Compositions and methods for treatment of Netherton Syndrome with LEKTI expressing recombinant microbes

Inventors

Whitfill, Travis Michael • Munivar, Azim Momin

Assignees

Azitra Inc

Abstract

The present disclosure provides, inter alia, engineered microbes expressing recombinant LEKTI domains that are effective to treat or ameliorate the symptoms of Netherton Syndrome. In certain embodiments, compositions, methods, and kits are provided comprising LEKTI domain expressing microbes.

Core Innovation

The patent describes compositions and recombinant microorganisms for the treatment of skin disease, including Netherton Syndrome, by using skin-colonizing recombinant microbes. The microbes are engineered to express LEKTI protein domains, including LEKTI domain 6 and LEKTI domains 8-11, so that the LEKTI polypeptide inhibits serine proteases associated with the skin disease.

A central aspect is the use of microbial expression constructs such as pJB38-LEKTI domain 6-complete plasmid construct and pJB38-LEKTI domain 8-11-complete plasmid construct in treatment compositions. The patent also describes recombinant microorganisms capable of secreting a LEKTI polypeptide, where an expression vector includes a first coding sequence for expressing the LEKTI polypeptide and a second coding sequence for expressing a cell penetrating peptide.

The disclosure further includes embodiments for on-skin delivery and microbial survival/multiplication, together with expression control concepts including inducible or constitutive expression control and secretion-related features. It also provides experimental support described for LEKTI domain 6 solubility, secretion, and in vitro inhibition of trypsin and KLK5/KLK7, and it outlines evaluation in a conditional SPINK5−/− mouse model.

Claims Coverage

The independent claims provide coverage for treatment compositions using microbes carrying specific pJB38-LEKTI complete plasmid constructs and for recombinant microorganisms that secrete LEKTI polypeptides containing either LEKTI domain 6 or LEKTI domains 8-11, with an expression vector that includes a cell penetrating peptide coding sequence. Across the independent claims identified, the inventive features are organized into four coverage themes.

Overall, the claim set covers skin-disease treatment compositions and secretion-capable recombinant microorganisms that express and/or secrete LEKTI polypeptides defined by LEKTI domain 6 or LEKTI domains 8-11. For the recombinant microorganism claims, the expression vector is required to include a coding sequence for a cell penetrating peptide in addition to the LEKTI coding sequence.

Stated Advantages

Documented Applications