Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Abstract

One sentence summary:In situ epigenome engineering approach for genomically scarless, durable, and non-addictive management of pain. ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, Na V 1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development.Specifically, a hereditary loss-of-function mutation in Na V 1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain.Towards this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both genomeengineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of Na V 1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7, a methodology we dub pain LATER, will have significant therapeutic potential, such as for preemptive administration in 2 anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.

The mechanism of analgesia in NaV1.7 null mutants

“…12 For intractable chronic pain, gene therapy strategies that mimic genetic loss-of-function will likely be required. 56 Taken together, these data support a mechanism where pain insensitivity of mice and humans lacking NaV1.7 principally involves opioid receptors ( Figure S6). Diminished peripheral excitability and die-back may also contribute to analgesia, but opioid-mediated suppression of neurotransmitter release plays a major role.…”

Acupoint Injection of Dextrose Attenuates Chronic Inflammatory Pain In Mice Through Modulation of Transient Receptor Potential V1 Channel Expression

“…Overexpression of the voltage-gated sodium channels Nav1.7 and Nav1.8 have also been observed in the DRG and SC of acute pain model animals [29]. Conversely, suppression of Nav1.7 was associated with long-lasting analgesia [30]. Furthermore, Nav1.8 is highly expressed by nociceptive sensory afferents, and expression increases during chronic pain [31].…”

A Biopsychosocial Model-Based Clinical Approach in Myofascial Pain Syndrome: A Narrative Review

“…Although a recent study by Moreno AM et al, 2021, which was conducted in mice, suggests that the clustered regularly interspaced short palindromic repeats-Cas9 (CRISP-Cas9) new technique could reduce or block genes (polymorphisms) encoding channels (NaV1.7 at Neuro2A cells in lumbar dorsal root ganglia), so an effective reduction in pain sensitivity occurs. Maybe similar studies will be soon conducted in humans [ 46 ].…”