Rlbp1-KO Mouse

RLBP1, encoding cellular retinaldehyde-binding protein (CRALBP), is a crucial gene in the visual cycle. CRALBP is essential in the rod and cone visual cycles, mainly occurring in the retinal pigment epithelium (RPE) and Müller cells of the neuroretina. By binding to 11-cis-retinoid, it augments the isomerase activity of retinoid isomerohydrolase RPE65, facilitates 11-cis-retinol oxidation to 11-cis-retinal, maintains the 11-cis configuration, and protects against unwanted retinaldehyde activity [2,3].

In Rlbp1/Cralbp-/-mice, reduced 11-cis-retinal levels, quantitative fundus autofluorescence (qAF), near-infrared autofluorescence (NIR-AF) intensities, and photoreceptor loss were consistent with the clinical presentation of affected siblings in humans, indicating that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration [3]. Also, in a five-year prospective natural history study of patients with retinal dystrophy caused by RLBP1 gene mutation, severely delayed dark-adaptation (DA) sensitivity recovery, a characteristic feature, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population [1]. In a phase 1/2 trial of gene therapy for RLBP1-associated retinal dystrophy, subretinal delivery of an adeno-associated viral vector (AAV8-RLBP1) was well-tolerated, and dark adaptation kinetics, the primary efficacy endpoint, improved significantly in all dose-cohorts, along with the resolution of disease-related retinal deposits [4].

In conclusion, RLBP1 is vital for the normal functioning of the visual cycle. Research on Rlbp1-deficient mouse models and human clinical trials has revealed its role in retinal diseases such as progressive retinal degeneration. These findings contribute to understanding the pathogenesis of RLBP1-associated retinal dystrophies and provide a basis for the development of gene-therapy-based treatments [1,3,4].

References:

1. Burstedt, Marie, Whelan, James H, Green, Jane S, He, Yunsheng, Stasi, Kalliopi. . Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study. In Investigative ophthalmology & visual science, 64, 42. doi:10.1167/iovs.64.13.42. https://pubmed.ncbi.nlm.nih.gov/37883093/

2. Damodar, Krishna, Dubois, Gregor, Guillou, Laurent, Brabet, Philippe, Kalatzis, Vasiliki. 2024. Dual CRALBP isoforms unveiled: iPSC-derived retinal modeling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 4319-4336. doi:10.1016/j.ymthe.2024.10.004. https://pubmed.ncbi.nlm.nih.gov/39385467/

3. Lima de Carvalho, Jose Ronaldo, Kim, Hye Jin, Ueda, Keiko, Tsang, Stephen H, Sparrow, Janet R. 2020. Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice. In The Journal of biological chemistry, 295, 6767-6780. doi:10.1074/jbc.RA120.012695. https://pubmed.ncbi.nlm.nih.gov/32188692/

4. Kvanta, Anders, Rangaswamy, Nalini, Holopigian, Karen, Stasi, Kalliopi, André, Helder. 2024. Interim safety and efficacy of gene therapy for RLBP1-associated retinal dystrophy: a phase 1/2 trial. In Nature communications, 15, 7438. doi:10.1038/s41467-024-51575-4. https://pubmed.ncbi.nlm.nih.gov/39256350/