阅读说明：本技术 用于治疗奥尔波特综合征的方法 (Methods for treating Alport syndrome ) 是由 T·莱特 于 2018-05-04 设计创作，主要内容包括：本文提供了用于使用靶向于miR-21的经修饰的寡核苷酸治疗奥尔波特综合征的方法。在某些实施方案中,靶向于miR-21的所述经修饰的寡核苷酸改善患有奥尔波特综合征的受试者的肾功能和/或降低其纤维化。在某些实施方案中,靶向于miR-21的所述经修饰的寡核苷酸的给予延迟患有奥尔波特综合征的受试者的终末期肾病的发作。在某些实施方案中,靶向于miR-21的所述经修饰的寡核苷酸延迟患有奥尔波特综合征的受试者对透析或肾移植的需要。(Provided herein are methods for treating alport syndrome using modified oligonucleotides targeted to miR-21. In certain embodiments, the modified oligonucleotide targeted to miR-21 improves renal function and/or reduces fibrosis in a subject 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 transplantation in a subject having alport syndrome.)

1, used for treating Alport syndromeThe method of (a), 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_EC_SATC_SAGTC_STGAU_SAAGC_STA_E-3 '(SEQ ID NO:3) wherein the nucleoside followed by NO subscript is β -D-deoxyribonucleoside, the nucleoside followed by a subscript "E" is a 2' -MOE nucleoside, the nucleoside followed by a subscript "S" is an S-cEt nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein doses of 1.5mg/kg are 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 brine solution is a 0.3% sodium chloride solution.

5. The method of any of claims 2-4, wherein the concentration of the modified oligonucleotide in the pharmaceutically acceptable diluent is at least 110 mg/mL.

6. The method of of any one of claims 1-5, wherein the dose is a single bolus of 110mg/mL of the modified oligonucleotide.

7. The method of of any one of claims 1-6, wherein the pharmaceutical composition is administered as a subcutaneous injection.

8. The method of claim 7, wherein the subcutaneous injection is administered in the subject's anterior abdominal wall.

9. The method of of any one of claims 1-8, comprising selecting a subject who has been diagnosed as having alport syndrome by clinical, histopathological, and/or genetic criteria.

10. The method of of any one of claims 1-9, wherein the subject's estimated glomerular filtration rate is 30ml/min/1.73m prior to receiving a dose of the modified oligonucleotide²。

11. The method of claim 15, wherein the subject's estimated glomerular filtration rate (eGFR) is at 45 and 90ml/min/1.73m prior to receiving the th dose of the modified oligonucleotide²In the meantime.

12. The method of of any one of claims 1-11, wherein the subject's estimated glomerular filtration rate is at or greater than 5ml/min/1.73m prior to receiving the dose of the modified oligonucleotide²The rate per year decreases.

13. The method of of any one of claims 1-12, wherein the subject is a male, has been diagnosed with X-linked alport syndrome, and is between the ages of 18 and 30.

14. The method of of any one of claims 1-13, wherein the subject's proteinuria is greater than 300 milligrams protein per gram creatinine prior to receiving the dose of the modified oligonucleotide.

15. The method of of any one of claims 1 to 14, wherein the subject experiences an improvement in or more parameters associated with alport syndrome selected from the group consisting of:

a. estimated glomerular filtration rate;

b. an estimated rate of decrease in glomerular filtration rate; and

c. using Short Form 36Health

16. The method of any of claims 1-15, wherein the subject 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. urinary protein/albumin ratio;

d. urinary albumin/creatine ratio;

e. creatinine;

urine podocyte urine;

g. kidney injury molecule-1;

h, β -2 microglobulin;

i. a cluster element;

j. cystatin C;

k. asymmetric dimethylarginine;

transforming growth factor- β;

connective tissue growth factor; and

a neutrophil gelatinase-associated lipocalin.

17. The method of of any one of claims 1-16, wherein or more of creatinine, cystatin C, renal injury molecule-1, β -2 microglobulin, and/or clusterin are measured in a blood sample of the subject.

18. The method of of any one of claims 1-16, wherein or more of creatinine, cystatin C, renal injury molecule-1, β -2 microglobulin, and/or clusterin are measured in a urine sample of the subject.

19. The method of of any one of claims 1-18, wherein the subject has been treated with an angiotensin II converting enzyme (ACE) inhibitor for at least 30 days prior to receiving the dose of oligonucleotide.

20. The method of of any one of claims 1-19, wherein the subject has been treated with an angiotensin II receptor blocker (ARB) for at least 30 days prior to receiving the dose of oligonucleotide.

21. The method of claim 19 wherein the angiotensin II converting enzyme (ACE) inhibitor is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril.

22. The method according to claim 20, wherein the angiotensin II receptor blocker (ARB) is selected from the group consisting of candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan and eprosartan.

23. The method of any of claims 1-22, 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 as having alport syndrome using clinical, histopathological, 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_EC_SATC_SAGTC_STGAU_SAAGC_STA_E-3' (SEQ ID NO:3) wherein the nucleoside followed by the subscript is β -D-deoxyribonucleoside, followed by the subscript "The nucleoside of E "is a 2' -MOE nucleoside; the nucleoside followed by the subscript "S" is an S-cEt nucleoside and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5mg/kg, and wherein the dose is administered at a frequency of two weeks between doses,

c. wherein after administration of the pharmaceutical composition, the subject exhibits an improvement of or more AS-associated parameters selected from the group consisting of:

i. estimated glomerular filtration rate (eGFR);

rate of decline of egfr; and

iii, e.g. by Short Form 36Health

25, a method for treating alport syndrome in a subject, the method comprising:

a. selecting a subject who has been diagnosed as having alport syndrome using clinical, histopathological, and/or genetic criteria, wherein the subject:

i. has a viscosity of at least 30ml/min/1.73m²The estimated glomerular filtration rate of;

ii, having a molecular weight of not less than 5ml/min/1.73m²A rate decrease in estimated glomerular filtration rate per year;

proteinuria having greater than or equal to 300mg protein/g creatinine; and is

Has 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_EC_SATC_SAGTC_STGAU_SAAGC_STA_E-3 '(SEQ ID NO:3) wherein the following nucleoside without subscript is β -D-deoxyribonucleoside and the following nucleoside with subscript "E" is 2' -MOAn E nucleoside; the nucleoside followed by the subscript "S" is an S-cEt nucleoside and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5mg/kg, and wherein the dose is administered at a frequency of two weeks between doses,

c. wherein following administration of the pharmaceutical composition, the subject exhibits an improvement in or more parameters associated with Alport syndrome selected from the group consisting of:

i. estimated glomerular filtration rate (eGFR);

rate of decline of egfr; and

iii, e.g. by Short Form 36Health

26, a method for reducing a decline in renal function over time in a subject having alport syndrome, the method comprising:

a. selecting a subject identified as having Alport syndrome by clinical, histopathological, and/or genetic criteria, wherein the subject:

i. has a viscosity of at least 30ml/min/1.73m²The estimated glomerular filtration rate of;

ii, having a molecular weight of not less than 5ml/min/1.73m²A rate decrease in estimated glomerular filtration rate per year;

proteinuria having greater than or equal to 300mg protein/g creatinine; and is

Has 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_EC_SATC_SAGTC_STGAU_SAAGC_STA_E-3' (SEQ ID NO:3) wherein the following non-subscripted nucleoside is β -D-deoxyribonucleosideThe nucleoside having the subscript "E" is a 2' -MOE nucleoside; the nucleoside followed by the subscript "S" is an S-cEt nucleoside and each internucleoside linkage is a phosphorothioate internucleoside linkage, wherein the dose of the modified oligonucleotide is 1.5mg/kg, and wherein the dose is administered at a frequency of two weeks between doses,

c. wherein following administration of the pharmaceutical composition, the subject exhibits improvements in one or more Alport syndrome-associated parameters selected from the group consisting of:

i. estimated glomerular filtration rate (eGFR);

rate of decline of egfr; and

iii, e.g. by Short Form 36Health

27. The method of any of claims 1-26, wherein the modified oligonucleotide has the structure:

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 of claims 1-29, wherein the modified oligonucleotide has the structure:

31. the method of of any one of claims 10-30, wherein the estimated glomerular filtration rate is calculated using the chronic renal disease epidemiological cooperation study (CKD-EPI) creatinine equation.

32. The method of of any one of claims 10-30, wherein the estimated glomerular filtration rate is calculated using the chronic renal disease epidemiological cooperation study (CKD-EPI) creatinine-cystatin C formula.

Technical Field

Provided herein are methods and compositions for treating alport syndrome.

Background

Type IV collagen (the major components of basement membrane) is a family of six α chains, the α 0-1 collagen (type IV), the α -2 collagen (type IV), the α -3 collagen (type IV), the α -4 collagen (type IV), the α -5 collagen (type IV) and the α -6 collagen (type IV), the α -3, α -4 and α -6 chains of collagen IV are essential components of the collagen network of the Glomerular Basement Membrane (GBM) which performs an important function in filtering blood through the kidneys.

Alport syndrome is genetic forms of kidney disease, in which an abnormal type of Glomerular Basement Membrane (GBM) is produced, leading to interstitial fibrosis, glomerulosclerosis and ultimately loss of renal function, said disease is also often characterized by hearing defects and ocular abnormalities alport syndrome is caused by mutations in Col4a3, Col4a4 or Col4a5, which encode type IV collagen α (IV), α (IV) and α (IV) chains, respectively, mutations in the Col4a5 gene on the X chromosome result in an X-linked form of alport syndrome, which accounts for 85% of all cases of the disease, the autosomal form is due to inheritance of mutations in each copy of Col4a3 or Col4a4, which are each located on chromosome 2, the autosomal dominant form of Col4a4 gene is due to the fact that the genetic mutation in Col4a3 or the gene-inactivated form of the Col4a4 gene is more severe in male females than in the de novo stage , but the majority of cases are due to the same degree of female cases of severe genetic disease.

Disclosure of Invention

Embodiment 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_EC_SATC_SAGTC_STGAU_SAAGC_STA_E-3’(SEQ ID NO:3), wherein the nucleoside followed by the subscript is β -D-deoxyribonucleoside, the nucleoside followed by the subscript "E" is a 2' -MOE nucleoside, the nucleoside followed by the subscript "S" is an S-cEt nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein a dose of 1.5mg/kg is administered at a frequency of two weeks between doses.