SYSTEMIC DELIVERY OF MYOSTATIN SHORT INTERFERING NUCLEIC ACIDS (siNA) CONJUGATED TO A LIPOPHILIC MOIETY

Abstract

The present invention provides methods comprising the in vivo delivery of small nucleic acid molecules capable of mediating RNA interference and reducing the expression of myostatin, wherein the small nucleic acid molecules are introduced to a subject by systemic administration. Specifically, the invention relates to methods comprising the in vivo delivery of short interfering nucleic acid (siNA) molecules that target a myostatin gene expressed by a subject, wherein the siNA molecule is conjugated to a lipophilic moiety, such as cholesterol. The myostatin siNA conjugates that are delivered as per the methods disclosed are useful to modulate the in vivo expression of myostatin, increase muscle mass and / or enhance muscle performance. Use of the disclosed methods is further indicated for treating musculoskeletal diseases or disorders and / or diseases or disorders that result in conditions in which muscle is adversely affected.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 902,358, filed Nov. 11, 2013, the entire contents of which are incorporated herein by reference.REFERENCE TO SEQUENCE LISTING[0002]A sequence listing text file is submitted via EFS-Web in compliance with 37 CFR §1.52(e)(5) concurrently with the specification. The sequence listing has the file name “A2038-7219WO Sequence Listing”, was created on Nov. 10, 2014, and is 24,773 bytes in size. The sequence listing is part of the specification and is incorporated in its entirety by reference herein.BACKGROUND OF THE INVENTION[0003]RNA interference (RNAi) is an evolutionarily conserved cellular mechanism of post-transcriptional gene silencing found in fungi, plants and animals that uses small RNA molecules to inhibit gene expression in a sequence-specific manner. RNAi is controlled by the RNA-induced silencing complex (RISC) that is initiated by short double-stranded RNA m...

AI Technical Summary

Benefits of technology

The present invention provides methods for delivering small nucleic acid molecules (siNA) that can reduce the expression of myostatin, a gene that plays a role in muscle development. These siNA molecules are attached to a lipophilic molecule, such as cholesterol, which helps to deliver them to muscle cells. By inhibiting the expression of myostatin, the siNA molecules can increase muscle mass and function. The methods can be used to treat muscle-related diseases and disorders, as well as conditions that affect muscle function. The siNA molecules are designed to target the myostatin gene and act through a process called RNA interference. The invention also includes pharmaceutical compositions containing the myostatin siNA molectrodes.

Problems solved by technology

Despite these major advances, siRNA delivery to a diverse range of tissues remains a major obstacle in vivo.

While siRNA delivery in vivo has been achieved in eye, lung, brain, tumor, and muscle by localized delivery (by intraocular, intranasal, intrathecal, intratumoral, and intramuscular injections, respectively), this delivery method is only suitable for target validation studies due to its invasive nature and has limited relevance as a clinical therapy (Golzio, M. et al., 2005, Gene Ther.

However, systemic siRNA delivery has remained limited to particular tissues, such as liver, tumors, spleen and jejunum (Abrams, M. T. et al., 2010, Mol. Ther. 18:171-80; Chien, P. Y. et al., 2005, Cancer Gene Ther.

However, IM injections have a long-standing history for causing pain, local muscle damage and inflammation, which also minimizes their usefulness for therapeutic applications (McMahon, J. M. et al., 1998, Gene Ther.

Although it showed successful delivery into multiple muscle groups in the limb and the ability for multiple dosing, delivery efficiency was low and it is still an invasive technique that requires a high degree of injection skill.

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