Compositions and methods of modulating HIF-2A to improve muscle generation and repair

Inventors

Yin, Hang • Xie, Liwei • Yin, Amelia Yao-Ye

Assignees

University of Georgia Research Foundation Inc

Abstract

Compositions and methods for modulating HIF-2α to meditate of hypoxia signaling in satellite cells and applications thereof for improving skeletal muscle generation and repair are provided. For example, methods of enhancing, increasing, accelerating or/and otherwise improving skeletal muscle generation or regeneration in a subject in need thereof are disclosed. In some embodiments, the methods include administering the subject an effective amount of HIF-2α inhibitor. The HIF-2α inhibitor can be effective to, for example, increase muscle satellite cell proliferation, differentiation, or a combination thereof in a subject. Composition and methods for improving respiration, and reducing or preventing the development or progression of fibrosis are also provided. The disclosed compositions and methods are particularly useful for treating muscular dystrophies, myopathies, and other muscle-related diseases and disorders.

Core Innovation

The patent describes treating a muscular dystrophy or myopathogenic disorder in a subject by administering an effective amount of a HIF-2b1 inhibitor. The disclosure connects HIF-2b1 biology in skeletal-muscle satellite cells to control of quiescence, self-renewal, differentiation behaviors, and Spry1 expression through promoter HREs. HIF-2b1 is described as abnormally stabilized in severe muscular dystrophy models and as showing elevated HIF-2b1 target gene expression in DMD patient muscle datasets.

HIF-2b1 inhibitor embodiments include HIF-2b1 antagonist compounds, including PT-2385, PT-2399, PT2977, and pharmaceutically acceptable salt, stereoisomer, and derivative variants. The disclosure also includes HIF-2b1 inhibitor embodiments as small molecule inhibitors and functional nucleic acid inhibitors, together with broader cyclic sulfone/sulfoximine and aryl compound embodiments defined by general structural formulas.

Pharmacologic inhibition of HIF-2b1 is described as accelerating regeneration and improving function and fibrosis outcomes under normal and hypoxic injury conditions, and in dystrophic muscle as increasing regeneration and satellite-cell proliferation while reducing fibrosis. The disclosure also contrasts HIF-2b1 perturbations in which genetic ablation results in spontaneous satellite-cell activation/proliferation and loss of quiescent self-renewal, while HIF-2b1 stabilization promotes quiescence/self-renewal and impairs differentiation.

Claims Coverage

The consolidated claim coverage centers on one method claim directed to treating muscular dystrophy or myopathogenic disorder by administering an effective amount of a HIF-2b1 inhibitor to a subject. Dependent refinements specify disease subtypes, inhibitor form, named small-molecule examples and variants, administration scope, and expected muscle-related outcomes.

Across the consolidated claim set, the core inventive concept is treatment of muscular dystrophy or myopathogenic disorder by administering an effective amount of a HIF-2b1 inhibitor, with refinements for inhibitor class, specific small-molecule examples and variants, local or systemic administration, disease subtype selection, and increased muscle-related properties linked to strength and/or muscle volume.

Stated Advantages

Documented Applications