Compositions and methods relating to a C-terminal peptide of troponin i with activity as a myofilament CA2+ desensitizer
Inventors
Assignees
Publication Number
US-12064468-B2
Publication Date
2024-08-20
Expiration Date
2040-08-07
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Abstract
Methods and compositions for treating a disorder of cardiac muscle and/or skeletal muscle in a subject according to aspects of the present disclosure. Treatment methods include administering a therapeutically effective dose of a C-terminal portion of troponin I capable of reducing sensitivity of cardiac muscle and/or skeletal muscle to Ca2+ without decreasing maximum force production. Assays for identification of compounds capable of reducing sensitivity of cardiac muscle and/or skeletal muscle to Ca2+ without decreasing maximum force production are further provided.
Core Innovation
The invention provides methods and compositions for treating disorders of cardiac muscle and/or skeletal muscle in a subject by administering a therapeutically effective dose of a C-terminal portion of troponin I. This C-terminal portion is characterized by its ability to reduce sensitivity of cardiac muscle and/or skeletal muscle to Ca2+ without decreasing maximum force production. The invention includes peptides comprising specific sequences such as SEQ ID NO:1 and variants thereof, as well as nucleic acids encoding such peptides, and extends to pharmaceutical compositions and expression cassettes containing these sequences.
The problem addressed by the invention is the lack of specific and effective treatments for heart failure, particularly diastolic heart failure characterized by inefficient filling of the heart chambers and related conditions involving impaired muscle relaxation. Existing therapies such as beta blockers often weaken force production, and positively inotropic drugs can increase energetic expenditure with only limited long-term benefit. There is a need for muscle-targeted compositions and methods that reduce muscle Ca2+ sensitivity without compromising maximum force output.
The invention further provides assays for identifying compounds capable of reducing muscle sensitivity to Ca2+ without decreasing maximum force production. These assays include contacting human alpha-tropomyosin, or a non-human homologue, with a test compound and measuring its effect on Ca2+ sensitivity and force production, thus enabling the identification of candidate therapeutics based on this unique mode of action.
Claims Coverage
The patent contains one independent claim with several key inventive features relating to the treatment of cardiac muscle disorders using a specific isolated C-terminal portion of troponin I.
Administration of isolated C-terminal portion of troponin I comprising SEQ ID NO:1 and variants for treating cardiac muscle disorders
A method for treating a disorder of cardiac muscle ameliorated by reduction of muscle sensitivity to Ca2+ without decreasing maximum force production, including conditions such as heart failure, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM), by administering a therapeutically effective dose of an isolated C-terminal portion of troponin I to the subject. The isolated C-terminal portion must be 23 to 35 amino acids in length and comprise SEQ ID NO:1.
Use of specific peptides or variants thereof for therapeutic efficacy
The composition may comprise a peptide selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:32, all functionally defined by their ability to reduce Ca2+ sensitivity without loss of maximum force.
Delivery via expression cassettes with muscle-specific promoters
The method includes administering an expression cassette comprising a nucleic acid encoding the specified isolated C-terminal portion of troponin I, operably linked to a promoter capable of driving expression in cardiac muscle and/or skeletal muscle. The promoter may be a cardiac or skeletal muscle protein promoter.
Combination therapy with additional therapeutic agents
Therapeutic methods may further comprise administering an additional therapeutic agent along with the isolated C-terminal portion of troponin I for treatment of cardiac muscle disorders.
In summary, the inventive features cover the administration of specific isolated C-terminal portions of troponin I, their defined peptide variants, gene delivery methods using appropriate expression cassettes, and their use alone or in combination with other therapeutic agents to treat various cardiac muscle disorders by reducing Ca2+ sensitivity without loss of force.
Stated Advantages
Reduces muscle sensitivity to Ca2+ without decreasing maximum force production.
Provides a targeted approach for the treatment of disorders such as heart failure, especially diastolic heart failure.
Offers methods and compositions that specifically modulate the cardiac muscle contraction and relaxation cycle.
Avoids negative inotropic effects seen with some current heart failure therapies.
Documented Applications
Treatment of disorders of cardiac muscle, including heart failure, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM).
Treatment of disorders of skeletal muscle, specifically coordination disorders of the skeletal muscles.
Treatment of diastolic heart failure (heart failure with preserved ejection fraction, HFpEF).
Use in assays to identify compounds capable of reducing cardiac and/or skeletal muscle sensitivity to Ca2+ without decreasing maximum force production.
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