the spinal cord induced by a partial ligation of a sciatic nerve, a commonly used model of neuropathic pain. sCSF1R is also released inside the DRG and the injured sciatic nerve, reducing the infiltration and proliferation of macrophages. Accumulation of macrophages in DRG and injured nerves is reported to contribute to neuropathic pain as well. The three-pronged action of sCSF1R leads to attenuation of mechanical allodynia associated with peripheral nerve injury.

Long-term and localized administration of therapeutic substances is effective for alleviating neuropathic pain by preventing microgliosis in the spinal cord and suppressing macrophage accumulation in the DRG. Unlike the small chemical based CSF1R antagonists, this molecular therapy approach does not deplete microglia in the spinal cord. According to the authors, this is safe and effective for microglia, monocytes, and macrophages in other areas of the central and peripheral nervous system. Hence the strength and function of the immune system remain unaffected.

In summary, the Queen Mary University of London scientists demonstrated using elegant molecular and cellular neurobiology experiments, the efficacy of increased expression of sCSF1R in the alleviation of neuropathic pain mediated by the suppression of microgliosis and accumulation of macrophages. This novel therapeutic strategy influences both the central and peripheral nervous systems in modulating neuropathic pain. The new study provides an opportunity for the development of treatment modalities based on the sCSF1R for treating neuropathic pain and neurodegenerative diseases.