Formulation and efficacy of ECO/pRHO-ABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model

Sun, Da; Sun, Wenyu; Gao, Songqi; Wei, Cheng; Naderi, Amirreza; Schilb, Andrew; Scheidt, Josef; Lee, Sangjoon; Kern, Timothy S.; Palczewski, Krzysztof; Lü, Zheng Rong

doi:10.1016/j.jconrel.2020.12.010

Cited by 16 publications

(12 citation statements)

References 47 publications

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“…The preferred gene therapy delivery system, adeno-associated viral (AAV) vector, only has a carrying capacity of ∼4.7 kb ( Grieger and Samulski, 2005 ). 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 ).…”

Section: Introductionmentioning

confidence: 99%

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%

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

2022

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“…More recently, promising results have been reported in animal models with a non-viral technique relying on subretinal delivery of self-assembled NPs (261,262). Compared to viral vectors, non-viral delivery systems have unlimited payload, low immunogenicity, and minimal side effects, features that may allow to circumvent the obstacles which are currently standing in the way of STGD gene therapy (263).…”

Section: Gene Therapymentioning

confidence: 99%

Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art

et al. 2021

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Background: Gene therapy cannot be yet considered a far perspective, but a tangible therapeutic option in the field of retinal diseases. Although still confined in experimental settings, the preliminary results are promising and provide an overall scenario suggesting that we are not so far from the application of gene therapy in clinical settings. The main aim of this review is to provide a complete and updated overview of the current state of the art and of the future perspectives of gene therapy applied on retinal diseases.Methods: We carefully revised the entire literature to report all the relevant findings related to the experimental procedures and the future scenarios of gene therapy applied in retinal diseases. A clinical background and a detailed description of the genetic features of each retinal disease included are also reported.Results: The current literature strongly support the hope of gene therapy options developed for retinal diseases. Although being considered in advanced stages of investigation for some retinal diseases, such as choroideremia (CHM), retinitis pigmentosa (RP), and Leber's congenital amaurosis (LCA), gene therapy is still quite far from a tangible application in clinical practice for other retinal diseases.Conclusions: Gene therapy is an extremely promising therapeutic tool for retinal diseases. The experimental data reported in this review offer a strong hope that gene therapy will be effectively available in clinical practice in the next years.

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“…No signs of toxicity were evident, but this was not specifically assessed in the study and needs further investigation. Given the encouraging recent attempts to enhance and optimise the formulation [89], these ECO nanoparticles seem a promising approach to pursue for supplementation of ABCA4.…”

Section: Nanoparticlesmentioning

confidence: 99%

Therapy Approaches for Stargardt Disease

2021

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Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide.

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Formulation and efficacy of ECO/pRHO-ABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model

Cited by 16 publications

References 47 publications

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

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

Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art

Therapy Approaches for Stargardt Disease

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