Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial
Abstract
Background Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. Methods In our open-label, prospective, phase 1b trial, we enrolled patients (aged ≥6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill University's Montreal Children's Hospital. Patients received 7 days of oral QLT091001 (10-40 mg/m(2) per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2·2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052. Findings Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6-38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28-683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2-30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients). Interpretation Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations. Funding QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision.
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Oral QLT091001 in patients with defective RPE65 and LRAT genes demonstrated improvement in vision in an open-label phase 1b trial.
“An open-label, prospective, multi-center, phase 1b clinical trial of oral administration of QLT091001 in patients with defective RPE65 and LRAT genes also demonstrated improvement in vision.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [121]
High doses of vitamin A in QLT091001 treatment caused side effects including headaches, photophobia, nausea, reduction in serum HDL, and increases in serum triglycerides, ALT, and AST.
“However, some patients noted headaches, photophobia, nausea, reduction in serum high density lipoprotein concentrations, and increases in serum triglycerides, alanine aminotransferase and aspartate aminotransferase concentrations due to high doses of vitamin A [120,121].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [121]
Treatment with oral synthetic cis-retinoid QLT091001 showed promising results in patients with LRAT pathogenic variants.
“Treatment with oral synthetic cis-retinoid QLT091001 showed promising results in patients.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [121]
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“In the initial clinical trial (phase 1b) oral administration of 40 mg/m2 of 9-cis-retinyl acetate (QLT091001) for seven consecutive days resulted in expansion of functional retinal area in 71% of enrolled LCA patients, 43% displayed improved visual acuity [138,139].”
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- Authors
- Koenekoop, R. K., Sui, R., Sallum, J., van den Born, L. I., Ajlan, R., Khan, A., den Hollander, A. I., Cremers, F. P. M., Mendola, J. D., Bittner, A. K., Dagnelie, G., Schuchard, R. A., & Saperstein, D. A.
- Affiliations
- Montreal Children's Hospital (CA)
- Peking Union Medical College Hospital (CN)
- Universidade Federal de São Paulo (BR)
- Radboud University Medical Center (NL)
- McGill University Health Centre (CA)
- Johns Hopkins University (US)
- Stanford Medicine (US)
- Corresponding author
- Koenekoop, Robert K
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 384
- Issue
- 9953
- Pages
- 1513-1520
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2099108621
- Cited by
- 103
- References
- 8
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 7 · 2018: 12 · 2017: 11 · 2016: 13 · 2015: 12 · 2014: 2
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Leber congenital amaurosis, RPE65 mutations, oral retinoid therapy, inherited retinal degeneration, childhood blindness, visual acuity, functional MRI, treatment safety
- MeSH terms
- Retinyl Esters, Retinoid Isomerohydrolase, Acyltransferases, Administration, Oral, Adolescent, Adult, Blindness, Child, Diterpenes, Humans, Mutation, Prospective Studies, Visual Acuity, Vitamin A, cis-trans-Isomerases, Young Adult, Leber Congenital Amaurosis
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