Preserved Outer Retina in AIPL1 Leber's Congenital Amaurosis: Implications for Gene Therapy

Aboshiha, Jonathan; Dubis, Adam M.; Spuy, Jacqueline van der; Nishiguchi, Koji M.; Cheeseman, Edward W.; Ayuso, Carmen; Ehrenberg, Miriam; Simonelli, Francesca; Bainbridge, James; Michaelides, Michel

doi:10.1016/j.ophtha.2014.11.019

Cited by 32 publications

(25 citation statements)

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“…This study identified p.W278X (c.834G>A) as the most common AIPL1 variant, occurring in at least one allele in 62% of patients. 61 Interestingly, hand-held OCT imaging identified four patients (three of whom harboured the aforementioned common variant) with relative preservation of central outer retinal structure, all of whom were younger than 4 years of age. 61 Gene replacement therapy using an AAV2/8 vector in an AIPL1 knock-out mouse model has been shown to result in restoration of cellular function with photoreceptor cell preservation and improved retinal function, despite the severe rapidly progressive early-onset retinal degeneration seen in this mouse model.…”

Section: Aipl1-associated Lcamentioning

confidence: 95%

“…61 Interestingly, hand-held OCT imaging identified four patients (three of whom harboured the aforementioned common variant) with relative preservation of central outer retinal structure, all of whom were younger than 4 years of age. 61 Gene replacement therapy using an AAV2/8 vector in an AIPL1 knock-out mouse model has been shown to result in restoration of cellular function with photoreceptor cell preservation and improved retinal function, despite the severe rapidly progressive early-onset retinal degeneration seen in this mouse model. 62 The early visual loss to perception of light or worse, the high-resolution OCT evidence of retained outer retinal structure early in life and the successfully treated animal models, raise the possibility of a gene therapy-based approach in AIPL1-LCA early in life; with a human clinical interventional study being in the advanced stages of development.…”

Section: Aipl1-associated Lcamentioning

confidence: 95%

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Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

et al. 2017

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Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70–80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.

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Section: Aipl1-associated Lcamentioning

confidence: 95%

Section: Aipl1-associated Lcamentioning

confidence: 95%

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

et al. 2017

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“…; Aboshiha et al. ) produces a truncated protein lacking the C‐terminal 107 amino acids, including most of the TPR3 domain, disrupting AIPL1‐NUB1 binding and forming cytoplasmic inclusions (van der Spuy et al. ; Kanaya et al.…”

Section: Resultsmentioning

confidence: 99%

“…; Aboshiha et al. ). Conducting global genetic analyses parallel with research into gene‐specific, pharmacogenetic, or pharmacologic therapy will be a key determinant in the timely deliverance of future treatment therapies.…”

Section: Discussionmentioning

confidence: 98%

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The genetic profile of Leber congenital amaurosis in an Australian cohort

Thompson

Roach

McLaren

et al. 2017

Molec Gen & Gen Med

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BackgroundLeber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease.MethodsWe have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology.ResultsWe present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort.ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.

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Gene and Cell Therapy for AIPL1-Associated Leber Congenital Amaurosis: Challenges and Prospects

Perdigão¹,

Spuy²

2019

Retinal Degenerative Diseases

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Leber congenital amaurosis (LCA) caused by AIPL1 mutations is one of the most severe forms of inherited retinal degeneration (IRD). The rapid and extensive photoreceptor degeneration challenges the development of potential treatments. Nevertheless, preclinical studies show that both gene augmentation and photoreceptor transplantation can regenerate and restore retinal function in animal models of AIPL1-associated LCA. However, questions regarding long-term benefit and safety still remain as these therapies advance towards clinical application. Ground-breaking advances in stem cell technology and genome editing are examples of alternative therapeutic approaches and address some of the limitations associated with previous methods. The continuous development of these cutting-edge biotechnologies paves the way towards a bright future not only for AIPL1-associated LCA patients but also other forms of IRD.

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Preserved Outer Retina in AIPL1 Leber's Congenital Amaurosis: Implications for Gene Therapy

Cited by 32 publications

References 4 publications

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

The genetic profile of Leber congenital amaurosis in an Australian cohort

Gene and Cell Therapy for AIPL1-Associated Leber Congenital Amaurosis: Challenges and Prospects

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