Gene therapy for retinal disease

doi:10.1016/j.trsl.2012.12.007

Translational Research

Volume 161, Issue 4, April 2013, Pages 241-254

https://doi.org/10.1016/j.trsl.2012.12.007 Get rights and content

Gene therapy strategies for the treatment of inherited retinal diseases have made major advances in recent years. This review focuses on adeno-associated viral (AAV) vector approaches to treat retinal degeneration and, thus, prevent or delay the onset of blindness. Data from human clinical trials of gene therapy for retinal disease show encouraging signs of safety and efficacy from AAV vectors. Recent progress in enhancing cell-specific targeting and transduction efficiency of the various retinal layers plus the use of AAV-delivered growth factors to augment the therapeutic effect and limit cell death suggest even greater success in future human trials is possible.

Section snippets

Cell-Specific Targeting Within the Retina: Serotype Tropism

The majority of IRDs are caused by mutations in genes specifically expressed in the photoreceptor of RPE cells, therefore, the ideal gene therapy would provide efficient transduction with restricted transgene expression to these cell types. Adeno-associated virus (AAV) is currently the favored vector for retinal gene therapy but lentiviral (LV) vectors are also being pursued. Whilst LV vectors have been shown to be efficient in targeting murine RPE cells,¹⁶ transduction of photoreceptors has

Promoter Choice in Retinal Gene Therapy

The use of ubiquitous promoters has helped reveal transduction patterns of AAV vectors (as described above), but as human gene therapy trials are becoming more frequent, the development of vectors that specifically target the cell of interest will increase safety and efficacy of the treatment. In retinal gene therapy animal studies, the commonly used ubiquitous promoters have been immediate-early cytomegalovirus (CMV) enhancer-promoter³⁷ and the CAG promoter, which combines the CMV enhancer

Self-Complementary AAV Vector use in Retinal Gene Therapy Studies

The onset of expression following AAV infection is delayed by numerous factors but the rate-limiting step is the synthesis of the complementary strand to the single stranded DNA AAV genome.59, 60 Self-complementary AAV (scAAV) vectors have been developed that can bypass this critical step. These vectors package a single-stranded transgene that contains both a forward and reverse copy of the therapeutic gene separated by an altered inverted terminal repeat. Following entry into the target cell

AAV Treatment of Autosomal Recessive Models of Retinal Disease

The majority of animal models of IRD exhibit null mutations, relevant to the study of autosomal recessive IRDs. Many studies have shown the feasibility of gene replacement therapy in such animal models. Peripherin2 is a rod photoreceptor-specific structural protein, mutations in which lead to autosomal recessive RP or macular dystrophy.⁶⁴ The retinal degeneration slow (rds) mouse is homozygous for a null mutation in the rds/peripherin-2 gene, completely lacking functional peripherin2.⁶⁵ Gene

AAV Treatment of Autosomal Dominant Models of Retinal Disease

The majority of animal models available for study of IRD carry null mutations, yet, there are numerous IRDs that do not show a complete lack of protein. Dominant mutations often yield mutated versions of a protein; if these impart a dominant-negative effect then provision of the wild-type gene and subsequent protein should resolve the phenotype as in the gene replacement strategies above. Dominant-negative mutations tend to eliminate 1 or more functions of the encoded protein, for example, the

Human AAV Clinical Trials for the Treatment of Retinal Disease

In 2008, data from 3 independent trials revealed evidence of improved visual function following rAAV2/2 subretinal delivery of hRPE65 to LCA patients (reviewed in reference¹⁴⁷). RPE65 (retinal pigment epithelium-specific protein 65kDa) is expressed in the RPE and is essential in the visual pathway for its role in regenerating the active chromophore required for light absorption, loss of function of RPE65, therefore, leads to loss of vision.¹⁴⁸ Whilst all 3 clinical trials were consistent in

Neuroprotection of the Retina

AAV delivery of growth and anti-apoptotic factors can be used to prevent cell loss when retinal degeneration is advanced and the causative mutation unknown and also to enhance the effects of a co-delivered therapeutic gene. Apoptosis of photoreceptor cells is common to most forms of IRD, therefore, preventing cell death could significantly slow degeneration and allow a greater window for gene therapy intervention. Minimizing rod photoreceptor death would also prolong cone survival and AAV

Summary

Gene therapy of retinal diseases is an advancing field. Identification of serotype tropism and enhancement of transduction efficiencies of the various retinal cell layers is allowing for targeted AAV treatment in various forms: growth factors and anti-apoptotic factors to prevent cell loss and also to enhance gene therapy in addition to gene-replacement and suppression-replacement therapies. All are showing success in animal models of retinal disease. Clinical trials of AAV-based gene therapy

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Cited by (59)

RPE based gene and cell therapy for inherited retinal diseases: A review
2022, Experimental Eye Research
Citation Excerpt :
The health of the inner cell layer of the retina plays a vital role in the proper functioning of vision. Mutations in certain genes of these cells can lead to IRD, but in most cases, it is caused by mutations in genes expressed in photoreceptors or RPE cells (McClements and MacLaren, 2013). Since the function of RPE plays an important role in the survival of rod and cone photoreceptors, gene mutations in RPE cells can lead to photoreceptor death and retinal degradation (Veleri et al., 2015).
The Retinal Pigment Epithelium (RPE) is the supportive layer located beneath the neural retina. Its health is essential for the proper function of photoreceptors. Indeed, any condition involving the RPE has the potential to induce an antegrade degeneration of the photoreceptors and inner retinal layers. Traditionally, degenerative disorders of the neural retina have been considered untreatable. However, the advent of gene and cell replacement therapies brings hope to halt or even cure retinal degenerative diseases. This study aims to review the most recent clinical trials registered on the RPE-based gene/cell intervention for the treatment of inherited retinal diseases (IRD). In this review, we provided an update on the clinical studies on the RPE-based gene/cell therapy for the treatment of IRD, summarized recent studies in this regard, and present the results of the corresponding clinical trials. A brief description of the details applied in the techniques, the advantages and withdraws of the utilized strategies were also included. This study provided evidence to show that gene therapy and cell replacement therapy have a great potential to become a successful treatment for IRD in the following decades, however, future studies should focus on novel methods to increase the safety and efficacy of the treatment.
Differences in Intraretinal Pigment Migration Across Inherited Retinal Dystrophies
2020, American Journal of Ophthalmology
To determine whether there are differences in the prevalence of intraretinal pigment migration (IPM) across ages and genetic causes of inherited retinal dystrophies (IRDs).
Retrospective cohort study.
Patients were evaluated at a single tertiary referral center. All patients with a clinical diagnosis of IRD and confirmatory genetic testing were included in these analyses. A total of 392 patients fit inclusion criteria, and 151 patients were excluded based on inconclusive genetic testing. Patients were placed into 3 groups, ciliary and ciliary-related photoreceptor, nonciliary photoreceptor, and retinal pigment epithelium (RPE), based on the cellular expression of the gene and the primary affected cell type. The presence of IPM was evaluated by using slit lamp biomicroscopy, indirect ophthalmoscopy, and wide-field color fundus photography.
IPM was seen in 257 of 339 patients (75.8%) with mutations in photoreceptor-specific genes and in 18 of 53 patients (34.0%) with mutations in RPE-specific genes (P < .0001). Pairwise analysis following stratification by age and gene category suggested significant differences at all age groups between patients with mutations in photoreceptor-specific genes and patients with mutations in RPE-specific genes (P < .05). A fitted multivariate logistic regression model was produced and demonstrated that the incidence of IPM increases as a function of both age and gene category.
IPM is a finding more commonly observed in IRDs caused by mutations in photoreceptor-specific genes than RPE-specific genes. The absence of IPM does not always rule out IRD and should raise suspicion for disease mutations in RPE-specific genes.
The Location of Exon 4 Mutations in RP1 Raises Challenges for Genetic Counseling and Gene Therapy
2019, American Journal of Ophthalmology
Citation Excerpt :
With the advent of gene therapy, disease inheritance patterns must be assessed to configure the best therapeutic approach. For disease caused by a dominant negative mechanism, a gene therapy strategy would require silencing of the expression of the mutated allele.21 As it is apparent in RP1 disease that a single allele is adequate for normal functionality, further gene supplementation would not be necessary.
Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency; however, most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 to examine the genetic basis of the exon 4 mutations.
Observational case series.
A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination.
Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs), and presented with severe early-onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited RP presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths, as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2, and p.(Gln917*).
The RP1 protein with a predicted length between 677 and 917 amino acids seems to have a dominant negative effect, whereas proteins shorter (486 amino acids) or longer than this (1526 amino acids) lead to a more severe phenotype, but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counseling, but recessive inheritance should be considered likely in severe early-onset cases.
Non-viral vectors based on cationic niosomes and minicircle DNA technology enhance gene delivery efficiency for biomedical applications in retinal disorders
2019, Nanomedicine: Nanotechnology, Biology, and Medicine
Low transfection efficiency is a major challenge to overcome in non-viral approaches to reach clinical practice. Our aim was to explore new strategies to achieve more efficient non-viral gene therapies for clinical applications and in particular, for retinal diseases. Cationic niosomes and three GFP-encoding genetic materials consisting on minicircle (2.3 kb), its parental plasmid (3.5 kb) and a larger plasmid (5.5 kb) were combined to form nioplexes. Once fully physicochemically characterized, in vitro experiments in ARPE-19 retina epithelial cells showed that transfection efficiency of minicircle nioplexes doubled that of plasmids ones, maintaining good cell viability in all cases. Transfections in retinal primary cells and injections of nioplexes in rat retinas confirmed the higher capacity of cationic niosomes vectoring minicircle to deliver the genetic material into retina cells. Therefore, nioplexes based on cationic niosomes vectoring minicircle DNA represent a potential tool for the treatment of inherited retinal diseases.
In silico and in vitro study of magnetic niosomes for gene delivery: The effect of ergosterol and cholesterol
2019, Materials Science and Engineering C
A low transfection efficiency and failure to deliver therapeutic genes to target organs limit the use of vesicular systems in gene therapy. In this study, magnetic niosomes were used to improve transfection efficiency and overcome limitations. In this light, Tween 60 and Span 60 molecules were employed as the bilayer component and ergosterol and/or cholesterol as membrane-stabilizing agents. We studied the structural and dynamical properties of cholesterol-containing niosomes (ST60/Chol) and ergosterol-containing vesicles (ST60/Ergo) using the molecular dynamics (MD) simulation technique. In in vitro experiments, the protamine-condensed DNA along with magnetic nanoparticles were prepared and incorporated into the niosome to form magnetic niosome-entrapped protamine-condensed DNA (M-NPD). The MD simulation comparison of two bilayers showed that the ST60/Ergo vesicles have better properties for gene delivery. Our in vitro results confirmed the in silico results and revealed that Ergo-niosomes have smaller size, better polydispersity, and slower release of plasmid than Chol-niosome. Moreover, M-NPD-Ergo showed higher cellular uptake and gene expresssion in HEK-293T cell line compared to M-NPD-Chol vesicles.
Current strides in AAV-derived vectors and SIN channels further relieves the limitations of gene therapy
2018, Egyptian Journal of Medical Human Genetics
Citation Excerpt :
For instance, Leber’s congenital amaurosis (LCA) (an early onset retinal dystrophy), characterized by a malfunction and deterioration of photoreceptors is caused by mutations in retinal pigment epithelium-specific protein 65 kDa (RPE65) gene [29–31]. This gene codes for a retinoid isomerase; a key factor in retinol function in the visual cycle [28,31,32], by using specific hRPE65 (resulting in a lower expression) or ubiquitously promoters (higher expression), after the injection of AAV2 vectors to the subretina, the over-expression of a functional copy of the gene RPE65 could improve vision [30]. As shown from the low immunogenicity, safety, clinical benefit and good tolerability, in three previous clinical trials, the immune system is an important factor that must be considered in all kinds of experimental and clinical research practices [28].

View all citing articles on Scopus

: Conflict of interests: All authors have read the journal’s policy on conflicts of interest and have none to declare.

View full text

Gene Therapy for Human Disease: Clinical Advances and ChallengesReview ArticleGene therapy for retinal disease

Section snippets

Cell-Specific Targeting Within the Retina: Serotype Tropism

Promoter Choice in Retinal Gene Therapy

Self-Complementary AAV Vector use in Retinal Gene Therapy Studies

AAV Treatment of Autosomal Recessive Models of Retinal Disease

AAV Treatment of Autosomal Dominant Models of Retinal Disease

Human AAV Clinical Trials for the Treatment of Retinal Disease

Neuroprotection of the Retina

Summary

Survey Ophthalmol

J AAPOS

Vis Res

Prog Mol Biol Transl Sci

Mol Ther

Curr Opin Biotechnol

Mol Ther

Mol Ther

Mol Ther

Mol Ther

Experimental Cell Res

J Biol Chem

Mol Ther

Mol Ther

Mol Ther

Mol Genetics Metab

Am J Hum Genetics

Am J Hum Genetics

Molecular therapy : the journal of the American Society of Gene Therapy

The implications of rod-dependent cone survival for basic and clinical research

Invest Ophthalmol Vis Sci

Identification and characterization of rod-derived cone viability factor

Nat Genetics

Molecular genetics of human retinal disease

Annu Rev Genetics

Retinitis pigmentosa: genes, proteins and prospects

Dev Ophthalmol

Update on the genetics of macular dystrophies

Retina (Philadelphia, Pa)

Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa

Nat Genetics

Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations

Gene Ther

Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina

Mol Vis

Changes in adeno-associated virus-mediated gene delivery in retinal degeneration

Hum Gene Ther

Gene therapy regenerates protein expression in cone photoreceptors in Rpe65(R91W/R91W) mice

PLOS One

Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors

J Gene Med

Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model

Hum Mol Genetics

Lentiviral vector-mediated gene transfer in adult mouse photoreceptors is impaired by the presence of a physical barrier

Gene Ther

Retinal degeneration progression changes lentiviral vector cell targeting in the retina

PLOS One

Gene transfer into the mouse retina mediated by an adeno-associated viral vector

Hum Mol Genetics

Novel AAV serotypes for improved ocular gene transfer

J Gene Med

Virus-mediated transduction of murine retina with adeno-associated virus: effects of viral capsid and genome size

J Virol

Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors

J Virol

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Gene Ther

Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina

Proc Natl Acad Sci U S A

Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina

Hum gene Ther

Recombinant adeno-associated virus targets passenger gene expression to cones in primate retina

J Opt Soc Am A Opt Image Sci Vis

AAV capsid structure and cell interactions

Methods Mol Biol (Clifton, NJ)

Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors

J Virol

Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors

J Virol

Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses

Gene Therapy for Human Disease: Clinical Advances and Challenges
Review Article
Gene therapy for retinal disease