Radikal Therapeutics (RTX) is pioneering a novel therapy to restore immune tolerance and arrest progressive depigmentation in vitiligo. At Loyola University (LUC), a variant to inducible Heat Shock Protein 70 was developed with remarkable potential for the prevention and treatment of autoimmune vitiligo. Carrying only a single amino acid modification to the protein, this variant HSP70iQ435A (designated "CM") was found to have a curative effect involving long-lasting tolerization of dendritic cells (DCs) and inhibition of T ell influx to the skin. Depigmentation was inhibited by CM DNA vaccination to a remarkable extent in both preventive and therapeutic settings using different spontaneous, T cell receptor transgenic mouse models of vitiligo. Translated to humans, the inflammatory CD11b+CD11c+ subset of DCs held responsible for precipitating and perpetuating vitiligo is found in increased abundance among circulating and skin infiltrating DC. We thus hypothesize that the CM will likewise interfere with progressive depigmentation in human vitiligo. Given the strength and innovation of the basic science investigations and the profound efficacy revealed in multiple animal models of vitiligo, and the clear path forward to clinical proof-of-concept, we now propose an SBIR Phase 1 proposal to advance the CM through demonstration of efficacy in a clinically-relevant large animal model of vitiligo.
Specific Aim #1 : Establish the efficacy of the M in a large vitiligo model with human-like skin. At RTX the DNA of interest will be subcloned into pUMCV3, a vector suited for human use and expression compared to the original plasmid. 150 mg of CM (>99% purity) in pUMVC3 will then be generated to support large animal efficacy studies as well as for follow-on GLP toxicology and safety pharmacology investigations. Our collaborator, Dr. Le Poole (LUC), will carry out studies in Sinclair pigs (n=6 per group). This model, developing vitiligo as well as melanoma, will serve to test CM DNA application by needle-less jet injection in a model that allows for testing in human-like skin while measuring side-effects on anti-melanoma responses. Efficacy is measured by quantifying changes in lesional area. Local and systemic adverse events will be followed, and immune monitoring performed to translate earlier findings to large animals. This includes analysis of dendritic cell and T cell profiles in blood and skin samples taken from the animals over time.
Specific Aim #2 : Prepare the CM for IND approval. At RTX, a clinical protocol will be prepared and studies planned to determine the NOAEL, culminating in a pre-IND meeting on preparation for IND approval for a Phase I clinical study. For follow-on GLP toxicology and safety pharmacology investigations, 150 mg of CM (>99% purity) in pUMVC3 will be generated. Clinical investigators will be trained in working with the CM and its application in a pre-clinical setting and to manage any adverse events if necessary. We expect that the CM will induce >50% reduction in vitiligo progression relative to the saline control group and that immune monitoring will determine a >50% reduction in T cell infiltration to the skin.
We are proposing a novel pharmaceutical therapy to block the progression of vitiligo, a disease in which skin pigment is lost, resulting in progressive growth of lesions without skin color. Our drug is a novel entity that targets the basic mechanisms of vitiligo and is intended as a lifelong therapy. We will undertake requisite manufacturing to prepare a supply of drug for preclinical studies and test this agent in a clinically-relevant large animal model of vitiligo.