Methods and compositions for treating muscle disease and disorders
Inventors
Georgopoulos, Lynne • Arnold, Susan • Ballance, David James
Assignees
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Publication Number
US-10688156-B2
Publication Date
2020-06-23
Expiration Date
Abstract
The present disclosure provides a method of treating muscle myopathy, including muscle dystrophies and cardiomyopathies, by administering stable, long-lasting vasoactive intestinal peptide therapeutic agents. These agents include one or more elastin-like peptides and can be administered at a low-dose.
Core Innovation
The invention relates to treating muscle myopathy, including muscular dystrophy and cardiomyopathy, by administering stable, long-lasting Vasoactive Intestinal Peptide (VIP) therapeutics with elastin-like peptides (ELPs). The compositions include VPAC1/VPAC2-active VIP therapeutics, with emphasis on VPAC1 and VPAC2 receptor signaling, and are directed to reducing fibrosis and inflammation through VIP signaling while providing a stable, long-lasting therapeutic effect.
In the muscular dystrophy context, the disclosed therapeutic composition combines a VPAC2-selective VIP with an elastin-like peptide comprising at least 90 repeating units of VPGXG (SEQ ID NO: 3), where X is independently selected from Val, Ala, and Gly at a ratio of about 5:3:2. The disclosure also describes VIP sequence variants and ELP structural units based on VPGXG repeat units, including [VPGXG]90/120/144/160/180 and related variants, as a pharmaceutical composition for treating or delaying the progression of muscular dystrophy.
The disclosure further describes sustained-release formulation concepts using inverse phase transition/coacervation around body temperature. Documented measurement endpoints include echocardiography and MRI-based cardiac function parameters, and histology/biomarkers for fibrosis and muscle function, with reported example results including preserved cardiac function parameters such as fractional area shortening, dP/dtmax, and Tau, protection against contraction-induced skeletal muscle damage, and reduced collagen/fibrosis and macrophage counts.
Claims Coverage
The independent claim is directed to a method for treating or delaying the progression of muscular dystrophy by administering a pharmaceutical composition containing a VPAC2-selective VIP and a defined elastin-like peptide repeat architecture. The inventive features further constrain the method to specific composition embodiments and to measured comparative outcomes versus an untreated myopathic patient, while additional dependents narrow patient administration details such as route, daily dose range, and dosing schedule frequency.
VPAC2-selective VIP plus defined VPGXG ELP for muscular dystrophy progression
A method for treating or delaying the progression of muscular dystrophy comprising administering to a patient in need thereof a pharmaceutical composition comprising a VPAC2-selective Vasoactive Intestinal Peptide (VIP) and an elastin-like peptide comprising at least 90 repeating units of VPGXG (SEQ ID NO: 3), where X is independently selected from Val, Ala, and Gly at a ratio of about 5:3:2.
ELP repeating units at least 90 with specified VPGXG composition ratio
The elastin-like peptide comprises at least 90 repeating units of VPGXG (SEQ ID NO: 3), where X is independently selected from Val, Ala, and Gly at a ratio of about 5:3:2.
ELP includes SEQ ID NO: 15
The method further defined such that the pharmaceutical composition includes SEQ ID NO: 15.
Comparative functional, fibrosis, and immune outcome effects versus untreated myopathic patient
Administering a pharmaceutical composition increases ventricular filling velocity and maximal rate of pressure rise and Tau constant of relaxation, or alternatively decreases collagen content or decreases immune cell count in muscle compared to an untreated myopathic patient.
Specified daily dose range
Administering the pharmaceutical composition at a daily dose between 1 mg/kg/day and 10 mg/kg/day.
Specified dosing frequency schedule
Administering the pharmaceutical composition on a schedule ranging from daily use to once or twice per month, including intermediate weekly frequencies.
Specified administration routes
Formulating the pharmaceutical composition for subcutaneous, intramuscular, or intravenous administration.
Across the claim set provided, the core inventive approach is a muscular dystrophy treatment method using a VPAC2-selective VIP combined with an elastin-like peptide defined by VPGXG repeating units (at least 90 repeats, with X selected from Val/Ala/Gly at about a 5:3:2 ratio). Dependent features further specify an ELP embodiment, define comparative outcomes versus an untreated myopathic patient, and constrain administration with a specific dose range, dosing schedule frequency, and administration routes.
Stated Advantages
Delays progression of muscular dystrophy.
Increases ventricular filling velocity.
Increases maximal rate of pressure rise and Tau constant of relaxation.
Decreases collagen content.
Decreases immune cell count in muscle.
Documented Applications
Treating or delaying the progression of muscular dystrophy in a patient in need thereof.
Treating muscle myopathy including muscular dystrophies and cardiomyopathies.
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