Manufacture of defined live microbial therapeutics for infectious and inflammatory disease

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY The approval of two fecal-based products for the treatment of recurrent Clostridioides difficile infection (rCDI) demonstrates the potential of microbial therapeutics to treat human disease. However, fecal-based products have a poorly defined safety profile that varies by fecal donor. In addition, fecal-based products are inherently not scalable as increasing drug production requires increasing stool donations provided by individual humans. Defined live biotherapeutic products (LBP) comprised of in vitro manufactured bacterial strains provide a scalable alternative to fecal products and ideally contain only the necessary active ingredients (i.e., bacterial strains) that are sufficient for the desired therapeutic benefit. The transition of the microbiome field from fecal products to defined consortium has been slow as the former requires a stool sample, a blending device and a crude filter, while the latter requires knowledge of in vitro manufacturing of anaerobic bacteria on animal-free media at scales sufficient to dose humans. We developed and manufactured the defined LBP MTC01, comprised of the 15 best engrafting bacterial strains isolated from a frequently successful fecal transplant donor. MTC01 is currently being tested in a phase 1b clinical trial comparing this defined consortium with fecal transplant with stool from the donor from which the MTC01 strains were isolated. Building on this successful transition from fecal based products to defined LBPs, we now propose to increase the scale and throughput of defined LBP generation to bringing new bacterial consortia to the clinic while sharing know-how to expand the number of translational studies in the microbiome field. We will develop a solid-state fermentation platform for manufacturing defined LBPs in parallel to decrease manufacturing times from months to weeks (Aim 1). We will develop strain characterization pipelines to estimate the feasibility of manufacturing each strain on animal- free media and to identify safety concerns related antibiotic resistance and the feasibility of standard microbial enumeration assays for non-sterile products (USP61/USP62) that are required for human defined LBPs. We will use these advances to develop multiple drug products for the treatment of UC, and we will seek regulatory feedback through preIND and IND submissions to the FDA (Aim 2). Finally, we will explore genetic engineering strategies to add new functions to stably-colonizing high abundance anaerobes for use in future defined LBPs (Aim 3). Collectively, these studies will advance defined LBP manufacturing technologies and concepts to streamline the generation of live microbial therapeutics, and they will advance multiple defined LBPs manufactured in this proposal through the regulatory steps necessary for at least two additional human trials of defined LBPs in rCDI and ulcerative colitis.