Long-lasting Analgesia via Targeted in situ Repression of NaV1.7
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA670519 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12873774_1.fastq.gz | Fastqsanger.gz | |||
| SRR12873774_2.fastq.gz | Fastqsanger.gz | |||
| SRR12873775_1.fastq.gz | Fastqsanger.gz | |||
| SRR12873775_2.fastq.gz | Fastqsanger.gz | |||
| SRR12873776_1.fastq.gz | Fastqsanger.gz |
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Project description:Current treatments for chronic pain rely largely on opioids despite their significant side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Towards this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both epigenome-engineering 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: i) effective repression of NaV1.7 in lumbar dorsal root ganglia; ii) reduced thermal hyperalgesia in the inflammatory state; iii) decreased tactile allodynia in the neuropathic state; and iv) no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain prevention and 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 in management of persistent pain states.
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