RNA-Based Therapeutic Strategies for Inherited Retinal Dystrophies

Garanto, Alejandro

doi:10.1007/978-3-030-27378-1_12

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…On the other hand, shRNAs have been proven particularly beneficial in the treatment of autosomal dominant disorders, such as those caused by RHO mutations [130] as well as in silencing VEGF production in AMD mouse models [131]. One of the most promising therapeutic agents are antisense oligonucleotides (AONs), small RNA molecules that bind complementarily to the pre-mRNA to correct aberrant splicing caused by the activation of cryptic splice sites [132][133][134]. AON-based therapies have shown promising results for mutations in CEP290 [135][136][137], OPA1 [138], CHM [139], USH2A [105] and ABCA4 [91,140], and are now being tested in clinical trials with patients.…”

Section: Therapeutic Strategies To Modulate Aberrant Splicingmentioning

confidence: 99%

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Aísa-Marín

García-Arroyo

Mirra

et al. 2021

IJMS

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Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing or the relative production of alternative transcripts. Modulation of alternative splicing in the retina is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it enables precision medicine for specific mutations.

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Section: Therapeutic Strategies To Modulate Aberrant Splicingmentioning

confidence: 99%

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Aísa-Marín

García-Arroyo

Mirra

et al. 2021

IJMS

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“…Several advantages of using RNA as a therapy consist of its ease of design, cost effectiveness, stability and easy combination with other drugs presenting also low immunogenicity [12]. The major RNA therapeutic methods are: (I) antisense oligonucleotides (AONs) which are small RNA or DNA chemically modified molecules that bind by complementary base pair to the pre-mRNA and their main functions are to exclude exons and pseudo-exons, include exons, degrade transcripts and block the translation [13]; (II) U1 spliceosomal RNA that utilizes a modified and an adapted U1 snRNA to the mutation favouring the correct splicing [5,12,14]; (III) trans-splicing therapy, that consists of introducing an exogen RNA containing a binding domain to the target mRNA and thus, activates the transsplicing process [5,15]; and (IV) post-transcriptional gene silencing therapy which can be approached by iRNA to degrade the transcripts or by AONs RNAse H which are based on the hybrids RNA/DNA are degraded by RNAse H activity [12,16,17].…”

Section: Rna Therapymentioning

confidence: 99%

Nanotechnology-Based Strategies to Overcome Current Barriers in Gene Delivery

Mirón-Barroso

Doménech

Trigueros

2021

IJMS

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Nanomaterials are currently being developed for the specific cell/tissue/organ delivery of genetic material. Nanomaterials are considered as non-viral vectors for gene therapy use. However, there are several requirements for developing a device small enough to become an efficient gene-delivery tool. Considering that the non-viral vectors tested so far show very low efficiency of gene delivery, there is a need to develop nanotechnology-based strategies to overcome current barriers in gene delivery. Selected nanostructures can incorporate several genetic materials, such as plasmid DNA, mRNA, and siRNA. In the field of nanotechnologies, there are still some limitations yet to be resolved for their use as gene delivery systems, such as potential toxicity and low transfection efficiency. Undeniably, novel properties at the nanoscale are essential to overcome these limitations. In this paper, we will explore the latest advances in nanotechnology in the gene delivery field.

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“…Such inactivation can be achieved, for example, by gene editing or small interfering RNA to allow gene augmentation therapy to work. In the latter case, to prevent inhibition of the newly introduced gene, codon-optimization of the transgene might prevent inactivation by the gene-editing or siRNA tools used [ 80 ]. Here, an rAAV vector expressing a wild-type RPGR transgene and downregulation of the mutant RPGR transgene could benefit patients.…”

Section: Discovery Of Cell-specific Promoters For Ocular Gene Thermentioning

confidence: 99%

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

Buck

Wijnholds

2020

IJMS

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Inherited retinal dystrophies and optic neuropathies cause chronic disabling loss of visual function. The development of recombinant adeno-associated viral vectors (rAAV) gene therapies in all disease fields have been promising, but the translation to the clinic has been slow. The safety and efficacy profiles of rAAV are linked to the dose of applied vectors. DNA changes in the rAAV gene cassette affect potency, the expression pattern (cell-specificity), and the production yield. Here, we present a library of rAAV vectors and elements that provide a workflow to design novel vectors. We first performed a meta-analysis on recombinant rAAV elements in clinical trials (2007–2020) for ocular gene therapies. We analyzed 33 unique rAAV gene cassettes used in 57 ocular clinical trials. The rAAV gene therapy vectors used six unique capsid variants, 16 different promoters, and six unique polyadenylation sequences. Further, we compiled a list of promoters, enhancers, and other sequences used in current rAAV gene cassettes in preclinical studies. Then, we give an update on pro-viral plasmid backbones used to produce the gene therapy vectors, inverted terminal repeats, production yield, and rAAV safety considerations. Finally, we assess rAAV transgene and bioactivity assays applied to cells or organoids in vitro, explants ex vivo, and clinical studies.

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RNA-Based Therapeutic Strategies for Inherited Retinal Dystrophies

Cited by 8 publications

References 40 publications

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Nanotechnology-Based Strategies to Overcome Current Barriers in Gene Delivery

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

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