The rare genetic Disorder pachyonychia congenita (PC) results from dominant mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. While disabling painful plantar Keratoderma is commonly accepted as the primary symptom affecting patient quality of life, hyperhidrosis appears to contribute to Blister formation and Pain. Supporting the involvement of hyperhidrosis to PC Pain, several teams worldwide have shown that multiple intradermal Injections of botulinum toxin (BTX), known to effectively treat hyperhidrosis, substantially reduce Pain and blistering in PC Patients (similar results were observed with the related genodermatosis, Epidermolysis Bullosa Simplex). Unfortunately, the number of Dermal Injections associated with the current treatment protocol makes this procedure costly and difficult on the patient (regional nerve blocks or general anesthesia are used). We propose to use TransDerm's proprietary Flex-PAD delivery system to administer BTX to the skin in a patient-friendly manner with little or no pain and with no requirement for anesthetic. in Phase 1, we aim to demonstrate that BTX can be effectively and efficiently loaded on Flex-PADs and that the resulting drug product has sufficient stability to be evaluated in mouse models and for future clinical trial use. The ability of the Flex-PADs to delivery BTX will be evaluated in head-to-head studies with intradermal injection of BTX and scored for its ability to block pilocarpine- induced Sweating in mouse paws. in Phase 2, we refine and streamline manufacture and loading of the Flex-PADs with BTX and perform IND-enabling stability and toxicity studies in Mice and minipig models in Preparation for Human studies. !
Public Health Relevance Statement: NARRATIVE Much progress has been made over the past two decades in identifying the underlying genes and mutations responsible for a large number of genodematoses, with over 100 disorders identified from mutations in intermediate filament genes alone. Despite these discoveries, few clinical treatments have emerged that modulate these molecular targets. in the skin Disorder pachyonychia congenita (PC), the causative genes for PC are expressed in Sweat glands and the structure of the Sweat gland is grossly altered and malformed. Preliminary Human studies suggest that botulinum toxin is effective in reducing hyperhidrosis and Pain in PC. Although injected botulinum toxin reduced PC Symptoms, administration is cumbersome and costly, with regional nerve blocks or General Anesthesia required. This project seeks to exploit the ability of TransDerm's Flex-PAD delivery platform to deliver large, charged proteins such as botulinum toxin in a patient-friendly (i.e., little or no Pain) fashion. Patient-friendly delivery of botulinum toxin by Flex-PADs has potential applicability to benefit not only PC Patients, but also other patients with hyperhidrosis and associated Pain including Psoriasis, such as epidermolysis bullosa simplex.
