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CN-122029285-A - Methods of treating hypertrophic cardiomyopathy with AAV gene therapy vectors and therapeutic formulations

CN122029285ACN 122029285 ACN122029285 ACN 122029285ACN-122029285-A

Abstract

Pharmaceutical compositions and methods of using the pharmaceutical compositions to treat hypertrophic cardiomyopathy in a human subject are described herein.

Inventors

  • P. AGARWAL
  • W. Yunemoto
  • E. Ayuso Lopez
  • T Voight
  • V. Ricotti
  • P. C. Colossi
  • J. Ishda
  • J. Kaltmann
  • E.Gu
  • S. Mosaic
  • M. P. Sumandia
  • S. Kishbo Vargas
  • C. Vitelli

Assignees

  • 迪纳柯公司

Dates

Publication Date
20260512
Application Date
20240906
Priority Date
20230906

Claims (20)

  1. 1. A pharmaceutical composition comprising recombinant adeno-associated virus (rAAV) particles optionally having AAV9 serotype capsids at a concentration of at least about 6e13 vg/ml to about 4e14 vg/ml, the pharmaceutical composition comprising a buffer, an isotonic agent, an additional MgCl 2 stabilizer, a cryopreservative, and a surfactant that is stable for at least about 1 year, 1.5 years, or 2 years during storage at about +≤60 ℃ (minus sixty degrees celsius) or less.
  2. 2. The pharmaceutical composition of claim 1, wherein the pH of the formulation is in the range of about 6 to about 9, optionally in the range of about 7 to about 7.8.
  3. 3. The pharmaceutical composition of claim 2, wherein the pH is 7.4.
  4. 4. A pharmaceutical composition comprising rAAV particles optionally having AAV9 serotype capsids at a concentration of at least about 6e13 vg/ml to about 4e14 vg/ml or about 1e14 vg/ml or less, tris hydrochloride buffer at a concentration of about 10 to about 30 mM, tris base at a concentration of about 1 to about 4 mM, sodium chloride at a concentration of about 100 mM to about 150 mM, mgCl 2 at a concentration of about 0.5 mM to about 3.0 mM, trehalose at a concentration of about 50 mM to about 90 mM, and poloxamer (poloxamer) or polysorbate at a concentration of about 0.05% to about 0.15% w/v.
  5. 5. The pharmaceutical composition of claim 4, wherein the concentration of rAAV particles is in the range of about 1e13 vg/ml to about 1e14 vg/ml.
  6. 6. The pharmaceutical composition of claim 4, wherein the concentration of rAAV particles is in the range of about 1e13 vg/ml to about 5e13 vg/ml, or about 5e13 vg/ml to about 1e14 vg/ml.
  7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the buffer comprises Tris hydrochloride and/or Tris base.
  8. 8. The pharmaceutical composition of claim 7, wherein the Tris hydrochloride is at a concentration of 17.6 mM and the Tris base is at a concentration of 2.4 mM.
  9. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the isotonic agent is NaCl at a concentration of 120 mM.
  10. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the stabilizer is MgCl 2 at a concentration of 1 mM.
  11. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the stabilizing agent is MgCl 2 in a concentration exceeding 1.5 mM.
  12. 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the stabilizing agent is MgCl 2 in a concentration of up to 3.0 mM.
  13. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the cryopreservative is a sugar.
  14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the cryopreservative is trehalose at a concentration of 74 mM.
  15. 15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the surfactant is poloxamer 188.
  16. 16. The pharmaceutical composition of claim 15, wherein the concentration of the surfactant is about 0.1% w/v.
  17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the composition is a liquid.
  18. 18. A pharmaceutical composition comprising rAAV particles at a concentration of about 6e13 vg/ml, 17.6 mM Tris hydrochloride, 2.4 mM Tris base, 120 mM sodium chloride, 1 mM MgCl 2 hexahydrate, 74 mM trehalose dihydrate, and 0.1% w/v poloxamer 188.
  19. 19. The pharmaceutical composition of claim 18, wherein the rAAV particle comprises an AAV type 9 capsid.
  20. 20. The pharmaceutical composition of claim 18, wherein the composition is a liquid.

Description

Methods of treating hypertrophic cardiomyopathy with AAV gene therapy vectors and therapeutic formulations Cross Reference to Related Applications The present application claims priority from U.S. provisional patent application No. 63/580,741 filed on 6 months 9 of 2023 and U.S. provisional patent application No. 63/591,172 filed on 18 months 10 of 2023, the disclosures of which are hereby incorporated by reference in their entireties. Technical Field Provided herein are recombinant adeno-associated virus (rAAV) gene therapy vectors and viral particles that are useful for the treatment and prevention of hypertrophic cardiomyopathy by increasing the expression of cardiac myosin binding protein C (cMyBP-C). Incorporated by reference into the sequence listing The present application includes a sequence listing (filename: sequencing listing. Xml, size: 489,630 bytes; creation date: 2023, 10 month 17 days) in computer-readable form as another part of the disclosure. The contents of the sequence listing xlm file are hereby incorporated by reference in their entirety. Background Although considerable progress has been made in the prevention of heart disease caused by environmental factors (e.g., nicotine, hypercholesterolemia, or diabetes) and in the symptomatic treatment of heart disorders, there is still a need for improved methods of treatment of hereditary cardiomyopathy. Cardiomyopathy caused by genetic factors are Hypertrophic Cardiomyopathy (HCM), dilated Cardiomyopathy (DCM) and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Hypertrophic cardiomyopathy is the most common hereditary heart disease and is characterized by unexplained left ventricular hypertrophy. Hypertrophic cardiomyopathy is associated with an initially normal systolic but diastolic function (Elliott et al, eur. Heart J. 29:270-6 (2008); gersch et al, J. Thorac. Cardiovasc. Surg. 142:el 53-203 (2011)). Hypertrophic cardiomyopathy has a particularly high prevalence of about 1:500 in the general population (Maron et al, circulation, 92:785-9 (1995)), and is a major cause of sudden cardiac death in young people, particularly athletes. Although HCM is a life threatening disease, there has been no curative treatment to date (Carrier et al, cardiovic. Res. 85:330-338 (2010); schlossarek et al, J. Mol. Cell. Cardiol. 50:613-20 (2011)). Hereditary hypertrophic cardiomyopathy is a genetic disease known to be caused by more than 1000 different mutations in at least 10 genes encoding components of the cardiac sarcomere, such as cardiac myosin binding protein C (cMyBP-C), beta-myosin heavy chain (MYH 7), cardiac troponin T (TNNT 2), cardiac troponin I (TNNI 3), myosin ventricular essential light chain 1 (MYL 3), myosin ventricular regulatory light chain 2 (MYL 2), cardiac alpha Actin (ACTC), alpha-tropomyosin (TPMl), actin (TTN), four semi-LIM protein 1 (FHL 1) (Richard et al, circulation, 107:2227-2232 (2003); schlossarek et al, j. Mol Cell cardiool. 50:613-20 (2011); friedrich et al, hum. Mol gene T. 21:37-54 (2012)). Many mutations are missense mutations encoding full-length mutant polypeptides, while other frameshift or splice site mutations can result in truncations (Marian et al, circle. Res. 121:749-70 (2017); walsh et al, genet. Med. 19:192-203 (2017)). The most common truncated mutant polypeptides are MYBPC3 and FHL1, which exhibit mainly frame shift mutations, resulting in a C-terminal truncated protein. The most frequently mutated gene in HCM is MYBPC3, which encodes cardiac myosin binding protein C (cMyBP-C) (Bonne et al, nat. Genet. 11:438-40 (1995); watkins et al, N.Engl. J. Med. 364:1643-56 (2011)). cMyBP-C is the major component of the sarcomere A band, where it interacts with myosin, actin and actin (Schlossarek et al, J.mol. Cell. Cardiol. 50:613-20 (2011)). In humans and mice cMyBP-C was detected only in the heart (Fougerousse et al, circ. Res. 82:130-3 (1998)) and was involved in the regulation of systole and diastole (Pohlmann et al, circ. Res. 101:928-38 (2007); schlossarek et al, J. Mol. Cell. Cardiol. 50:613-20 (2011)). About 70% of the mutations in the MYBPC3 gene lead to frame shifts and the production of C-terminal truncated proteins (Carrier et al, circle. Res. 80:427-34 (1997)). Truncated proteins are unstable and have never been detected in myocardial tissue of patients (Marston et al, circle. Res. 105:219-22 (2009); van Dijk et al, circulation, 119:1473-83 (2009); van Dijk et al, circle. Heart fat. 5:36-46 (2012)). Current drug-based treatments of HCM alleviate symptoms but do not treat the underlying genetic cause of the disease. Gene-based or RNA-based therapies would be the sole curative treatment for HCM. Gene therapy has been successfully tested for non-hereditary heart disease (Jessup et al, circulation, 124:304-13 (2011)). Disclosure of Invention Embodiments described herein relate to pharmaceutical compositions comprising recombinant AAV particles and methods of treating heart disease using recombinant AA