Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient

Elsayed, Maram E. A. Abdalla; Kaukonen, Maria; Király, Péter; Cehajic-Kapetanovic, Jasmina; MacLaren, Robert E.

doi:10.3390/genes13112103

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…In conclusion, the promise of base editing in severe progressive retinal degeneration with congenital retinal abnormalities such as CRB1 lies in its potential to address the underlying genetic mutations responsible for these conditions [67][68][69]. Base editing offers a precise and targeted approach to correcting specific nucleotide changes associated with these disorders, potentially halting or even reversing disease progression at the genetic level.…”

Section: Discussionmentioning

confidence: 99%

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

Shamsnajafabadi,

Kaukonen,

Bellingrath

et al. 2024

Genes

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Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three CRB1 variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone–rod dystrophy and retinal thickening typical of CRB1 retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone–rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic CRB1 variants, including a novel c.2833G>A variant associated with early-onset cone–rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition.

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Section: Discussionmentioning

confidence: 99%

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

Shamsnajafabadi,

Kaukonen,

Bellingrath

et al. 2024

Genes

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“…A meta-analysis showed that RAP lesions respond better to anti-VEGF treatment than other neovascular AMD subtypes [9]. Choroidal neovascularization (CNV) has been associated with several IRDs: Stargardt disease, Best vitelliform dystrophy, Sjögren reticular dystrophy, pattern dystrophy, gyrate atrophy, Sorsby fundus dystrophy, and RP [10,11]. In RP, CNV is extremely rare [11], with the majority of case reports describing either classic CNV [12][13][14][15], pachychoroid neovasculopathy [12],…”

Section: Introductionmentioning

confidence: 99%

Retinal Angiomatous Proliferation in a Patient with Retinitis Pigmentosa

Kiraly

Downes

Fischer

2023

Genes

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Retinal angiomatous proliferation (RAP) and other types of choroidal neovascularization (CNV) are very rarely reported in patients with retinitis pigmentosa (RP). We present a case report of a 91-year-old patient with an obvious RP phenotype, who presented with a sudden onset of vision worsening and metamorphopsia in the left eye. Genetic testing on the UK inherited retinal disease panel did not identify a pathogenic variant. Multimodal imaging comprising optical coherence tomography (OCT), OCT angiography, and fluorescein and indocyanine green angiography showed a RAP lesion in the left macula. The patient received three treatments of monthly injections of aflibercept, with excellent morphological and functional outcomes. Taking into account the patient’s age at presentation of the RAP lesion, it is not clear whether the RAP was associated or coincidental with RP. This case report highlights the importance of possessing an awareness that RAP lesions can occur in RP. Moreover, due to a good response and potential safety concerns with continuous anti-VEGF injections in RP patients, a pro re nata (PRN) regimen might be the safest option.

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Genetic therapies and potential therapeutic applications of CRISPR activators in the eye

Ng,

Kaukonen,

McClements

et al. 2024

Progress in Retinal and Eye Research

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Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient

Cited by 4 publications

References 41 publications

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

In Silico CRISPR-Cas-Mediated Base Editing Strategies for Early-Onset, Severe Cone–Rod Retinal Degeneration in Three Crumbs homolog 1 Patients, including the Novel Variant c.2833G>A

Retinal Angiomatous Proliferation in a Patient with Retinitis Pigmentosa

Genetic therapies and potential therapeutic applications of CRISPR activators in the eye

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