OPA1 antisense oligomers for treatment of conditions and diseases

Abstract

A variable splicing event in a gene can result in a non-productive mRNA transcript, which in turn can result in abnormal protein expression, and a therapeutic agent that can target a variable splicing event in a gene can modulate the expression level of a functional protein and / or inhibit abnormal protein expression in a patient. Such therapeutic agents are useful for the treatment of conditions or diseases caused by protein deficiency and / or mitochondrial function deficiency.

Claims

1. A method for treating a subject suffering from a disease or condition, or for reducing the likelihood of said subject suffering from said disease or condition, the method comprising administering to the subject a pharmaceutical composition comprising an antisense oligomer. The antisense oligomer comprises a nucleotide sequence having at least 80% sequence identity with the sequence shown in any of SEQ ID NO: 6-275 or 280-299, and The method includes administering the pharmaceutical composition to one eye of the subject at a dose of about 0.005 mg to about 20 mg of the antisense oligomer.

2. A method for treating a subject suffering from a disease or condition, or for reducing the likelihood of said subject suffering from said disease or condition, the method comprising administering to said subject a pharmaceutical composition comprising an antisense oligomer. The antisense oligomer comprises a nucleotide sequence having at least 80% sequence identity with the sequence shown in any of SEQ ID NO: 6-275 or 280-299. The disease or condition mentioned includes autosomal dominant optic atrophy (ADOA), and the subject mentioned is characterized by: (i) Possesses a heterozygous OPA1 gene variant; (ii) It has a transparent ocular medium to allow full visualization of the vitreous body and fundus and to achieve the appropriate quality for all ophthalmic assessments; (iii) AREDS clinical lens criteria for posterior subcapsular (PSC) opacity <1; (iv) A BCVA EDTRS alphabet score of ≥35 and ≤70, measured individually for each eye where the pharmaceutical composition was applied; or Any combination of (v) (i)-(iv).

3. A method for treating a subject suffering from a disease or condition, or for reducing the likelihood of said subject suffering from said disease or condition, the method comprising administering to said subject a pharmaceutical composition comprising an antisense oligomer. The antisense oligomer comprises a nucleotide sequence having at least 80% sequence identity with the sequence shown in any of SEQ ID NO: 6-275 or 280-299. The disease or condition mentioned includes autosomal dominant optic atrophy (ADOA), and the subject mentioned is characterized by: (1) The OPA1 gene does not have gain-of-function variants or complex heterozygous or homozygous pathogenic or potentially pathogenic variants; (2) The OPA1 gene does not contain only benign or possibly benign variants; (3) Does not have the ocular morphological features of (syndromic) ADOA (ADOA-plus); (4) Not diagnosed with Behr syndrome; (5) The other gene associated with optic nerve atrophy or retinal disease does not have a known pathogenic mutation; (6) Does not have diabetic retinopathy with the potential to develop into proliferative diabetic retinopathy, diabetic macular edema or optic neuropathy. (7) Neither eye has any ocular symptoms or a history of any ocular symptoms; (8) No history of intraocular surgery or corneal surgery, including refractive surgery, in either eye within 12 weeks prior to the application; (9) No history of retinal photocoagulation; (10) No history of retinal vein occlusion or no retinal vein occlusion; (11) There is no condition that would be considered a risk of uveitis or eye infection due to any of the following: an active outbreak of non-infectious uveitis or an onset of infectious uveitis or other eye infection in either eye within 12 months prior to the application; (12) Neither eye has dry age-related macular degeneration; (13) Does not have high myopia (refractive error > 6); (14) No history of cancer (except for a diagnosis of basal cell carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ that has been successfully treated); (15) No drugs or treatments that could or may cause optic neuropathy have been used or used at any time; (16) No history of any nutritional deficiency (including B12 and / or folic acid deficiency), or no known serum B12 or folic acid deficiency, and no history of weight loss surgery; or (17) Any combination of (1)-(16).

4. A method for treating a subject suffering from a disease or condition or reducing the likelihood of said subject suffering from said disease or condition, the method comprising administering to said subject a pharmaceutical composition comprising an antisense oligomer, wherein said antisense oligomer is a compound according to any one of the following chemical structures: ; ; ; ; or its pharmaceutically acceptable salt.

5. The method of any one of claims 2 to 4, wherein the method comprises administering the pharmaceutical composition to one eye of the subject at a dose of about 0.005 mg to about 20 mg of the antisense oligomer.

6. The method of any one of claims 1 to 5, wherein the method comprises administering the pharmaceutical composition to one eye of the subject at the following doses of the antisense oligomer: about 0.005 mg to about 15 mg, about 0.005 mg to about 10 mg, about 0.005 mg to about 5 mg, about 0.005 mg to about 1 mg, about 0.01 mg to about 15 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 2.5 mg, about 0.01 mg to about 1.0 mg, about 0.01 mg to about 0.5 mg, about 0.01 mg to about 0.25 mg, about 0.01 mg to about 0.1 mg, about 0.01 mg to about 0.05 mg, about 0.05 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.05 mg to about 2.5 mg, about 0.05 mg to about 1.0 mg, about 0.05 mg to about 0.5 mg. mg, about 0.05 mg to about 0.25 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 2.5 mg, about 0.1 mg to about 1.5 mg, about 0.1 mg to about 1.0 mg, about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 0.25 mg.

7. The method of any one of claims 1 to 5, wherein the method comprises administering the pharmaceutical composition to one eye of the subject at the following doses of the antisense oligomer: about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10 mg, about 12.5 mg. mg, approximately 15 mg, approximately 17.5 mg, or approximately 20 mg.

8. The method of any one of claims 1 to 5, wherein the method comprises administering the pharmaceutical composition to one eye of the subject in the following doses of the antisense oligomer: about 0.1 mg to about 1.5 mg, about 0.1 mg to about 1.4 mg, about 0.1 mg to about 1.2 mg, about 0.1 mg to about 1.0 mg, about 0.1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.5 mg, about 0.1 mg to about 0.3 mg, about 0.2 mg to about 1.5 mg, about 0.2 mg to about 1.4 mg, about 0.2 mg to about 1.2 mg, about 0.2 mg to about 1.0 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.5 mg, about 0.3 mg to about 1.5 mg, about 0.3 mg to about 1.4 mg, about 0.3 mg to about 1.2 mg, about 0.3 mg to about 1.0 mg. mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.5 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1.4 mg, about 0.5 mg to about 1.2 mg, about 0.5 mg to about 1.0 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.7 mg to about 1.5 mg, about 0.7 mg to about 1.4 mg, about 0.7 mg to about 1.2 mg, about 0.7 mg to about 1.0 mg, about 0.8 mg to about 1.5 mg, about 0.8 mg to about 1.4 mg, about 0.8 mg to about 1.2 mg, about 0.8 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 1.4 mg, about 1.0 mg to about 1.2 mg, about 1.2 mg to about 1.5 mg, or about 1.2 mg to about 1.4 mg.

9. The method of any one of claims 1 to 5, wherein the method comprises administering the pharmaceutical composition to one eye of the subject at the following doses of the antisense oligomer: about 0.1 mg, about 0.2 mg, about 0.3 mg, 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, or about 1.5 mg.

10. The method of any one of claims 1 to 9, wherein the method comprises administering the pharmaceutical composition to one eye of the subject in the following volumes: about 5 µL to about 250 µL, about 10 µL to about 250 µL, about 20 µL to about 250 µL, about 30 µL to about 250 µL, about 40 µL to about 250 µL, about 50 µL to about 250 µL, about 60 µL to about 250 µL, about 70 µL to about 250 µL, about 80 µL to about 250 µL, about 100 µL to about 250 µL, about 120 µL to about 250 µL, about 150 µL to about 250 µL, about 160 µL to about 250 µL, about 180 µL to about 500 µL, about 200 µL to about 250 µL, about 220 µL to about 250 µL, about 5 µL to about 220 µL, about 10 µL to about 25 ... Approximately 20 µL to 220 µL, approximately 30 µL to 220 µL, approximately 40 µL to 220 µL, approximately 50 µL to 220 µL, approximately 60 µL to 220 µL, approximately 70 µL to 220 µL, approximately 80 µL to 220 µL, approximately 100 µL to 220 µL, approximately 120 µL to 220 µL, approximately 150 µL to 220 µL, approximately 160 µL to 220 µL, approximately 180 µL to 220 µL, approximately 5 µL to 200 µL, approximately 10 µL to 200 µL, approximately 20 µL to 200 µL, approximately 30 µL to 200 µL, approximately 40 µL to 200 µL, approximately 50 µL to 200 µL, approximately 60 µL to 200 µL, approximately 70 µL to 220 µL, approximately 70 µL to 220 µL, approximately 100 µL to 220 µL, approximately 120 µL to 220 µL, approximately 150 µL to 220 µL, approximately 160 µL to 220 µL, approximately 180 µL to 220 µL, approximately 5 µL to 200 µL, approximately 10 µL to 200 µL, approximately 200 µL to 200 µL, approximately 30 µL to 200 µL, approximately 40 µL to 200 µL, approximately 50 µL to 200 µL, approximately 60 µL to 200 µL, approximately 70 µL to 220 µL, approximately 70 µL to 220 µL, approximately 100 µL to Approximately 10 µL to 200 µL, approximately 80 µL to 200 µL, approximately 100 µL to 200 µL, approximately 120 µL to 200 µL, approximately 150 µL to 200 µL, approximately 160 µL to 200 µL, approximately 180 µL to 200 µL, approximately 5 µL to 180 µL, approximately 10 µL to 180 µL, approximately 20 µL to 180 µL, approximately 30 µL to 180 µL, approximately 40 µL to 180 µL, approximately 50 µL to 180 µL, approximately 60 µL to 180 µL, approximately 70 µL to 180 µL, approximately 80 µL to 180 µL, approximately 100 µL to 180 µL, approximately 120 µL to 180 µL, approximately 150 µL to 180 µL, approximately 5 µL to 150 µL, approximately 10 About 150 µL, about 20 µL to about 150 µL, about 30 µL to about 150 µL, about 40 µL to about 150 µL, about 50 µL to about 150 µLµL, about 60 µL to about 150 µL, about 70 µL to about 150 µL, about 80 µL to about 150 µL, about 100 µL to about 150 µL, about 120 µL to about 150 µL, about 5 µL to about 150 µL, about 10 µL to about 120 µL, about 20 µL to about 120 µL, about 30 µL to about 120 µL, about 40 µL to about 120 µL, about 50 µL to about 120 µL, about 60 µL to about 120 µL, about 70 µL to about 120 µL, about 80 µL to about 120 µL, about 100 µL to about 120 µL, about 5 µL to about 100 µL, about 10 µL to about 100 µL, about 20 µL to about 100 µL, about 30 µL to about 100 µL, about 40 µL to about 100 µL µL, about 50 µL to about 100 µL, about 60 µL to about 100 µL, about 70 µL to about 100 µL, about 80 µL to about 100 µL, about 5 µL to about 80 µL, about 10 µL to about 80 µL, about 20 µL to about 80 µL, about 30 µL to about 80 µL, about 40 µL to about 80 µL, about 50 µL to about 80 µL, about 60 µL to about 80 µL, about 5 µL to about 60 µL, about 10 µL to about 60 µL, about 20 µL to about 60 µL, about 30 µL to about 60 µL, about 40 µL to about 60 µL, or about 50 µL to about 60 µL.

11. The method of any one of claims 1 to 9, wherein the method comprises administering the pharmaceutical composition to one eye of the subject in the following volumes: about 5 µL, about 8 µL, about 10 µL, about 12 µL, about 15 µL, about 18 µL, about 20 µL, about 25 µL, about 28 µL, about 30 µL, about 35 µL, about 40 µL, about 45 µL, about 48 µL, about 50 µL, about 55 µL, about 60 µL, about 65 µL, about 70 µL, about 75 µL, about 80 µL, about 90 µL, about 100 µL, about 120 µL, about 150 µL, about 160 µL, about 180 µL, about 200 µL, about 220 µL, or about 250 µL.

12. The method of any one of claims 1 to 11, wherein the method comprises administering the pharmaceutical composition to both the left and right eyes of the subject.

13. The method of claim 12, wherein the method comprises administering the pharmaceutical composition to both the left and right eyes of the subject at the same dose.

14. The method of claim 12, wherein the method comprises administering the pharmaceutical composition to the left and right eyes of the subject at different doses.

15. The method of any one of claims 1 to 3 or 5 to 14, wherein the antisense oligomer comprises a nucleotide sequence having at least 90% or 100% sequence identity with the sequence shown in any one of SEQ ID NO: 6-275 or 280-299.

16. The method of any one of claims 1 to 3 or 5 to 14, wherein the antisense oligomer comprises a nucleotide sequence having at least 80%, at least 90%, or 100% sequence identity with the sequence shown in any one of SEQ ID NO: 36, 236, 242, 250, 280-283, 288, or 290-292.

17. The method of any one of claims 1 to 3 or 5 to 14, wherein the antisense oligomer regulates the splicing of nonsense-mediated RNA decay exons (NMD exons) from precursor mRNA in the cells of the subject, wherein the precursor mRNA encodes the OPA1 protein and contains the NMD exons, thereby regulating the level of processed mRNA processed from the precursor mRNA and regulating the expression of the OPA1 protein in the cells.

18. The method of claim 17, wherein the antisense oligomer: (a) Binds to the target region of the precursor mRNA; (b) Modulating the binding of factors involved in the splicing of the NMD exons; or (c) A combination of (a) and (b).

19. The method of claim 18, wherein the targeting portion of the precursor mRNA is adjacent to the NMD exon.

20. The method of claim 18, wherein the targeting portion of the precursor mRNA is located at up to about 1,500 nucleotides, about 1,000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the 5' end of the NMD exon.

21. The method of claim 18, wherein the targeting portion of the precursor mRNA is located at at least about 1,500 nucleotides, about 1,000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides, about 40 nucleotides, about 30 nucleotides, about 20 nucleotides, about 10 nucleotides, about 5 nucleotides, about 4 nucleotides, about 2 nucleotides, or about 1 nucleotide upstream of the 5' end of the NMD exon.

22. The method of claim 18, wherein the targeting portion of the precursor mRNA is located downstream of the 3' end of the NMD exon for up to about 1,500 nucleotides, about 1,000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides.

23. The method of claim 18, wherein the targeting portion of the precursor mRNA is located downstream of the 3' end of the NMD exon by at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides, about 40 nucleotides, about 30 nucleotides, about 20 nucleotides, about 10 nucleotides, about 5 nucleotides, about 4 nucleotides, about 2 nucleotides, or about 1 nucleotide.

24. The method of claim 18, wherein the target portion of the precursor mRNA is located at up to about 1,500 nucleotides, about 1,000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr3193628509.

25. The method of claim 18, wherein the target portion of the precursor mRNA is located approximately 1500 nucleotides, approximately 1000 nucleotides, approximately 800 nucleotides, approximately 700 nucleotides, approximately 600 nucleotides, approximately 500 nucleotides, approximately 400 nucleotides, approximately 300 nucleotides, approximately 200 nucleotides, approximately 100 nucleotides, approximately 80 nucleotides, approximately 70 nucleotides, approximately 60 nucleotides, and approximately 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr3 193628509.

26. The method of claim 18, wherein the target portion of the precursor mRNA is located downstream of the genomic site GRCh38 / hg38:chr3193628616 for up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides.

27. The method of claim 18, wherein the target portion of the precursor mRNA is located approximately 1500 nucleotides, approximately 1000 nucleotides, approximately 800 nucleotides, approximately 700 nucleotides, approximately 600 nucleotides, approximately 500 nucleotides, approximately 400 nucleotides, approximately 300 nucleotides, approximately 200 nucleotides, approximately 100 nucleotides, approximately 80 nucleotides, approximately 70 nucleotides, approximately 60 nucleotides, and approximately 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr3 193628616.

28. The method of claim 18, wherein the targeting portion of the precursor mRNA is located in an intron region between two typical exon regions of the precursor mRNA, and wherein the intron region contains the NMD exon.

29. The method of claim 18, wherein the targeting portion of the precursor mRNA at least partially overlaps with the NMD exon.

30. The method of claim 18, wherein the targeting portion of the precursor mRNA at least partially overlaps with an intron located upstream or downstream of the NMD exon.

31. The method of claim 18, wherein the targeting portion of the precursor mRNA comprises a 5' NMD exon-intron junction or a 3' NMD exon-intron junction.

32. The method of claim 18, wherein the targeting portion of the precursor mRNA is located within the NMD exon.

33. The method of claim 18, wherein the targeting portion of the precursor mRNA comprises about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more consecutive nucleotides of the NMD exon.

34. The method of any one of claims 17 to 33, wherein the NMD exon comprises a sequence having at least 80%, at least 90%, or 100% sequence identity with SEQ ID NO:

279.

35. The method of any one of claims 17 to 33, wherein the NMD exon comprises the sequence of SEQ ID NO:

279.

36. The method of claim 18, wherein the target portion of the precursor mRNA is located within exons GRCh38 / hg38:chr3 193628509 to 193628616 of the inducible nonsense-mediated RNA decay.

37. The method of claim 18, wherein the target portion of the precursor mRNA is located upstream or downstream of the exons GRCh38 / hg38:chr3 193628509 to 193628616 that induce nonsense-mediated RNA decay.

38. The method of claim 18, wherein the targeting portion of the precursor mRNA comprises an exon-intron junction of exons GRCh38 / hg38: chr3 193628509 to 193628616.

39. The method of any one of claims 17 to 38, wherein the OPA1 protein expressed by the processed mRNA is a full-length OPA1 protein or a wild-type OPA1 protein.

40. The method of any one of claims 17 to 38, wherein the OPA1 protein expressed by the processed mRNA is a functional OPA1 protein.

41. The method of any one of claims 17 to 38, wherein the OPA1 protein expressed by the processed mRNA has at least partial functionality compared to the wild-type OPA1 protein.

42. The method of any one of claims 17 to 38, wherein the OPA1 protein expressed by the processed mRNA has at least partial functionality compared to the full-length wild-type OPA1 protein.

43. The method of any one of claims 17 to 42, wherein the antisense oligomer promotes the exclusion of the NMD exon from the precursor mRNA.

44. The method of claim 43, wherein, compared to the absence of the antisense oligomer, the exclusion of the NMD exon from the precursor mRNA in the cells contacted with the antisense oligomer is increased by about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 7 times, about 1.1 to about 8 times, about 1 .1 to 9 times, about 2 to 5 times, about 2 to 6 times, about 2 to 7 times, about 2 to 8 times, about 2 to 9 times, about 3 to 6 times, about 3 to 7 times, about 3 to 8 times, about 3 to 9 times, about 4 to 7 times, about 4 to 8 times, about 4 to 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times.

45. The method of any one of claims 17 to 44, wherein the method causes an increase in the level of the processed mRNA in the cells.

46. ​​The method of claim 45, wherein, compared to the absence of the antisense oligomer, the level of the processed mRNA in the cells contacted with the antisense oligomer increases by about 1.1 times to about 10 times, about 1.5 times to about 10 times, about 2 times to about 10 times, about 3 times to about 10 times, about 4 times to about 10 times, about 1.1 times to about 5 times, about 1.1 times to about 6 times, about 1.1 times to about 7 times, about 1.1 times to about 8 times, about 1.1 times to... Approximately 9 times, approximately 2 times to approximately 5 times, approximately 2 times to approximately 6 times, approximately 2 times to approximately 7 times, approximately 2 times to approximately 8 times, approximately 2 times to approximately 9 times, approximately 3 times to approximately 6 times, approximately 3 times to approximately 7 times, approximately 3 times to approximately 8 times, approximately 3 times to approximately 9 times, approximately 4 times to approximately 7 times, approximately 4 times to approximately 8 times, approximately 4 times to approximately 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, at least approximately 5 times, or at least approximately 10 times.

47. The method of any one of claims 17 to 46, wherein the method causes an increase in the expression of the OPA1 protein in the cells.

48. The method of claim 47, wherein, compared to the absence of the antisense oligomer, the level of the OPA1 protein expressed by the processed mRNA in the cells contacted with the antisense oligomer increases by about 1.1 times to about 10 times, about 1.5 times to about 10 times, about 2 times to about 10 times, about 3 times to about 10 times, about 4 times to about 10 times, about 1.1 times to about 5 times, about 1.1 times to about 6 times, about 1.1 times to about 7 times, about 1.1 times to about 8 times, Approximately 1.1 times to approximately 9 times, approximately 2 times to approximately 5 times, approximately 2 times to approximately 6 times, approximately 2 times to approximately 7 times, approximately 2 times to approximately 8 times, approximately 2 times to approximately 9 times, approximately 3 times to approximately 6 times, approximately 3 times to approximately 7 times, approximately 3 times to approximately 8 times, approximately 3 times to approximately 9 times, approximately 4 times to approximately 7 times, approximately 4 times to approximately 8 times, approximately 4 times to approximately 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, at least approximately 5 times, or at least approximately 10 times.

49. The method of any one of claims 1 to 3 or 5 to 48, wherein the antisense oligomer comprises a main chain modification comprising a thiophosphate bond or a phosphodiamid bond.

50. The method of any one of claims 1 to 3 or 5 to 48, wherein the antisense oligomer comprises phosphodiamidomorpholino, locked nucleic acid, peptide nucleic acid, 2'-O-methyl moiety, 2'-fluorine moiety, 2'-ON-methylacetamide (2'-NMA) or 2'-O-methoxyethyl moiety.

51. The method of any one of claims 1 to 3 or 5 to 48, wherein the antisense oligomer comprises at least one modified sugar moiety.

52. The method of claim 51, wherein each sugar portion is a modified sugar portion.

53. The method of any one of claims 1 to 3 or 5 to 52, wherein the antisense oligomer comprises 5'-methylcytosine (5'-MeC).

54. The method of any one of claims 1 to 3 or 5 to 53, wherein each cytosine of the antisense oligomer is 5'-methylcytosine (5'-MeC).

55. The method of any one of claims 1 to 3 or 5 to 54, wherein the antisense oligomer comprises 5'-methyluracil (5'-MeU).

56. The method of any one of claims 1 to 3 or 5 to 55, wherein the antisense oligomer comprises a thiophosphate bond.

57. The method of any one of claims 1 to 3 or 5 to 56, wherein each nucleoside bond of the ASO is a phosphate thioester bond.

58. The method of any one of claims 1 to 3 or 5 to 57, wherein the antisense oligomer comprises locked nucleic acid (LNA).

59. The method of any one of claims 1 to 3 or 5 to 58, wherein the length of the antisense oligomer is 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases, 11 to 15 nucleobases, 12 to 50 nucleobases, 12 to 40 nucleobases, 12 to 35 nucleobases, 12 to 30 nucleobases, 12 to 25 nucleobases, 12 to 20 nucleobases, or 12 to 15 nucleobases.

60. The method of any one of claims 1 to 3 or 5 to 59, wherein the antisense oligomer is a compound according to any one of the following chemical structures: ; ; ; ; or its pharmaceutically acceptable salt.

61. The method of claim 4 or 60, wherein the antisense oligomer is a compound according to any one of the following structures: ; ; ; ;or .

62. The method of any one of claims 1 to 61, wherein the pharmaceutical composition is a liquid composition.

63. The method of any one of claims 1 to 62, wherein the method comprises administering the pharmaceutical composition by bolus injection.

64. The method of any one of claims 1 to 63, wherein the method comprises administering the pharmaceutical composition by bolus injection within 1 to 60 minutes, 1 to 50 minutes, 1 to 40 minutes, 1 to 30 minutes, 1 to 20 minutes, 1 to 10 minutes, 1 to 5 minutes, or 1 to 3 minutes.

65. The method of any one of claims 1 to 64, wherein the antisense oligomer is dissolved or diluted in a solution containing one or more of sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, or water for injection.

66. The method of any one of claims 1 to 64, wherein the antisense oligomer is dissolved or diluted in a solution comprising one or more of sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, and water for injection.

67. The method of any one of claims 1 to 66, wherein the antisense oligomer is dissolved or diluted in an isotonic solution.

68. The method of any one of claims 1 to 67, wherein the antisense oligomer is dissolved or diluted in a phosphate buffer solution with a pH of at least 5.

8.

69. The method of any one of claims 1 to 67, wherein the antisense oligomer is dissolved or diluted in a phosphate buffer (pH 6.6–7.6) solution.

70. The method of any one of claims 1 to 69, wherein the pharmaceutical composition does not contain a preservative.

71. The method of any one of claims 1 to 70, wherein the antisense oligomer is present in the pharmaceutical composition at a concentration of about 2 mg / mL to about 200 mg / mL.

72. The method of any one of claims 1 to 70, wherein the antisense oligomer is present in the pharmaceutical composition at the following concentrations: about 2 mg / mL to about 200 mg / mL, about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 200 mg / mL, about 15 mg / mL to about 200 mg / mL, about 20 mg / mL to about 200 mg / mL, about 25 mg / mL to about 200 mg / mL, about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, or 2 mg / mL to about 150 mg / mL. mg / mL, about 5 mg / mL to about 150 mg / mL, about 10 mg / mL to about 150 mg / mL, about 15 mg / mL to about 150 mg / mL, about 20 mg / mL to about 150 mg / mL, about 25 mg / mL to about 150 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL to about 150 mg / mL, 2 mg / mL to about 100 mg / mL, about 5 mg / mL to about 100 mg / mL, about 10 mg / mL to about 100 mg / mL, about 15 mg / mL to about 100 mg / mL, about 20 mg / mL to about 100 mg / mL, about 25 mg / mL mg / mL to about 100 mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, 2 mg / mL to about 80 mg / mL, about 5 mg / mL to about 80 mg / mL, about 10 mg / mL to about 80 mg / mL, about 15 mg / mL to about 80 mg / mL, about 20 mg / mL to about 80 mg / mL, about 25 mg / mL to about 80 mg / mL, about 30 mg / mL to about 10 ...mg / mL to about 80 mg / mL, about 35 mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, 2 mg / mL to about 60 mg / mL, about 5 mg / mL to about 60 mg / mL, about 10 mg / mL to about 60 mg / mL, about 15 mg / mL to about 60 mg / mL, about 20 mg / mL to about 60 mg / mL, about 25 mg / mL to about 60 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, about 40 mg / mL to about 60 mg / mL, 2 mg / mL to about 40 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 40 mg / mL, about 20 mg / mL to about 40 mg / mL, or about 25 mg / mL to about 40 mg / mL.

73. The method of any one of claims 1 to 70, wherein the antisense oligomer is present in the pharmaceutical composition at concentrations of about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, or about 200 mg / mL.

74. The method of any one of claims 1 to 73, wherein the pharmaceutical composition is prepared by diluting a concentrate containing the antisense oligomer.

75. The method of claim 74, wherein the antisense oligomer is present in the concentrate at concentrations of: about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL... mg / mL to about 150 mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, about 30 mg / mL to about 80 mg / mL, about 35 mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL.

76. The method of claim 74, wherein the antisense oligomer is present in the concentrate at the following concentrations: about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, or about 200 mg / mL.

77. The method of any one of claims 74 to 76, wherein the concentrate is a phosphate buffer solution.

78. The method of any one of claims 1 to 77, wherein the subject is a human subject.

79. The method of any one of claims 1 or 4 to 78, wherein the disease or symptom is related to a deficiency in the amount or activity of the OPA1 protein.

80. The method of any one of claims 1 to 79, wherein the disease or symptom includes an eye disease or symptom.

81. The method of any one of claims 1 to 79, wherein the disease or symptom includes cardiovascular disease or symptom.

82. The method of any one of claims 1 to 79, wherein the disease or symptom includes a neurological disease or symptom.

83. The method of any one of claims 1 to 79, wherein the disease or condition includes ADOA-plus syndrome; mitochondrial disease; glaucoma; normal-tension glaucoma; Charcot-Marie-Tooth disease; mitochondrial dysfunction; diabetic retinopathy; age-related macular degeneration; retinal ganglion cell death; mitochondrial fission-mediated mitochondrial dysfunction; progressive extraocular muscle palsy; deafness; ataxia; motor neuropathy; sensory neuropathy; myopathy; Behr syndrome; brain dysfunction; encephalopathy; peripheral neuropathy; fatal. Infantile mitochondrial encephalomyopathy; hypertrophic cardiomyopathy; spastic-ataxia syndrome; sensorimotor peripheral neuropathy; hypotonia; gastrointestinal motility disorders and dysphagia; optic atrophy; optic atrophy plus syndrome; mitochondrial DNA depletion syndrome; late-onset cardiomyopathy; diabetic cardiomyopathy; Alzheimer's disease; focal segmental glomerulosclerosis; nephropathy; Huntington's disease; cognitive decline with healthy aging; prions; late-onset dementia and Parkinson's disease; mitochondrial myopathy; Leigh syndrome; Friedreich's ataxia; Parkinson's disease; MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes); pyruvate dehydrogenase complex deficiency; chronic kidney disease; Leber hereditary optic neuropathy; obesity; age-related systemic neurodegeneration; skeletal muscle atrophy; ischemic injury to the heart and brain; or massive hepatocyte apoptosis.

84. The method of any one of claims 1 to 79, wherein the disease or symptom includes type 1 optic atrophy.

85. The method of any one of claims 1 or 4 to 79, wherein the disease or symptom includes autosomal dominant optic atrophy (ADOA).

86. The method of claim 85, wherein the subject is characterized in that: (i) Possesses a heterozygous OPA1 gene variant; (ii) It has a transparent ocular medium to allow full visualization of the vitreous body and fundus and to achieve the appropriate quality for all ophthalmic assessments; (iii) AREDS clinical lens criteria for posterior subcapsular (PSC) opacity <1; (iv) A BCVA EDTRS alphabet score of ≥35 and ≤70, measured individually for each eye where the pharmaceutical composition was applied; or Any combination of (v) (i)-(iv).

87. The method of claim 86, wherein the subject is further characterized by: (1) The OPA1 gene does not have gain-of-function variants or complex heterozygous or homozygous pathogenic or potentially pathogenic variants; (2) The OPA1 gene does not contain only benign or possibly benign variants; (3) Does not have the ocular morphological features of (syndromic) ADOA (ADOA-plus); (4) Not diagnosed with Behr syndrome; (5) The other gene associated with optic nerve atrophy or retinal disease does not have a known pathogenic mutation; (6) Does not have diabetic retinopathy with the potential to develop into proliferative diabetic retinopathy, diabetic macular edema or optic neuropathy. (7) Neither eye has any ocular symptoms or a history of any ocular symptoms; (8) No history of intraocular surgery or corneal surgery, including refractive surgery, in either eye within 12 weeks prior to the application; (9) No history of retinal photocoagulation; (10) No history of retinal vein occlusion or no retinal vein occlusion; (11) There is no condition that would be considered a risk of uveitis or eye infection due to any of the following: an active outbreak of non-infectious uveitis or an onset of infectious uveitis or other eye infection in either eye within 12 months prior to the application; (12) Neither eye has dry age-related macular degeneration; (13) Does not have high myopia (refractive error > 6); (14) No history of cancer (except for a diagnosis of basal cell carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ that has been successfully treated); (15) No drugs or treatments that could or may cause optic neuropathy have been used or used at any time; (16) No history of any nutritional deficiency (including B12 and / or folic acid deficiency), or known serum B12 or folic acid deficiency, and has not undergone weight loss surgery; (17) Any combination of (1)-(16).

88. The method of any one of claims 1 to 87, wherein administration comprises administering multiple doses of the pharmaceutical composition to the human subject.

89. The method of claim 88, wherein administration comprises administering a first dose of the pharmaceutical composition to the human subject and administering subsequent doses of the pharmaceutical composition to the human subject.

90. The method of claim 89, wherein the subsequent dose is lower than the previous dose after administration intolerance is indicated by the previous dose.

91. The method of claim 89, wherein after administration tolerance to the previous dose is indicated, the subsequent dose is the same as the previous dose.

92. The method of claim 89, wherein the subsequent dose is higher than the previous dose after administration tolerance to the indicated previous dose has been reached.

93. The method of claim 89, wherein after the administration of the previous dose has been effective, the subsequent dose is the same as the previous dose.

94. The method of claim 89, wherein the subsequent dose is lower than the previous dose after the administration of the indicated previous dose has been effective.

95. The method of claim 89, wherein the subsequent dose is higher than the previous dose after the administration of the indicated previous dose has been ineffective.

96. The method of any one of claims 1 to 95, wherein the pharmaceutical composition is administered via intraventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, synovial injection, intravitreal administration, subretinal injection, local application, implantation, or intravenous injection.

97. The method of any one of claims 1 to 87, wherein the pharmaceutical composition is administered via intravitreal injection.

98. The method of any one of claims 1 to 97, wherein the method further comprises administering an additional therapeutic agent.

99. The method of claim 98, wherein the additional therapeutic agent comprises a small molecule.

100. The method of claim 98, wherein the additional therapeutic agent comprises an antisense oligomer.

101. The method of claim 98, wherein the additional therapeutic agent comprises an ophthalmic drug.

102. An antisense oligomer, which is a compound according to any of the following structures: ; ; ; ; or its pharmaceutically acceptable salt.

103. An antisense oligomer having any of the following structures: ; ; ; ;or .

104. A pharmaceutical formulation comprising: (a) an antisense oligomer, wherein the antisense oligomer comprises a sequence having at least 80% sequence identity with any one of SEQ ID NO: 6-275 or 280-299; and (b) A pharmaceutically acceptable diluent; The antisense oligomer is dissolved or suspended in solution at a concentration of about 1 mg / mL to about 200 mg / mL.

105. A pharmaceutical formulation comprising: (a) antisense oligomers; and (b) A pharmaceutically acceptable diluent; The antisense oligomer is dissolved or suspended in the solution, and The antisense oligomer is a compound with any of the following chemical structures: ; ; ; ; or its pharmaceutically acceptable salt.

106. A pharmaceutical formulation comprising: (a) antisense oligomers; and (b) A pharmaceutically acceptable diluent; The antisense oligomer is dissolved or suspended in the solution, and The antisense oligomers described herein have any of the following chemical structures: ; ; ; ;or .

107. The pharmaceutical formulation of claim 105 or 106, wherein the antisense oligomer is present in the solution at a concentration of about 1 mg / mL to about 200 mg / mL.

108. The pharmaceutical formulation of claim 104 or 107, wherein the antisense oligomer is present in the solution at the following concentrations: about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 200 mg / mL, about 15 mg / mL to about 200 mg / mL, about 20 mg / mL to about 200 mg / mL, about 25 mg / mL to about 200 mg / mL, about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, 2 mg / mL to about 150 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 200 mg / mL, about 2 mg / mL to about 150 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 2 mg / mL to about 150 mg / mL, about 5 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, mg / mL to about 150 mg / mL, about 10 mg / mL to about 150 mg / mL, about 15 mg / mL to about 150 mg / mL, about 20 mg / mL to about 150 mg / mL, about 25 mg / mL to about 150 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL to about 150 mg / mL, about 2 mg / mL to about 100 mg / mL, about 5 mg / mL to about 100 mg / mL, about 10 mg / mL to about 100 mg / mL, about 15 mg / mL to about 100 mg / mL, about 20 mg / mL to about 100 mg / mL, about 25 mg / mL to about 100 mg / mL mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, 2 mg / mL to about 80 mg / mL, about 5 mg / mL to about 80 mg / mL, about 10 mg / mL to about 80 mg / mL, about 15 mg / mL to about 80 mg / mL, about 20 mg / mL to about 80 mg / mL, about 25 mg / mL to about 80 mg / mL, about 30 mg / mL to about 80 mg / mL, about 35 ...mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, 2 mg / mL to about 60 mg / mL, about 5 mg / mL to about 60 mg / mL, about 10 mg / mL to about 60 mg / mL, about 15 mg / mL to about 60 mg / mL, about 20 mg / mL to about 60 mg / mL, about 25 mg / mL to about 60 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, about 40 mg / mL to about 60 mg / mL, 2 mg / mL to about 40 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 40 mg / mL, about 20 mg / mL to about 40 mg / mL, or about 25 mg / mL to about 40 mg / mL.

109. The pharmaceutical formulation of claim 104, wherein the antisense oligomer is present in the solution at the following concentrations: about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, or about 200 mg / mL. mg / mL.

110. The pharmaceutical formulation of any one of claims 104 to 109, wherein the pharmaceutical composition is prepared by diluting a concentrate containing the antisense oligomer.

111. The pharmaceutical formulation of claim 110, wherein the antisense oligomer is present in the concentrate at the following concentrations: about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL. mg / mL, about 100 mg / mL to about 150 mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, about 30 mg / mL to about 80 mg / mL, about 35 mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL.

112. The pharmaceutical composition of claim 110, wherein the antisense oligomer is present in the concentrate at the following concentrations: about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, or about 200 mg / mL.

113. The pharmaceutical formulation of any one of claims 104 to 112, wherein the concentrate is phosphate buffered.

114. The pharmaceutical formulation of any one of claims 104 to 113, wherein the antisense oligomer is dissolved or diluted in a solution containing one or more of sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, or water for injection.

115. The pharmaceutical formulation of any one of claims 104 to 113, wherein the antisense oligomer is dissolved or diluted in a solution comprising sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate and water for injection.

116. The pharmaceutical formulation of any one of claims 104 to 113, wherein the antisense oligomer is dissolved or diluted in an isotonic solution.

117. The pharmaceutical formulation of any one of claims 104 to 116, wherein the antisense oligomer is dissolved or diluted in a phosphate buffer solution at a pH of at least 5.

8.

118. The pharmaceutical formulation of any one of claims 104 to 116, wherein the antisense oligomer is dissolved or diluted in a phosphate buffer (pH 6.6–7.6) solution.

119. The pharmaceutical formulation of any one of claims 104 to 118, wherein the pharmaceutical composition does not contain a preservative.

120. The pharmaceutical formulation of any one of claims 104 to 119, wherein the pharmaceutical formulation is suitable for intravitreal injection.

121. The pharmaceutical preparation of any one of claims 104 to 120, wherein the pharmaceutical preparation is packaged in a disposable vial.

122. A reagent kit comprising: (i) a concentrate comprising an antisense oligomer (ASO), wherein the ASO comprises a sequence having at least 80% sequence identity with any one of SEQ ID NO: 6-275 or 280-299; and (ii) a diluent, wherein the concentrate is miscible with the diluent; and (iii) Instructions for diluting the concentrate with the diluent.

123. The kit of claim 122, wherein the antisense oligomer is present in the concentrate at the following concentrations: about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL... mg / mL to about 150 mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, about 30 mg / mL to about 80 mg / mL, about 35 mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, or about 40 mg / mL to about 60 mg / mL.

124. The kit of claim 122, wherein the antisense oligomer is present in the concentrate at the following concentrations: about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, or about 200 mg / mL.

125. The kit according to any one of claims 122 to 124, wherein the concentrate is phosphate buffered.

126. The kit according to any one of claims 122 to 125, wherein the diluent is a solution comprising one or more of sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, or water for injection.

127. The kit according to any one of claims 122 to 125, wherein the diluent is a solution comprising sodium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, and water for injection.

128. The kit of any one of claims 122 to 127, wherein the diluent comprises an isotonic solution.

129. The kit of any one of claims 122 to 128, wherein the diluent comprises a phosphate buffer solution with a pH of at least 5.

8.

130. The kit of any one of claims 122 to 128, wherein the diluent comprises a phosphate buffer (pH 6.6–7.6) solution.

131. The kit according to any one of claims 122 to 130, wherein the concentrate or the diluent does not contain preservatives.

132. The kit according to any one of claims 122 to 131, wherein the instructions for diluting the concentrate with the diluent include instructions for diluting or dissolving the ASO in the diluent to a concentration of about 2 mg / mL to 200 mg / mL.

133. The kit of any one of claims 122 to 132, wherein the instructions for diluting the concentrate with the diluent include instructions for diluting or dissolving the ASO in the diluent to the following concentrations: about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 200 mg / mL, about 15 mg / mL to about 200 mg / mL, about 20 mg / mL to about 200 mg / mL, about 25 mg / mL to about 200 mg / mL, about 30 mg / mL to about 200 mg / mL, about 35 mg / mL to about 200 mg / mL, about 40 mg / mL to about 200 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 200 mg / mL, about 80 mg / mL to about 200 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, 2 mg / mL to about 150 mg / mL, about 5 mg / mL to about 150 mg / mL, about 10 mg / mL to about 150 mg / mL, about 15 mg / mL to about 150 mg / mL, about 20 mg / mL to about 150 mg / mL, about 25 mg / mL to about 150 mg / mL, about 30 mg / mL to about 150 mg / mL, about 35 mg / mL to about 150 mg / mL, about 40 mg / mL to about 150 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 80 mg / mL to about 150 mg / mL, about 100 mg / mL to about 150 mg / mL, about 2 mg / mL to about 100 mg / mL, about 5 mg / mL to about 100 mg / mL, about 10 mg / mL to about 100 mg / mL, about 15 mg / mL to about 100 mg / mL, about 20 mg / mL to about 100 mg / mL mg / mL, about 25 mg / mL to about 100 mg / mL, about 30 mg / mL to about 100 mg / mL, about 35 mg / mL to about 100 mg / mL, about 40 mg / mL to about 100 mg / mL, about 50 mg / mL to about 100 mg / mL, about 60 mg / mL to about 100 mg / mL, about 80 mg / mL to about 100 mg / mL, 2 mg / mL to about 80 mg / mL, about 5 mg / mL to about 80 mg / mL, about 10 mg / mL to about 80 mg / mL, about 15 mg / mL to about 80 mg / mL, about 20 mg / mL to about 80 mg / mL, about 25 mg / mLmg / mL to about 80 mg / mL, about 30 mg / mL to about 80 mg / mL, about 35 mg / mL to about 80 mg / mL, about 40 mg / mL to about 80 mg / mL, about 60 mg / mL to about 80 mg / mL, 2 mg / mL to about 60 mg / mL, about 5 mg / mL to about 60 mg / mL, about 10 mg / mL to about 60 mg / mL, about 15 mg / mL to about 60 mg / mL, about 20 mg / mL to about 60 mg / mL, about 25 mg / mL to about 60 mg / mL, about 30 mg / mL to about 60 mg / mL, about 35 mg / mL to about 60 mg / mL, about 40 mg / mL to about 60 mg / mL, 2 mg / mL to about 40 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 40 mg / mL, about 20 mg / mL to about 40 mg / mL or about 25 mg / mL mg / mL to approximately 40 mg / mL.

134. The kit of any one of claims 122 to 132, wherein the instructions for diluting the concentrate with the diluent include instructions for diluting or dissolving the antisense oligomer in the diluent to the following concentrations: about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 12 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 18 mg / mL, about 20 mg / mL, about 22 mg / mL, about 24 mg / mL, about 26 mg / mL, about 28 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 80 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 16 ... mg / mL, approximately 180 mg / mL, or approximately 200 mg / mL.

135. The pharmaceutical composition or kit of any one of claims 104 or 108 to 134, wherein the antisense oligomer comprises a nucleotide sequence having at least 90% or 100% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 6-275 or 280-299.

136. The pharmaceutical composition or kit of any one of claims 104 or 108 to 134, wherein the antisense oligomer comprises a nucleotide sequence having at least 80%, at least 90%, or 100% sequence identity with a sequence selected from the group consisting of SEQ ID NO: 36, 236, 242, 250, 280-283, 288, and 290-292.

137. The pharmaceutical composition or kit of any one of claims 104 or 108 to 136, wherein the antisense oligomer comprises a main chain modification comprising a thiophosphate bond or a phosphodiamid bond.

138. The pharmaceutical composition or kit of any one of claims 104 or 108 to 137, wherein the antisense oligomer comprises phosphodiamidomorpholino, locked nucleic acid, peptide nucleic acid, 2'-O-methyl moiety, 2'-fluoro moiety, 2'-ON-methylacetamide (2'-NMA), or 2'-O-methoxyethyl moiety.

139. The pharmaceutical composition or kit of any one of claims 104 or 108 to 138, wherein the antisense oligomer comprises at least one modified sugar moiety.

140. The pharmaceutical composition or kit of claim 139, wherein each sugar moiety is a modified sugar moiety.

141. The pharmaceutical composition or kit of any one of claims 104 or 108 to 140, wherein the antisense oligomer comprises 5'-methylcytosine (5'-MeC).

142. The pharmaceutical composition or kit of any one of claims 104 or 108 to 141, wherein each cytosine of the antisense oligomer is 5'-methylcytosine (5'-MeC).

143. The pharmaceutical composition or kit of any one of claims 104 or 108 to 142, wherein the antisense oligomer comprises 5'-methyluracil (5'-MeU).

144. The pharmaceutical composition or kit of any one of claims 104 or 108 to 143, wherein the antisense oligomer comprises a thiophosphate bond.

145. The pharmaceutical composition or kit of any one of claims 104 or 108 to 144, wherein each nucleoside internucleotide bond of the ASO is a phosphate thioester bond.

146. The pharmaceutical composition or kit of any one of claims 104 or 108 to 145, wherein the antisense oligomer comprises locked nucleic acid (LNA).

147. The pharmaceutical composition or kit of any one of claims 104 or 108 to 146, wherein the antisense oligomer has a length of 8 to 50 nucleotides, 8 to 40 nucleotides, 8 to 35 nucleotides, 8 to 30 nucleotides, 8 to 25 nucleotides, 8 to 20 nucleotides, 8 to 15 nucleotides, 9 to 50 nucleotides, 9 to 40 nucleotides, 9 to 35 nucleotides, 9 to 30 nucleotides, 9 to 25 nucleotides, 9 to 20 nucleotides, 9 to 15 nucleotides, 10 to 50 nucleotides, or 10 to 40 nucleotides. 10 to 35 nucleotides, 10 to 30 nucleotides, 10 to 25 nucleotides, 10 to 20 nucleotides, 10 to 15 nucleotides, 11 to 50 nucleotides, 11 to 40 nucleotides, 11 to 35 nucleotides, 11 to 30 nucleotides, 11 to 25 nucleotides, 11 to 20 nucleotides, 11 to 15 nucleotides, 12 to 50 nucleotides, 12 to 40 nucleotides, 12 to 35 nucleotides, 12 to 30 nucleotides, 12 to 25 nucleotides, 12 to 20 nucleotides, or 12 to 15 nucleotides.

148. The pharmaceutical composition or kit according to any one of claims 104 or 108 to 134, wherein the antisense oligomer is a compound according to any one of the following chemical structures: ; ; ; ; or its pharmaceutically acceptable salt.

149. The pharmaceutical composition or kit according to any one of claims 104 or 108 to 134, wherein the antisense oligomer has any one of the following chemical structures: ; ; ; ;or .

150. Use of an antisense oligomer in the preparation of a medicament for treating a disease or condition in a human subject in need or reducing the likelihood of said subject having said disease or condition, said disease or condition being characterized by reduced expression or function of OPA1 protein, wherein said medicament is administered to one eye of said subject at a dose of about 0.005 mg to about 20 mg, and wherein said antisense oligomer comprises a sequence having at least 80% sequence identity with any one of SEQ ID NO: 6-275 or 280-299.

151. The use as claimed in claim 150, wherein the drug is administered to the subject's eye in the following doses of the antisense oligomer: about 0.005 mg to about 15 mg, about 0.005 mg to about 10 mg, about 0.005 mg to about 5 mg, about 0.005 mg to about 1 mg, about 0.01 mg to about 15 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 2.5 mg, about 0.01 mg to about 1.0 mg, about 0.01 mg to about 0.5 mg, about 0.01 mg to about 0.25 mg, about 0.01 mg to about 0.1 mg, about 0.01 mg to about 0.05 mg, about 0.05 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.05 mg to about 2.5 mg, about 0.05 mg to about 1.0 mg, about 0.05 mg to about 0.5 mg. mg, about 0.05 mg to about 0.25 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 2.5 mg, about 0.1 mg to about 1.5 mg, about 0.1 mg to about 1.0 mg, about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 0.25 mg.

152. The use as described in claim 150, wherein the drug is administered to the subject's eye in the following doses of the antisense oligomer: about 0.005 mg, about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10 mg, about 12.5 mg. mg, approximately 15 mg, approximately 17.5 mg, or approximately 20 mg.

153. The use as claimed in claim 150, wherein the drug is administered to the subject's eye in the following doses of the antisense oligomer: about 0.1 mg to about 1.5 mg, about 0.1 mg to about 1.4 mg, about 0.1 mg to about 1.2 mg, about 0.1 mg to about 1.0 mg, about 0.1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.5 mg, about 0.1 mg to about 0.3 mg, about 0.2 mg to about 1.5 mg, about 0.2 mg to about 1.4 mg, about 0.2 mg to about 1.2 mg, about 0.2 mg to about 1.0 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.5 mg, about 0.3 mg to about 1.5 mg, about 0.3 mg to about 1.4 mg, about 0.3 mg to about 1.2 mg, about 0.3 mg to about 1.0 mg, about 0.3 mg to about 1.0 mg, about 0.3 mg to about 1.5 mg, about 0.3 mg to about 1.4 mg, about 0.3 mg to about 1.2 mg, about 0.3 mg to about 1.0 mg, about 0.3 mg to about 1.5 ... mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.5 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 1.4 mg, about 0.5 mg to about 1.2 mg, about 0.5 mg to about 1.0 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.7 mg to about 1.5 mg, about 0.7 mg to about 1.4 mg, about 0.7 mg to about 1.2 mg, about 0.7 mg to about 1.0 mg, about 0.8 mg to about 1.5 mg, about 0.8 mg to about 1.4 mg, about 0.8 mg to about 1.2 mg, about 0.8 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.0 mg to about 1.4 mg, about 1.0 mg to about 1.2 mg, about 1.2 mg to about 1.5 mg, or about 1.2 mg to about 1.4 mg.

154. The use as claimed in claim 150, wherein the drug is administered to the subject's eye in the following doses of the antisense oligomer: about 0.1 mg, about 0.2 mg, about 0.3 mg, 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, or about 1.5 mg.

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