Methods for Treatment of Alport Syndrome
Provided herein are methods for the treatment of Alport syndrome, using a modified oligonucleotide targeted to miR-21. In certain embodiments, the modified oligonucleotide targeted to miR-21 improves kidney function and/or reduces fibrosis in subjects having Alport syndrome. In certain embodiments, administration of the modified oligonucleotide targeted to miR-21 delays the onset of end-stage renal disease in a subject having Alport syndrome. In certain embodiments, the modified oligonucleotide targeted to miR-21 delays the need for dialysis or kidney transplant in a subject having Alport syndrome.
1 . A method for treating Alport syndrome comprising administering to a subject having Alport syndrome two or more doses of a modified oligonucleotide, wherein the modified oligonucleotide consists of 19 linked nucleosides and has the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′ (SEQ ID NO: 3), where nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein a dose of 1.5 mg/kg is administered at a frequency of two weeks between doses.
2 . The method of claim 1 , wherein the dose is delivered in a pharmaceutically acceptable diluent.
3 . The method of claim 2 , wherein the pharmaceutically acceptable diluent is a saline solution.
4 . The method of claim 3 , wherein the saline solution is a 0.3% sodium chloride solution.
5 . The method of any one of claims 2 to 4 , wherein the concentration of the modified oligonucleotide in the pharmaceutically acceptable diluent is at least 110 mg/mL.
6 . The method of any one of claims 1 to 5 , wherein the dose is a single bolus injection of 110 mg/mL of the modified oligonucleotide.
7 . The method of any one of claims 1 to 6 , wherein the pharmaceutical composition is administered as a subcutaneous injection.
8 . The method of claim 7 , wherein the subcutaneous injection is administered in the anterior abdominal wall of the subject.
9 . The method of any one of claims 1 to 8 , comprising selecting a subject who has been diagnosed with Alport syndrome by clinical, histopathologic, and/or genetic criteria.
10 . The method of any of claims 1 to 9 , wherein the subject has an estimated glomerular filtration rate of 30 ml/min/1.73 m 2 prior to receiving the first dose of the modified oligonucleotide.
11 . The method of claim 15 , wherein the subject has an estimated glomerular filtration rate (eGFR) between 45 and 90 ml/min/1.73 m 2 prior to receiving the first dose of the modified oligonucleotide.
12 . The method of any one of claims 1 to 11 , wherein the estimated glomerular filtration rate of the subject is declining at a rate ≥5 ml/min/1.73 m 2 /year prior to receiving the first dose of the modified oligonucleotide.
13 . The method of any one of claims 1 to 12 , wherein the subject is male, has been diagnosed with X-linked Alport syndrome, and is between 18 and 30 years of age.
14 . The method of any one of claims 1 to 13 , wherein the subject has proteinuria of greater than 300 milligrams of protein per gram of creatinine prior to receiving the first dose of the modified oligonucleotide.
15 . The method of any one of claims 1 to 14 , wherein the subject, following administration of the modified oligonucleotide, experiences an improvement in one or more parameters associated with Alport syndrome selected from the group consisting of:
a. estimated glomerular filtration rate;
b. rate of decline in estimated glomerular filtration rate; and
c. quality of life using the Short Form 36 Health Survey®.
16 . The method of any one of claims 1 to 15 , wherein the subject, following administration of the modified oligonucleotide, exhibits an improvement in one or more renal biomarkers selected from the group consisting of:
a. miR-21 in biopsy tissue;
b. blood urea nitrogen;
c. urine protein/albumin ratio;
d. urine albumin/creatine ratio;
e. creatinine;
f. urine podocyturia;
g. kidney injury molecule-1;
h. beta-2 microglobulin;
i. clusterin;
j. cystatin C;
k. asymmetric dimethylarginine;
l. transforming growth factor-beta;
m. connective tissue growth factor; and
n. neutrophil gelatinase-associated lipocalin.
17 . The method of any one of claims 1 to 16 , wherein one or more of creatinine, cystatin C, kidney injury molecule-1, beta-2 microglobulin, and/or clusterin is measured in a blood sample of the subject.
18 . The method of any one of claims 1 to 16 , wherein one or more of creatinine, cystatin C, kidney injury molecule-1, beta-2 microglobulin, and/or clusterin is measured in a urine sample of the subject.
19 . The method of any one of claims 1 to 18 , wherein the subject has been treated with an angiotensin II converting enzyme (ACE) inhibitor for at least 30 days prior to receiving the first dose of the oligonucleotide.
20 . The method of any one of claims 1 to 19 , wherein the subject has been treated with an angiotensin II receptor blocker (ARB) for at least 30 days prior to receiving the first dose of the oligonucleotide.
21 . The method of claim 19 wherein the angiotensin II converting enzyme (ACE) inhibitors is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril.
22 . The method of claim 20 wherein the angiotensin II receptor blockers (ARB) is selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan.
23 . The method of any one of claims 1 to 22 , wherein at least 24 doses are administered to the subject.
24 . A method for treating Alport syndrome in a subject, the method comprising:
a. selecting a subject who has been diagnosed with Alport syndrome using clinical, histopathologic, and/or genetic criteria;
b. administering to the subject two or more doses of a pharmaceutical composition comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 19 linked nucleosides and has the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′ (SEQ ID NO: 3), where nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5 mg/kg and wherein the doses are administered with a frequency of two weeks between doses,
c. wherein the subject, following administration of the pharmaceutical composition, exhibits an improvement in one or more AS associated parameters selected from:
i. estimated glomerular filtration rate (eGFR);
ii. rate of decline of eGFR; and
iii. quality of life (QOL) as measured by the Short Form 36 Health Survey®.
25 . A method for treating Alport syndrome in a subject, the method comprising:
a. selecting a subject who has been diagnosed with Alport syndrome using clinical, histopathologic, and/or genetic criteria, wherein the subject has:
i. an estimated glomerular filtration rate of at least 30 ml/min/1.73 m 2 ;
ii. a decline in the rate of estimated glomerular filtration rate of ml/min/1.73 m 2 /year;
iii. proteinuria greater equal to or greater than 300 mg protein/g creatinine; and
iv. been treated with a stable dosing regimen of an ACE inhibitor and/or an ARB for at least 30 days;
b. administering to the subject two or more doses of a pharmaceutical composition comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 19 linked nucleosides and has the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′ (SEQ ID NO: 3), where nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5 mg/kg and wherein the doses are administered with a frequency of two weeks between doses,
c. wherein the subject, following administration of the pharmaceutical composition, exhibits an improvement in one or more parameters associated with Alport syndrome selected from:
i. estimated glomerular filtration rate (eGFR);
ii. rate of decline of eGFR; and
iii. quality of life (QOL) as measured by the Short Form 36 Health Survey®.
26 . A method for reducing decline in renal function over time in a subject with Alport syndrome, the method comprising:
a. selecting a subject diagnosed with Alport syndrome confirmed by clinical, histopathologic, and/or genetic criteria, wherein the subject has:
i. an estimated glomerular filtration rate of at least 30 ml/min/1.73 m 2 ;
ii. a decline in the rate of estimated glomerular filtration rate of ml/min/1.73 m 2 /year;
iii. proteinuria greater equal to or greater than 300 mg protein/g creatinine; and
iv. been treated with a stable dosing regimen of an ACE inhibitor and/or an ARB for at least 30 days;
b. administering to the subject two or more doses of a pharmaceutical composition comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 19 linked nucleosides and has the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′ (SEQ ID NO: 3), where nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5 mg/kg and wherein the doses are administered with a frequency of two weeks between doses,
c. wherein the subject, following administration of the pharmaceutical composition, exhibits an improvement in one or more Alport syndrome associated parameters selected from:
i. estimated glomerular filtration rate (eGFR);
ii. rate of decline of eGFR; and
iii. quality of life (QOL) as measured by the Short Form 36 Health Survey®.
27 . The method of any one of claims 1 to 26 , wherein the modified oligonucleotide has the structure:
or a pharmaceutically acceptable salt thereof.
28 . The method of claim 27 , wherein the modified oligonucleotide is present as a pharmaceutically acceptable salt of the structure.
29 . The method of claim 28 , wherein the modified oligonucleotide is present as a sodium salt of the structure.
30 . The method of any one of claims 1 to 29 , wherein the modified oligonucleotide has the structure:
31 . The method of any one of claims 10 to 30 , wherein the estimated glomerular filtration rate is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation.
32 . The method of any one of claims 10 to 30 , wherein the estimated glomerular filtration rate is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation.