Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease that leads to the development of hundreds to thousands of adenomas in the rectum and the colon. Current medical management involves endoscopic monitoring, resection of advanced polyps and ultimately colectomy in the second decade of life. The risk of developing colorectal cancer is 100% and chemoprevention has not been successful. We have demonstrated that oral administration of our proprietary sustained-release particulate formulation of Interleukin- 10 (IL-10NanoCap) suppresses: a) intestinal polyposis in the APCmin/+ mouse model; b) intestinal/colon carcinogenesis in the APCmin/+ mouse / Bacteroides fragilis compound model; and c) sporadic adenocarcinoma in the CDX2P-NLS Cre;APC+/loxP genetic colon cancer model. These findings, which were published in Cancer Research and Oncoimmunology provide the requisite milestones and the underpinning rationale for this Fast- track application. In Phase I segment, Aim 1 we will establish final proof-of-principle for in vivo therapeutic efficacy of our recently-developed scaled-up commercial batch IL-10NanoCap in the APCmin/+ / Bacteroides fragilis murine FAP model. In Phase II segment, Aim 2 we will optimize the treatment protocol; determine long- term efficacy in early (preventive) and established (treatment) disease settings using the new regimen; delineate the effect of long-term treatment on gut/systemic immune activity; identify serum response markers; and obtain preliminary PK/PD data in the above model.
In Aim 3 we will produce multiple large-batches of bulk human IL- 10NanoCap, demonstrate lot-to-lot consistency and determine long-term stability prior to use in standard GLP rat toxicology studies (Aim 4). The pre-clinical data from Aims 1-4 will constitute the basis of the written questions and the briefing package that will be submitted to the FDA for a type C pre-pre-IND meeting (Aim 5). Successful completion of these studies will inform and incentivize future SBIR Phase IIb-supported non-human primate toxicology and an open IND in preparation for clinical trials.
-PUBLIC HEALH RELEVANCE Familial Adenomatous Polyposis (FAP) is an incurable autosomal dominant genetic disease afflicting some 50,000 Americans. Hundreds to thousands of adenomas develop in the rectum and colon, forcing colectomy usually in the second decade of life, to avoid colorectal cancer. This Fast-track proposal seeks to further the development of an oral formulation of the key regulatory cytokine interleukin-10 (IL-10NanoCap) as a novel therapy for FAP that can safely, sustainably and conveniently deliver this potent immune signal directly to the gut.
