Compositions and methods for treating renal disease

Abstract

Compositions and methods are disclosed herein for treating or reducing the symptoms of a renal disease, such as focal segmental glomerulosclerosis (FSGS), hypertensive end-stage kidney disease (ESKD), and HIV-associated nephropathy (a distinct form of FSGS, also termed collapsing glomerulopathy). The compositions include the common variant of APOL1 and fragments thereof, as well as antibodies and fragments thereof that bind and neutralize pathogenic APOL1, nucleic acid molecules that encode the common variant of APOL1 and fragments thereof, and other compounds that bind and neutralize pathogenic APOL1. The methods of the invention include administering one or more of the compositions of the invention to a subject having or at risk of developing renal disease.

What is claimed is: 
     
       1. A method of treating or reducing the likelihood of development of a renal disease comprising administering to a human subject expressing at least one pathogenic human APOL1 polypeptide comprising an S342G substitution, an I384M substitution, or a deletion removing amino acids N388 and Y389 a composition comprising an anti-APOL1 antibody or fragment thereof that specifically binds to the pathogenic APOL1 polypeptide, but does not specifically bind, or binds at a substantially greater dissociation constant, to a non-pathogenic APOL1 polypeptide, wherein said composition decreases a deleterious effect of the pathogenic APOL1 polypeptide. 
     
     
       2. The method of  claim 1 , wherein said anti-APOL1 antibody or fragment thereof neutralizes said human pathogenic APOL1 polypeptide. 
     
     
       3. The method of  claim 1 , wherein said composition treats or substantially inhibits development of said renal disease or treats or reduces one or more symptoms associated with said renal disease. 
     
     
       4. The method of  claim 1 , wherein said renal disease glomerulosclerosis. 
     
     
       5. The method of  claim 1  further comprising, prior to administering said inhibitor, determining the expression of at least one pathogenic APOL1 polypeptide in said subject. 
     
     
       6. The method of  claim 5 , wherein the subject is homozygous or heterozygous for at least one or more APOL1 alleles that encode said pathogenic APOL1 polypeptide. 
     
     
       7. The method of  claim 1 , wherein the subject is an African-American subject. 
     
     
       8. The method of  claim 1  further comprising administering to said subject a therapeutic agent selected from the group consisting of a blood pressure medication and a cholesterol-lowering medication. 
     
     
       9. The method of  claim 1 , wherein said renal disease is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), end-stage kidney disease (ESKD), hypertensive ESKD, idiopathic nephritic syndrome, and human immunodeficiency virus (HIV)-associated nephropathy. 
     
     
       10. A method of treating or reducing the likelihood of developing a renal disease in a subject with an apolipoprotein L1 (APOL1) genotype selected from the group consisting of:
 i) at least one copy of the G1 allele of APOL1;   ii) at least one copy of the G2 allele of APOL1;   iii) at least one copy of the G3 allele of APOL1; and   iv) at least one copy of the del6 allele of APOL1;   wherein the G1 allele, the G2 allele, the G3 allele, and the del6 allele of APOL1 encode a pathogenic APOL1 polypeptide,   wherein the method comprises administering to the subject a composition comprising a nucleic acid molecule comprising at least 15 contiguous nucleotides identical or complementary to a portion of a sequence encoding said pathogenic APOL1 polypeptide.   
     
     
       11. The method of claim 10, wherein said nucleic acid molecule is a ribonucleic acid interfering (RNAi) molecule or an antisense oligonucleotide. 
     
     
       12. The method of claim 11, wherein said RNAi molecule is an siRNA, shRNA, dsRNA, or miRNA. 
     
     
       13. The method of claim 10, wherein said nucleic acid molecule is an antisense oligonucleotide. 
     
     
       14. The method of claim 10, wherein said nucleic acid molecule comprises a sequence complementary to at least 15 contiguous nucleotides set forth within nucleotides 1-1197 of SEQ ID NO: 1. 
     
     
       15. The method of claim 14, wherein said nucleic acid molecule comprises a sequence complementary to at least 15 contiguous nucleotides set forth within nucleotides 1-200 of SEQ ID NO: 1. 
     
     
       16. The method of claim 14, wherein said nucleic acid molecule comprises a sequence complementary to at least 15 contiguous nucleotides set forth within nucleotides 1014-1197 of SEQ ID NO: 1. 
     
     
       17. The method of claim 10, wherein said nucleic acid molecule comprises:
 (a) a nucleotide sequence having at least 85% sequence identity to a nucleotide sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1, and   (b) one or more mutations associated with the G1, G2, G3, or del6 allele of APOL1.   
     
     
       18. The method of claim 10 wherein said nucleic acid molecule comprises a sequence having at least 90% sequence identity to said sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1. 
     
     
       19. The method of claim 18, wherein said nucleic acid molecule comprises a sequence having at least 95% sequence identity to said sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1. 
     
     
       20. The method of claim 19, wherein said nucleic acid molecule comprises a sequence having at least 97% sequence identity to said sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1. 
     
     
       21. The method of claim 20, wherein said nucleic acid molecule comprises a sequence having at least 99% sequence identity to said sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1. 
     
     
       22. The method of claim 21, wherein said nucleic acid molecule comprises a sequence having 100% sequence identity to said sequence complementary to at least 15 contiguous nucleotides set forth in SEQ ID NO: 1. 
     
     
       23. The method of claim 14, wherein said nucleic acid molecule comprises a sequence complementary to at least 50 contiguous nucleotides set forth within nucleotides 1-1197 of SEQ ID NO: 1. 
     
     
       24. The method of claim 10, wherein said nucleic acid molecule decreases the level of expression of the pathogenic APOL1 polypeptide by at least about 20%. 
     
     
       25. The method of claim 10, wherein said composition further comprises a vector comprising said nucleic acid molecule. 
     
     
       26. The method of claim 25, wherein said vector is a viral or non-viral vector. 
     
     
       27. The method of claim 25, wherein said viral vector is an adenoviral, rhabdoviral vector, retroviral vector, adeno-associated vector, poxviral vector, herpes viral vector, or Sindbis viral vector. 
     
     
       28. The method of claim 10, wherein said composition further comprises a pharmaceutically acceptable excipient, diluent, or salt. 
     
     
       29. The method of claim 10, further comprising delivering said nucleic acid molecule into a cell of the subject, wherein said nucleic acid molecule reduces or inhibits expression of the pathogenic APOL1 polypeptide in the cell. 
     
     
       30. The method of claim 10, wherein said subject is a human. 
     
     
       31. The method of claim 30, wherein said subject is of African or Hispanic ancestry. 
     
     
       32. The method of claim 10, wherein said renal disease is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), end-stage kidney disease (ESKD), hypertensive ESKD, nephropathy secondary to systemic lupus erythematosus, diabetic nephropathy, hypertensive nephropathy, IgA nephropathy, nephritis, human immunodeficiency virus (HIV)-associated nephropathy, non-diabetic chronic kidney disease, and xanthine oxidase deficiency. 
     
     
       33. The method of claim 32, wherein said renal disease is FSGS or ESKD. 
     
     
       34. The method of claim 10, wherein the nucleic acid molecule comprises a locked nucleic acid (LNA). 
     
     
       35. The method of claim 24, wherein the nucleic acid molecule decreases the level of expression of the pathogenic APOL1 polypeptide by at least 50%. 
     
     
       36. The method of claim 10, wherein the subject is homozygous for the G1 allele, G2 allele, G3 allele, and/or del6 allele of APOL1. 
     
     
       37. The method of claim 12, wherein the siRNA molecule contains 3′ overhangs selected from the group consisting of:
 i) a single uracil overhang at each 3′ end of the siRNA; 
 ii) a double uracil overhang at each 3′ end of the siRNA; 
 iii) a single thymine overhang at each 3′ end of the siRNA; or 
 iv) a double uracil overhang at each 3′ end of the siRNA.