Therapy Approaches for Stargardt Disease

Piotter, Elena; McClements, Michelle E.; MacLaren, Robert E.

doi:10.3390/biom11081179

Cited by 34 publications

(25 citation statements)

References 153 publications

(197 reference statements)

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“…Stargardt macular degeneration (STGD1) is the most common inherited childhood blindness worldwide, with a prevalence of 1 in 8–10,000 ( Cremers et al, 2020 ; Piotter et al, 2021 ). Furthermore, potentially pathogenic ABCA4 alleles have a population frequency of 1:20, underscoring the impact of ABCA4 in retinopathies ( Maugeri et al, 1999 ; Yatsenko et al, 2001 ; Jaakson et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

“…Alongside this, there are ∼1,200 known pathogenic variants, creating a complex genetic landscape ( Allikmets, 2007 ; Cornelis et al, 2017 ; Cremers et al, 2020 ). Given the slow progression of the disease, there exists an ample treatment window, however, no treatments currently exist although various forms of therapy have been investigated ( Cremers et al, 2020 ; Piotter et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…To overcome this, multiple alternative approaches have been tested, such as a dual vector approach ( Trapani et al, 2014 ; Trapani et al, 2015 ; McClements et al, 2019 ), lentiviral vector delivery ( Binley et al, 2013 ), nanoparticles ( Sun et al, 2021 ), and intein-mediated reconstitution ( Tornabene et al, 2019 ). These studies have had varying degrees of success (more details can be found in detailed reviews, Cremers et al and Piotter et al) ( Cremers et al, 2020 ; Piotter et al, 2021 ). While any of these approaches would be immensely beneficial as a treatment option and would offer a single treatment option regardless of the ABCA4 mutation, it is unknown for how long transgenes express, and show improvements in humans, given that retinal degenerations often progress over a lifetime ( Cideciyan et al, 2013 ; Bainbridge et al, 2015 ; Jacobson et al, 2015 ; Gardiner et al, 2020 ; Suh et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

2022

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Stargardt macular dystrophy (STGD1) is the most common form of inherited childhood blindness worldwide and for which no current treatments exist. It is an autosomal recessive disease caused by mutations in ABCA4. To date, a variety of gene supplementation approaches have been tested to create a therapy, with some reaching clinical trials. New technologies, such as CRISPR-Cas based editing systems, provide an exciting frontier for addressing genetic disease by allowing targeted DNA or RNA base editing of pathogenic mutations. ABCA4 has ∼1,200 known pathogenic mutations, of which ∼63% are transition mutations amenable to this editing technology. In this report, we screened the known “pathogenic” and “likely pathogenic” mutations in ABCA4 from available data in gnomAD, Leiden Open Variation Database (LOVD), and ClinVar for potential PAM sites of relevant base editors, including Streptococcus pyogenes Cas (SpCas), Staphylococcus aureus Cas (SaCas), and the KKH variant of SaCas (Sa-KKH). Overall, of the mutations screened, 53% (ClinVar), 71% (LOVD), and 71% (gnomAD), were editable, pathogenic transition mutations, of which 35–47% had “ideal” PAM sites. Of these mutations, 16–20% occur within a range of multiple PAM sites, enabling a variety of editing strategies. Further, in relevant patient data looking at three cohorts from Germany, Denmark, and China, we find that 44–76% of patients, depending on the presence of complex alleles, have at least one transition mutation with a nearby SaCas, SpCas, or Sa-KKH PAM site, which would allow for potential DNA base editing as a treatment strategy. Given the complexity of the genetic landscape of Stargardt, these findings provide a clearer understanding of the potential for DNA base editing approaches to be applied as ABCA4 gene therapy strategies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

2022

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“…Subretinal co-delivery of these constructs yielded robust full-length ABCA4 expression in photoreceptor outer segments and successfully reduced accumulation of toxic bis-retinoids that accumulate in the ABCA4-deficient retina. Human clinical trials involving the use of dual AAV systems are in the planning stage but have yet to be initiated (Piotter et al, 2021). Nonviral approaches to IRD gene replacement have been explored with the aim of overcoming the gene size limitation of AAV in addition to improving the safety profile and production costs associated with viral vector-based approaches.…”

Section: Gene Replacement Strategiesmentioning

confidence: 99%

Gene-Based Therapeutics for Inherited Retinal Diseases

et al. 2022

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Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber’s congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

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“…The review article by Piotter, McClements, and MacLaren provides a comprehensive discussion on how nucleic acid technologies represent promising therapies against Stargardt disease, one of the most prevalent causes of inherited blindness in children [ 6 ]. While this disease can be identified at an early age, this condition unfortunately progresses over the lifetime of the afflicted individual.…”

mentioning

confidence: 99%