Methods of treating bone marrow failure syndromes and compositions for use in the same

Inventors

Sakamoto, Kathleen Miho • Wilkes, Mark

Assignees

Leland Stanford Junior University

Abstract

Methods of treating a subject for a bone marrow failure syndrome, e.g., DBA, are provided. Aspects of the methods include administering to the subject an effective amount of a Nemo-Like Kinase (NLK) inhibitor. Also provided are compositions that find use in practicing embodiment of the invention.

Core Innovation

The invention relates to treating a subject diagnosed as having a bone marrow failure syndrome by administering an effective amount of a nemo-like kinase (NLK) inhibitor. NLK is described as hyperactivated in erythroid progenitors in human and murine Diamond-Blackfan anemia models and in patient samples. NLK inhibition is described as improving erythroid expansion while sparing other lineages.

Mechanistic findings described in the document state that NLK phosphorylation of c-Myb and raptor results in c-Myb ubiquitination and proteasomal degradation, reduced mTORC1 lysosomal recruitment, and decreased mTOR activity. The document further describes increased autophagy associated with NLK inhibition. Additional mention is made of p53 in the context of the described findings.

The document also describes compound rationale including TGFβR1 inhibitors with off-target NLK inhibition, where rescue of erythropoiesis is reported for agents including SD208 and SB431542. Metformin is described as suppressing NLK expression via induction of miR-26a targeting the NLK 3′UTR. The document indicates supporting evidence across human, murine, zebrafish, and related lineage assays and presents NLK inhibitor modalities including small molecules, NLK expression inhibitors, and NLK binding agents.

Claims Coverage

The independent claim covers administering an effective amount of an NLK inhibitor to treat a subject diagnosed with a bone marrow failure syndrome. Across the dependent claims, the coverage is narrowed into specific inventive features including inhibitor class selection, particular small-molecule selections, and alternative NLK inhibitor modalities, plus an erythroid expansion outcome.

Overall, the claim set covers NLK-targeted treatment of bone marrow failure syndrome using an NLK inhibitor, with dependent claims narrowing the inhibitor to small molecules (including named examples), NLK-specific binding members (including antibody or antibody binding fragments), and specifying that NLK inhibition increases erythroid expansion.

Stated Advantages

Documented Applications