Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic <i>CRB1</i> single nucleotide variant.

Bellingrath, J-S; McClements, M E; Shanks, M; Clouston, P; Fischer, M D; MacLaren, R E

Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic CRB1 single nucleotide variant.

Bellingrath, J-S; McClements, M E; Shanks, M; Clouston, P; Fischer, M D; MacLaren, R E.

Afiliación

Bellingrath JS; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
McClements ME; Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Shanks M; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Clouston P; Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Fischer MD; Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
MacLaren RE; Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Ophthalmic Genet ; 43(5): 661-670, 2022 10.

Article en En | MEDLINE | ID: mdl-35538629

RESUMEN

BACKGROUND: Inherited retinal degeneration (IRD) associated with mutations in the Crumbs homolog 1 (CRB1) gene is associated with a severe, early-onset retinal degeneration for which no therapy currently exists. Base editing, with its capability to precisely catalyse permanent nucleobase conversion in a programmable manner, represents a novel therapeutic approach to targeting this autosomal recessive IRD, for which a gene supplementation is challenging due to the need to target three different retinal CRB1 isoforms. PURPOSE: To report and classify a novel CRB1 variant and envision a possible therapeutic approach in form of base editing. METHODS: Case report. RESULTS: A 16-year-old male patient with a clinical diagnosis of early-onset retinitis pigmentosa (RP) and characteristic clinical findings of retinal thickening and coarse lamination was seen at the Oxford Eye Hospital. He was found to be compound heterozygous for two CRB1 variants: a novel pathogenic nonsense variant in exon 9, c.2885T>A (p.Leu962Ter), and a likely pathogenic missense change in exon 6, c.2056C>T (p.Arg686Cys). While a base editing strategy for c.2885T>A would encompass a CRISPR-pass mediated "read-through" of the premature stop codon, the resulting missense changes were predicted to be "possibly damaging" in in-silico analysis. On the other hand, the transversion missense change, c.2056C>T, is amenable to transition editing with an adenine base editor (ABE) fused to a SaCas9-KKH with a negligible chance of bystander edits due to an absence of additional Adenines (As) in the editing window. CONCLUSIONS: This case report records a novel pathogenic nonsense variant in CRB1 and gives an example of thinking about a base editing strategy for a patient compound heterozygous for CRB1 variants.

Asunto(s)

Proteínas del Ojo; Degeneración Retiniana; Adenina; Adolescente; Secuencia de Aminoácidos; Sistemas CRISPR-Cas; Codón sin Sentido; Proteínas del Ojo/genética; Humanos; Masculino; Proteínas de la Membrana/genética; Mutación; Proteínas del Tejido Nervioso/genética; Nucleótidos; Degeneración Retiniana/genética

Palabras clave

CRB1; CRISPR; base editing; genetics; inherited retinal disease

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Proteínas del Ojo Tipo de estudio: Prognostic_studies Límite: Adolescent / Humans / Male Idioma: En Revista: Ophthalmic Genet Asunto de la revista: GENETICA MEDICA / OFTALMOLOGIA Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido

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