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Recombinant dimeric PICK1 protein inhibitors for long-term relief of chronic pain by AAV therapeutics

ABSTRACT: Chronic neuropathic pain’s impact, persistence, and limited treatments render it relevant for gene therapy. Here, we describe the development and application of self-assembling dimeric peptide inhibitors of the pain-associated scaffolding protein PICK1 (protein interacting with C-kinase 1) delivered by adeno-associated viral (AAV) vectors. In mice, these peptides prevented mechanical allodynia in inflammatory and neuropathic pain models and reversed neuropathic pain for up to one year. Targeting of somatosensory pain pathways relieved pain without overt side effects, while selective transduction of dorsal root ganglion (DRG) neurons was sufficient for providing pain relief. Using proteomic and phosphoproteomic analysis of DRG tissue, we identified protein kinase C alpha (PRKCA) substrate candidate, that potentially shape this pain-relieving phenotype. We also confirmed PICK1 expression and peptide target engagement in mice and human donor tissue, supporting the potential of AAV-based PICK1 inhibitors as a clinically meaningful strategy for neuropathic pain conditions.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spinal Ganglion

SUBMITTER: Antonio Marino

LAB HEAD: Andreas T. Sørensen

PROVIDER: PXD073925 | Pride | 2026-04-10

REPOSITORIES: Pride

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			Action	DRS
	20250514_ASC1_NEO3_PRI_Trap_IO25cm_120min_P0059_R1634_Phospho_TMT32_X2784_MS3_MSA_RTS_FDR_Fr1.raw	Raw
	20250514_ASC1_NEO3_PRI_Trap_IO25cm_120min_P0059_R1634_Phospho_TMT32_X2784_MS3_MSA_RTS_FDR_Fr10.raw	Raw
	20250514_ASC1_NEO3_PRI_Trap_IO25cm_120min_P0059_R1634_Phospho_TMT32_X2784_MS3_MSA_RTS_FDR_Fr10_0_-571137486_realtimesearch.tsv	Tabular
	20250514_ASC1_NEO3_PRI_Trap_IO25cm_120min_P0059_R1634_Phospho_TMT32_X2784_MS3_MSA_RTS_FDR_Fr11.raw	Raw
	20250514_ASC1_NEO3_PRI_Trap_IO25cm_120min_P0059_R1634_Phospho_TMT32_X2784_MS3_MSA_RTS_FDR_Fr11_0_-571137486_realtimesearch.tsv	Tabular

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Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).

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Recombinant dimeric PICK1 protein inhibitors for long-term relief of chronic pain by AAV therapeutics

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