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EP-4739351-A1 - GENE REPLACEMENT THERAPY FOR ALPK3 CARDIOMYOPATHY

EP4739351A1EP 4739351 A1EP4739351 A1EP 4739351A1EP-4739351-A1

Abstract

The present disclosure relates, in part, to gene replacement to treat cardiomyopathy. In embodiments, the invention provides compositions and methods of use to treat ALPK3 cardiomyopathy. In embodiments, invention provides a composition comprising a nucleic acid encoding all or a portion of an ALPK3 protein.

Inventors

  • CHEN, JU
  • FENG, Wei

Assignees

  • The Regents of the University of California

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method of treating cardiomyopathy, comprising administering to a subject in need thereof an effective amount of a composition comprising a nucleic acid encoding all or a portion of an ALPK3 protein.
  2. 2. The method of claim 1, wherein the nucleic acid is a mini ALPK3 gene comprising a sequence that encodes at least 700, 800. 900, 1000. 1100, 1200, 1300 or 1400 amino acids of a the ALKP3 protein.
  3. 3. The method of claim 1, wherein the nucleic acid is a mini ALPK3 gene comprising a sequence that encodes about 1308 amino acids of the ALPK3 protein.
  4. 4. The method of claim 1, wherein the nucleic acid contains fewer nucleotides than a naturally occurring ALPK3 gene.
  5. 5. The method of claim 1, wherein the nucleic acid is a mini ALPK3 gene having at least a deletion of a portion of exon 6 sequence of the naturally occurring ALKP3 gene.
  6. 6. The method of claim 5, wherein the composition further comprises a vector operationally linked to the portion of the mini ALPK3 gene.
  7. 7. The method of claim 6, wherein the vector is a muscle adeno-associated virus 2A (MyoAAV 2A).
  8. 8. The method of claim 1, wherein the nucleic acid is cDNA or RNA.
  9. 9. The method of claim 1, wherein the cardiomyopathy is ALPK3 cardiomyopathy.
  10. 10. The method of claim 9, wherein the cardiomyopathy exhibits left ventricular hypertrophy.
  11. 11. The method of claim 1, wherein the cardiomyopathy is dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM).
  12. 12. The method of claim 1, wherein the subject is a human.
  13. 13. A pharmaceutical composition comprising a nucleic acid encoding all or a portion of an ALPK3 protein.
  14. 14. The pharmaceutical composition of claim 13, wherein the nucleic acid is a mini ALPK3 gene comprising a sequence that encodes at least 700, 800. 900, 1000. 1100, 1200, 1300 or 1400 amino acids of the ALKP3 protein.
  15. 15. The pharmaceutical composition of claim 13, wherein the nucleic acid encodes a mini ALPK3 gene comprising a sequence that encodes about 1308 amino acids of the ALKP3 protein.
  16. 16. The pharmaceutical composition of claim 13, wherein the nucleic acid contains fewer nucleotides than a naturally occurring ALPK3 gene.
  17. 17. The pharmaceutical composition of claim 13, wherein the nucleic acid encodes a mini ALPK3 gene having at least a deletion of a portion of exon 6 sequence of the naturally occurring ALKP3 gene.
  18. 18. The pharmaceutical composition of claim 17, wherein the composition further comprises a vector operationally linked to the portion of ALPK3 gene.
  19. 19. The pharmaceutical composition of claim 18. wherein the vector is a muscle adeno- associated virus 2A (MyoAAV 2A).
  20. 20. The pharmaceutical composition of claim 13, wherein the nucleic acid is cDNA or RNA.

Description

GENE REPLACEMENT THERAPY FOR ALPK3 CARDIOMYOPATHY CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Application No. 63/512,200 filed on July 6, 2023, which is incorporated herein by reference. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 28, 2024, is named 24978-0916, SL.xml and is 35,220 bytes in size. GOVERNMENT SPONSORSHIP [0003] This invention was made with government support under grant HL 146759 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD [0004] The present invention relates to treatments for cardiomyopathy. BACKGROUND [0005] Alpha Protein Kinase 3 (ALPK3) is an aty pical protein kinase that is a member of the alpha (a)-kinase family. Individuals carrying homozygous or compound heterozygous loss-of-function pathogenic ALPK3 mutations often exhibit a range of cardiomyopathy phenotypes. These frequently present at birth or early childhood as severe early-onset dilated cardiomyopathy (DCM) and subsequently progress towards a hypertrophic cardiomyopathy (HCM) phenotype over time. In contrast, individuals carrying heterozygous truncated variants in ALPK3 typically exhibit a late onset of hypertrophic cardiomyopathy (HCM). This is often accompanied by significant myocardial fibrosis, leading to the progression of heart failure. According to the genoAD database, loss-of- function ALPK3 variants are found in approximately 1 in 2,500 individuals. In two separate cohorts of HCM patients, comprising 770 and 2,047 patients respectively, it was found that 1.56% of HCM patients carried heterozy gous loss-of-function ALPK3 variants. Currently, no specific treatments are available for patients diagnosed with ALPK3 cardiomyopathy. SUMMARY OF THE INVENTION [0006] The present disclosure relates, in part, to gene replacement to treat cardiomyopathy. In embodiments, the invention provides compositions and methods of use to treat ALPK3 cardiomyopathy. In embodiments, invention provides a composition comprising a nucleic acid of an ALPK3 gene, encoding ALPK3 protein. [0007] In embodiments, the invention provides that the nucleic acid is a mini ALPK.3 gene comprising a sequence that encodes at least 700, 800, 900, 1000, 1100, 1200, 1300 or 1400 amino acids of a protein corresponding to the ALKP3 gene. In embodiments, the invention provides that the nucleic acid is a mini ALPK3 gene comprising a sequence that encodes about 1308 amino acids of a protein corresponding to the ALKP3 gene. In embodiments, the invention provides that the nucleic acid is not found in nature and contains fewer nucleotides that a naturally occurring ALPK3 gene. [0008] In embodiments, the invention provides that the nucleic acid is a mini ALPK3 gene having at least a deletion of a portion of exon 6 sequence. In embodiments, the invention provides that the nucleic acid is a mini ALPK3 gene having at least a deletion of a portion of exons 5 and/or 6. [0009] In embodiments, the invention provides that the composition further comprises a vector operationally linked to the portion of ALPK3 gene. In embodiments, invention provides that the vector is a muscle adeno-associated virus 2A (MyoAAV 2A). In embodiments, invention provides that the nucleic acid is cDNA or RNA. [0010] In embodiments, the invention provides a composition comprising a tagged ALPK3 gene. In embodiments, the tag is a 3xFLAG tag. In embodiments, the tag is incorporated at the C-terminus of ALPK3 gene. In embodiments, the protein expressed by the tagged ALPK3 tag can be isolated with an antibody against the tag. [0011] In embodiments, the invention provides means for expressing a portion of an ALPK3 gene and method of use. In embodiments, the invention provides means for isolating a portion of an ALPK3 gene and method of use. [0012] In embodiments, invention provides methods for treating cardiomyopathy, comprising administering to a subject in need thereof an effective amount of the compositions or means described herein. In embodiments, the invention provides that the cardiomyopathy is ALPK3 cardiomyopathy. In embodiments, the ALKP3 gene is human. In embodiments, the subject is human. BRIEF DESCRIPTION OF THE DRAWINGS [0013] Figure 1. Loss of ALPK3 in mice induces premature death. (Fig. 1 Panel A) RT-qPCR shows that ALPK3 mRNA is significantly downregulated in ALPK3 global knockout (gKO) mice. (Fig. 1 Panel B) Survival curve showed that ALPK3 gKO mice starts to die after one week of birth, half of gKO mice died before wean age. [0014] Figure 2. Loss of ALPK3 in mice induces cardiac dysfunction. Fraction shortening (FS) is used for measurement of contractile function. Left ventricle internal dimension at diastole (LVIDd) and left ventricle internal dimension at systole (LVIDs) are use