Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset
Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved..
PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).
DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.
PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.
METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.
MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.
RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.
CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
| Errataetall: |
CommentIn: Ophthalmology. 2021 May;128(5):661-662. - PMID 33892900 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:128 |
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| Enthalten in: |
Ophthalmology - 128(2021), 5 vom: 01. Mai, Seite 649-660 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Newman, Nancy J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.10.2021 Date Revised 22.03.2023 published: Print-Electronic ClinicalTrials.gov: NCT02652767 CommentIn: Ophthalmology. 2021 May;128(5):661-662. - PMID 33892900 Citation Status MEDLINE |
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| doi: |
10.1016/j.ophtha.2020.12.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Newman, Nancy J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset |
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| 500 | |a Date Completed 08.10.2021 | ||
| 500 | |a Date Revised 22.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02652767 | ||
| 500 | |a CommentIn: Ophthalmology. 2021 May;128(5):661-662. - PMID 33892900 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON) | ||
| 520 | |a DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial | ||
| 520 | |a PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included | ||
| 520 | |a METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye | ||
| 520 | |a MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96 | ||
| 520 | |a RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively | ||
| 520 | |a CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes | ||
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Humphrey visual field perimetry | |
| 650 | 4 | |a Leber Hereditary Optic Neuropathy | |
| 650 | 4 | |a Phase 3 randomized double-masked clinical trial | |
| 650 | 4 | |a Quality of life | |
| 650 | 4 | |a best-corrected visual acuity | |
| 650 | 4 | |a bilateral visual improvement | |
| 650 | 4 | |a contrast sensitivity | |
| 650 | 4 | |a efficacy | |
| 650 | 4 | |a intravitreal gene therapy | |
| 650 | 4 | |a retinal anatomic measures | |
| 650 | 4 | |a safety | |
| 650 | 7 | |a DNA, Mitochondrial |2 NLM | |
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| 700 | 1 | |a Sergott, Robert C |e verfasserin |4 aut | |
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| 700 | 1 | |a Sadun, Alfredo A |e verfasserin |4 aut | |
| 700 | 1 | |a Barboni, Piero |e verfasserin |4 aut | |
| 700 | 1 | |a DeBusk, Adam A |e verfasserin |4 aut | |
| 700 | 1 | |a Girmens, Jean François |e verfasserin |4 aut | |
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| 700 | 1 | |a Hage, Rabih |e investigator |4 oth | |
| 700 | 1 | |a Catarino, Claudia B |e investigator |4 oth | |
| 700 | 1 | |a Priglinger, Claudia |e investigator |4 oth | |
| 700 | 1 | |a Priglinger, Siegfried |e investigator |4 oth | |
| 700 | 1 | |a Thurau, Stephan |e investigator |4 oth | |
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| 700 | 1 | |a Pressler, Angelika |e investigator |4 oth | |
| 700 | 1 | |a Schertler, Cosima |e investigator |4 oth | |
| 700 | 1 | |a Hildebrandt, Martin |e investigator |4 oth | |
| 700 | 1 | |a Neuenhahn, Michael |e investigator |4 oth | |
| 700 | 1 | |a Heilweil, Gad |e investigator |4 oth | |
| 700 | 1 | |a Tsui, Irena |e investigator |4 oth | |
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| 700 | 1 | |a Contin, Manuela |e investigator |4 oth | |
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