NIH grant: Development and validation of human NIS-lncRNA ASO as a novel potential drug to neuropathic pain treatment (1R61NS145978-01)

retained text

NIH grant 1R61NS145978-01: Development and validation of human NIS-lncRNA ASO as a novel potential drug to neuropathic pain treatment
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Li Min  Chen. Award: $787111.
Start: 2026-09-05T00:00:00.
Summary
Chronic neuropathic pain is a complex and debilitating public health problem due to its high incidence in the
general population, associated social burden, and limited efficacy of current treatments. Opioids are the last
option for pharmacological treatment of this disorder, but an overreliance on opioid prescription for pain
management causes a significant and alarming epidemic of opioid addiction and overdose death. Developing
safe, effective, non-opioid, and non-addictive approaches is thus critically urgent. We recently identified nerve
injury-specific long non-coding RNA (NIS) as a key player and potential target in chronic neuropathic pain.
Given that the humanized NIS mouse model is not feasible and that NIS sequence and its promoter between
humans and monkeys are almost identical, this proposal will develop the antisense oligonucleotide (ASO)
specifically targeting both human and monkey NIS and validate it as a safe, non-opioid, non-addictive, long-
lasting analgesics in the nonhuman primate model of nerve injury-induced neuropathic pain. In the R61 phase,
we will first design, synthesize and purify translationally suitable ASOs and then screen these ASO candidates
by evaluating their inhibitory efficacies on high glucose- or paclitaxel-induced increases in the levels of NIS and
its downstream genes, selectivity/specificity of these inhibitory effects, and potential toxicity in cultured human
induced pluripotent stem cell-derived sensory neurons. Inhibitory efficacy of optimal NIS ASO (based on the
criteria: strongest inhibitory effect, highest selectivity/specificity, and lack of cytotoxicity) will also be validated in
cultured dorsal root ganglion (DRG) neurons from monkey or human donors. Finally, specifically inhibitory
efficacy of intrathecal optimal NIS ASO on human NIS overexpression in mouse microinjected DRGs will be
evaluated. The R33 phase will further validate optimal NIS ASO identified above in in vivo monkey model of
neuropathic pain. In Specific Aim 1, we will validate dose-dependent and long-lasting antinociception of
intrathecal optimal NIS ASO against the development and maintenance of neuropathic pain in the nonhuman
primates with unilateral L7 spinal nerve ligation (SNL) using behavioral assays, functional magnetic resonance
imaging measure and machine-learning DeepLabCut video-based analysis. The efficacy of intrathecal optimal
NIS ASO in blocking SNL-induced increases in the levels of NIS and its downstream genes in injured DRG of
monkeys will also be examined. In Specific Aim 2, potential toxicity in the DRG, spinal cord and brain regions,
central nerve system-related key dysfunctions, and systemic side effects following intrathecal optimal NIS ASO
will be monitored in the nonhuman primates. Completing this proposal will demonstrate NIS ASO as a safe, non-
opioid, non-addictive, highly efficiency and long-lasting analgesics for neuropathic pain therapies.

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