Pain Relief With Interference shRNA Proves Viable

Figure 1: Confocal micrograph of pain sensing neurons of rat trigeminal ganglion stained for TRPV1 (green) and neurofilament – M (red) targeted with therapeutic vectors. 

Pain is the number one cause of distress, signaling the onset of tissue damage. In the vast majority of cases, pain sensation is induced by the overstimulation of specific types of sensory nerve fibers, which respond to injurious stimuli that reach or exceed a tolerable intensity threshold.

The aim of the wise is not to secure pleasure, but to avoid pain – Aristotle

Contingent upon the site of origin, two types of pain (i.e. somatic and visceral) can be distinguished, whereas based on modality, pain sensation is most commonly classified into three categories: thermal (induced by heat or cold), chemical (induced by corrosive stimuli or inflammatory factors) or mechanical (tearing or crushing). Just as the most recognized factors and debilitating manifestation of a disease can vary widely so too does the degree of pain interference that contributes to life quality. Depending on the intensity of pain-related distress, the sensation can range from mild localized discomfort to generalized agony capable of lapsing into life-threatening neurogenic shock due to overactivation of the parasympathetic nervous system.

Currently, between 20 – 70% of pain cases are amenable to existing medications yet the wide range of remaining pain-related conditions represent a major source of suffering and a serious healthcare problem. Moreover, the majority of currently used analgesic drugs have limited safety margin, carry the risk of addiction and potential dangerous off-target effects. Thus, there is a pressing need for a novel and effective means for better pain management with the ideal analgesic treatment anticipated to show high selectivity, tolerability and long-acting effects localized to the site of injury or distress.

Discovery of such a ‘dream-drug’ was the prime motivation for researchers from the International Centre for Neurotherapeutics at Dublin City University, Ireland in collaboration with the Institute for Biological and Medical Imaging at Helmholtz Zentrum Munchen, Germany. This yielded promising results with the use of a new, gene therapy based method that utilizes the targeting of lentiviral particles for retrograde axonal delivery of TRPV1 receptor interference shRNA to pain-sensing neurons of the trigeminal ganglion in a murine model. Known also as a receptor for capsaicin, the pungent ingredient in hot chili peppers, TRPV1 is enriched in C and type 2 A-δ pain-sensing afferents and has been implicated in the molecular processes of painful sensation, with its depletion expected to render sensory axons irresponsive to pain.

One of the key challenges in depleting TRPV1 in nociceptors is the development of effective mechanisms for specific targeting and transfer of anti-TRPV1 therapeutic shRNA to pain-sensing neurons. Indeed, the poor accessibility and tight protection of sensory neurons by the blood-brain barrier prevent the vast majority of therapeutics from reaching sensory neurons and the brain where pain sensation unfolds. Advantageously, the majority of neurons and axons that mediate pain sensation rely on a supply of trophic factors from the peripheral tissue and therefore are enriched with specific neurotrophin receptors for their binding and internalization.

The researchers used an IgG192 antibody against one of the neurotrophin receptors (p75 receptor) to target viral particles to pain-sensing nerve endings at the periphery. This enhanced the entry and load of viral particles onto axonal transport compartments in type C and 2 A-δ afferents only. By inserting a small shRNA encoding gene into viral particles, capable of neutralizing the transcripts for TRPV1 receptors in sensory neurons, depletion of pain-sensing TRPV1 receptors has been achieved. This was proven by the loss of the neuronal response to the active ingredient of chili pepper capsaicin, as revealed in electrophysiological and behavioral tests. Through such a highly specific and targeted approach, the widely sought after ‘magic-bullet’ for long-lasting pain elimination has been achieved. This innovative methodology and promising experimental results have been published in the recent study led by Dr. Valerie B. O’Leary in the journal of Neurotherapeutics.

The researchers are hopeful that their approach holds major potential for the development and optimization of future gene-therapy based anti-nociceptive interventions. It is envisioned that these will lead to better management of drug-resistant pain of various origins, including chronic neuropathic pain, neuroinflammatory disorders resultant of hypersensitivity of peripheral sensation, and potentially cancer pain. On the road towards what Aristotle regarded as the greatest goal of the wise, this development is a significant step in the direction of permanent pain avoidance.

This work was directed by Saak V. Ovsepian, MD, Ph.D., Adjunct Professor; Institute of Biological and Medical Imaging at Helmholtz Zentrum Munchen, Germany & International Centre for Neurotherapeutics, Dublin City University, Dublin, Republic of Ireland.

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