Wide varieties of peripheral neuropathies accompanied by severe chronic pain are among the most common and debilitating human afflictions. Existing treatments have little long term benefits and often have severe side effects. Increasing evidence indicates that pathologies in the structure and chemistry of the skin and its innervation are likely contributors to painful peripheral neuropathies and are a high priority target for potential therapeutics. Moreover, the skin and its innervation are frequent sites of drug side effects. Consequently, punch biopsies of human skin are increasingly being used as a tool for diagnosing peripheral neuropathies and for assessing the efficacy and risk of potential therapeutics. Instead of tapping the full diagnostic potential of these valuable biopsies, most analyses have been limited to few biomarkers such as the sole use of anti-PGP9.5 to assess the density of sensory endings strictly in the epidermis. This phase I STTR submission proposes to vastly expand the utility of skin biopsies by integrating multi-immunolabeling analyses of biopsy structure and chemistry (particularly the innervation) with laser-capture microdissection assessments of the genomics and transcriptomics of intrinsic skin cellular components (e.g. epidermis, hair follicles, blood vessels, papillary dermis). The founders of Integrated Tissue Dynamics LLC (Intidyn) have decades of documented experience in using extensive multimmunolabeling to assess the morphology and biochemistry of cutaneous innervation in a variety of experimental animal models and in human neuropathic conditions. This expertise has documented pain-related pathologies among different types of cutaneous innervation, not only in the epidermis, but also in association with hair follicles and vasculature. Importantly, their recent immunochemical findings have shown that keratinocytes in the epidermis play a direct role in skin sensation, and that pathologies in the epidermal chemistry likely contribute to chronic pain. Intidyn was recently founded to increase the infrastructure to the growing demand for this expertise from the public and private sector. Recognizing the importance of the intrinsic skin pathology to the diagnosis and treatment chronic pain, this Phase 1 STTR proposal is designed to integrate our immunochemical expertise with genomic and transciptomic assays. Biopsies from normal humans and patients with postherpetic neuralgia, will be compared by using alternating sections for immunofluorescence and genomic and transcriptomic arrays.
A wide variety of peripheral neuropathies, such as diabetic and shingles-related neuropathies, are among the most common and debilitating human afflictions due to the occurrence of severe, intractable pain. Existing treatments have little long term benefits and often have severe side effects. The funding requested in this Phase I STTR proposal is to translate the Principal Investigators'extensive research experience on peripheral nerve diseases to large scale pharmaceutical development of more effective therapeutics. Recently, several lines of evidence have implicated the skin as a potential contributor to neuropathic pain with significant alterations occurring in both the cutaneous innervation and the immunochemistry of the skin. Here, funding is requested to further characterize the pathologic mechanisms present in skin from patients with PHN by integrating protein immunochemistry results with genomic and transcriptomic data each obtained from the same punch biopsy. The results will greatly aid the development of novel and efficacious therapeutic interventions directed at the skin.
