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NIH grant 1I01RD000444-01A2: Targeted Degradation of Sodium Channel Nav1.8 for Analgesia
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Stephen Waxman. Award: $.
Start: 2026-10-01T00:00:00.
Significance to the VA: Chronic intractable pain is highly prevalent in Veterans, and often leads to disability,
mental health challenges, and an increased risk of suicide, particularly in Veterans with PTSD or other comorbid
conditions. Widely used opiates are addicive and not very effective for chronic pain, and the newly approved of
sensory neuron-selective sodium channel Nav1.8 blocker Suzetrigene has a moderate effect size with a
significant number of non-responsive patients. Additional therapy options are needed. The goal of our research
is to develop a new analgesic through targeted degradation of Nav1.8, which is essential for repetitive firing in
dorsal root ganglion (DRG) neurons, thus avoiding CNS side effects and potential for addiction. The development
of effective, durable and non-addictive analgesic will have a positive impact on the quality of life of Veterans,
enable more effective rehabilitation and mitigate conditions leading to attempted suicide among Veterans.
Innovation and Impact: Our approach for the development of a novel selective bifunctional protein, UbiquiNaV,
which targets the reduction of the Nav1.8 channel levels at the cell surface of nociceptors and act as an analgesic
is conceptually innovative. Using live imaging experiments in DRG neurons to investigate the mechanisms
underlying spatial and temporal regulation of NaV1.8 channels are technologically innovative. UbiquiNaV will
demonstrate the viability of selective sodium channel degradation as a modality for a non-addictive therapy of
chronic pain and an investigative tool to fill foundational knowledge gaps about the life cycle of the channel.
Specific Aims: Our overall goal is to show that targeted degradation of a specific channel, Nav1.8, is an
innovative gene therapy approach to treat intractable pain. We propose 3 related but independent aims,
supported by extensive pilot data. SA1) Determine channel and neuronal selectivity of UbiquiNaV. We will
determine whether UbiquiNaV is selective against NaV1.8 channels and does not impact other NaV channels or
other components of the electrogenisome in PNS and CNS neurons. SA2) Determine mechanism of action of
UbiquiNaV against NaV1.8 channels. We will elucidate the mechanism of action of UbiquiNaV and its regulation
of time-dependent regulation of distribution of the channel at the cell surface of DRG neurons. SA3) Evaluate
UbiquiNav as an analgesic agent. We will investigate the analgesic effect of UbiquiNaV in pre-clinical models of
acute inflammatory pain (TNF-α) and in a chronic neuropathic pain model (spared nerve injury).
Methodology: We will use our newly developed live imaging of channel trafficking in sensory neurons and
high throughput automated electrophysiology, together with manual patch-clamp electrophysiology (voltage-
and current-clamp recordings) to assess selectivity of UbiquiNav at the channel and cellular levels, and
biochemical methods to study ubiquitination of the channel. Pain will be assessed using a battery of tests
including affective aspects of pain, and behavioral data will be correlated with electrophysiological recordings
in DRG neurons. Scientific rigor will be ensured by randomization of animals for the different control and
experimental groups and blinding of experimenters to conditions. Appropriate controls, requisite replicates and
power analysis to determine sample sizes are included in the experimental design. Sex and age as biological
variables are considered. Necropsy analysis and neurodegeneration biomarker will be used to assess toxicity.
Path to Translation: While AAV-based gene therapy is relatively invasive, it has the potential to be efficacious
and durable and provides a treatment approach for a significant Veteran population with chronic pain who do not
respond to other treatments and are at a higher risk of suicide. To advance this program to T0-3 level and de-
risk clinical development, future studies will test UbiquiNav in animal models of diabetic neuropathy and
chemotherapy induced pain, which recapitulate aspects of common pain disorders among Veterans. In line with
the new FDA and NIH directive to use more human tissue in pre-clinical studies, we will also test UbiquiNav in
human DRG neurons and sensory neurons differentiated from induced pluripotent stem cells.document fetched 2026-10-24 02:46