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-11266719-B2
Publication Date
2022-03-08
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 clastin-like peptides and can be administered at a low-dose.
Core Innovation
The invention provides a method for treating a patient having muscular dystrophy by slowing skeletal muscle deterioration through administration of a pharmaceutical composition. The composition includes 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. The therapeutics are described as stable and long-acting vasoactive intestinal peptide (VIP) therapeutics formulated with elastin-like peptides (ELPs).
The document connects the VPAC2-selective VIP therapeutics to anti-fibrotic and anti-inflammatory pathways, including effects such as reduced TGF-β and modulation of immune cells. In support of these effects, the document reports outcomes including reduced collagen/fibrosis and reduced macrophage counts. The described approach also includes sustained-release intent using elastin-like peptide composition features with tunable inverse phase transition properties for depot or sustained release.
The elastin-like peptide compositions are defined using repeating structural units such as VPGXG (SEQ ID NO: 3) and related motifs with tunable inverse phase transition properties, including inverse phase transition temperature (Tt) behavior for reversible matrix sustained release. In addition, the document describes the use of VPAC2-selective VIP therapeutics as a formulation that can be provided as a VIP-ELP fusion or as co-formulated separate components, supporting long-acting delivery for treating myopathy conditions including muscular dystrophies and cardiomyopathies. High-level supporting direction includes mouse data indicating preserved cardiac function parameters and protection against contraction-induced skeletal muscle damage.
Claims Coverage
The partial content provides one independent claim covering a method for slowing skeletal muscle deterioration in a muscular dystrophy patient using a VPAC2-selective VIP elastin-like peptide composition. The claim set includes additional dependent refinements that specify dystrophy types and comparative outcome targets, and further restrict dosage and dosing schedule.
VPAC2-selective VIP with VPGXG elastin-like peptide repeating units
Administering to a patient in need 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.
Treatment of skeletal muscular dystrophy using the VPAC2-selective VIP composition
Using the method for skeletal muscular dystrophy selected from Myotonic muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, Limb-girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, Congenital muscular dystrophy, Oculopharyngeal muscular dystrophy, Distal muscular dystrophy, or Emery-Dreifuss muscular dystrophy.
Daily dose range for the VPAC2-selective VIP/ELP composition
Carrying out the method by administering the pharmaceutical composition at a daily dose ranging from 1 mg/kg/day to 10 mg/kg/day.
Dosing schedule for the VPAC2-selective VIP/ELP composition
Carrying out the method by administering the pharmaceutical composition on a dosing schedule selected from daily, 1–3 times per week, weekly, or 1–2 times per month.
Decreased collagen or immune-cell count compared to an untreated myopathic patient
Administering the pharmaceutical composition that reduces collagen content in muscle or reduces immune cell count in muscle versus an untreated myopathic patient.
Macrophage immune-cell reduction target
The immune cells are macrophages.
Overall, the claims coverage centers on a VPAC2-selective VIP combined with a specified VPGXG elastin-like peptide structure, with dependent features narrowing the muscular dystrophy types, adding dosing dose and dosing-schedule constraints, and specifying comparative targets that include reduced collagen/fibrosis or reduced immune-cell (macrophage) counts versus an untreated myopathic patient.
Stated Advantages
Slows skeletal muscle deterioration in a patient having muscular dystrophy.
Reduces collagen content in muscle versus an untreated myopathic patient.
Reduces immune cell count in muscle versus an untreated myopathic patient.
Produces reductions in macrophage counts.
Documented Applications
Treating muscular dystrophy, including skeletal muscular dystrophy and cardiomyopathy, by administration of VPAC2-selective VIP therapeutics formulated with elastin-like peptides.
A randomized placebo-controlled clinical trial in DMD/BMD patients to evaluate effects using echocardiography and cardiac MRI with late gadolinium enhancement.
Mouse applications (PB1046) reported as preserving cardiac function parameters and protecting against contraction-induced skeletal muscle damage, with reduced collagen/fibrosis and reduced macrophage counts.
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