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Open Access 19.12.2023 | REVIEW

Gene Therapy for Inherited Retinal Diseases: From Laboratory Bench to Patient Bedside and Beyond

verfasst von: Anand Singh Brar, Deepika C. Parameswarappa, Brijesh Takkar, Raja Narayanan, Subhadra Jalali, Sohini Mandal, Kaoru Fujinami, Srikanta Kumar Padhy

Erschienen in: Ophthalmology and Therapy | Ausgabe 1/2024

Abstract

This comprehensive review provides a thorough examination of inherited retinal diseases (IRDs), encompassing their classification, genetic underpinnings, and the promising landscape of gene therapy trials. IRDs, a diverse group of genetic conditions causing vision loss through photoreceptor cell death, are explored through various angles, including inheritance patterns, gene involvement, and associated systemic disorders. The focal point is gene therapy, which offers hope for halting or even reversing the progression of IRDs. The review highlights ongoing clinical trials spanning retinal cell replacement, neuroprotection, pharmacological interventions, and optogenetics. While these therapies hold tremendous potential, they face challenges like timing optimization, standardized assessment criteria, inflammation management, vector refinement, and raising awareness among vision scientists. Additionally, translating gene therapy success into widespread adoption and addressing cost-effectiveness are crucial challenges to address. Continued research and clinical trials are essential to fully harness gene therapy’s potential in treating IRDs and enhancing the lives of affected individuals.

Key Summary Points

Wide-ranging impact: inherited retinal diseases (IRDs) significantly contribute to childhood and adult blindness due to the deterioration of photoreceptor cells.

Diverse classifications: IRDs encompass a varied spectrum, categorized by inheritance patterns, genes, and organelle involvement, presenting diagnostic complexities, especially in syndromic cases.

Holistic therapeutic approaches: beyond gene therapy, innovative strategies such as retinal cell replacement, neuroprotection, pharmacology, and optogenetics offer avenues for vision restoration.

Gene therapy breakthrough: the success of Luxturna exemplifies the transformative potential of gene therapy, demonstrating promising outcomes for patients with Leber congenital amaurosis and pioneering the role of viral vector-based treatments.

Navigating challenges for progress: addressing optimal intervention timing, standardized outcome assessments, inflammation mitigation, awareness enhancement, and equitable access are key to advancing IRD treatments and reshaping the landscape of visual impairment.

Introduction

Inherited retinal diseases (IRDs), variously referred to as retinal dystrophies and inherited retinal degenerations/disorders, refer to a diverse group of genetic conditions involving pathogenic variants in genes critical to retinal function that usually lead to photoreceptor cell death [1, 2]. The cell death may be due to a primary degeneration affecting the photoreceptors or secondary to abnormal retinal pigment epithelium (RPE) or choroid [3]. IRDs are a significant cause of blindness in childhood and the working-age group population in the developed world and are also a major cause of familial blindness and visual impairment in the young [4‐6]. Addressing the economic aspects associated with visual disability induced by IRDs provides a comprehensive understanding of the broader consequences, emphasizing the need for effective and cost-efficient treatment strategies. The prevalence of disability is higher in areas practicing inbreeding and consanguinity. It comprises genetic defects in various chorioretinal components—photoreceptors, RPE, choroid as well as vitreoretinopathies.

IRDs commonly present in childhood or early life with mild-to-severe vision loss and variable progression leading to legal blindness in early age groups. IRDs can also present as part of a systemic syndrome [7]. Early detection and phenotypic-genotypic diagnosis are imperative for genetic counselling, prognosis as well as judging eligibility for approved gene therapies/participation in trials. Earlier thought to be blinding disorders without hope of improvement, significant progress in the field of gene therapy has ignited prospects of reducing the morbidity and improving the functioning in IRDs. This review will look at the various IRDs, ongoing gene therapy trials, and the advances and challenges with gene therapy.

Methodology

A comprehensive literature search was conducted using PubMed database. The search strategy, performed in April 2023, focused on articles published between January 2001 and March 2023 to capture recent developments in gene therapy and inherited retinal diseases. The search terms included combinations of controlled vocabulary terms (MeSH terms) and keywords related to inherited retinal diseases (e.g., “inherited retinal diseases,” “retinal dystrophies,” “retinal degenerations”), gene therapy (e.g., “gene therapy,” “gene augmentation,” “CRISPR-Cas9”), and associated concepts. Titles and abstracts of retrieved articles were screened for relevance to the review’s objectives, with irrelevant articles being excluded. Full-text articles of relevant references were then reviewed, and data were extracted, categorized, and synthesized on the basis of key themes such as classification of inherited retinal degenerations, gene therapy strategies, ongoing clinical trials, challenges, efficacy assessment, and translation to the public. The methodology acknowledges limitations in terms of database coverage and potential bias in article selection, while aiming to provide a systematic overview of the advancements and challenges in gene therapy and inherited retinal diseases.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Classification of Inherited Retinal Degenerations

IRDs can be classified on the basis of the inheritance pattern, gene involved, organelle involved, layer of retina involved, and the type of functional loss. Clinical classification can be based on pan-retinal vs. macular involvement, or progressive vs. non-progressive disease (Table 1). Although non-progressive IRDs can at times be minimally progressive or appear progressive due to adjoining conditions like degenerative myopia [8]. However, misdiagnosis can be avoided by relying on electrophysiological tests, or electrotyping the patient. The age of onset has traditionally been used to classify IRDs, but molecular analysis has revealed its usefulness to be limited. Syndromic IRDs consist of systemic disorders that may include associated bony deformities, hearing defects, speech affection, vestibular dysfunction, renal, endocrine or neurological abnormalities. Marked phenotypic heterogeneity and overlap makes diagnosis of syndromic IRDs extremely challenging [9]. Recent advances in genotype and phenotype characterization of IRDs has enormously expanded the literature on this subject and therefore, reiterating descriptions of the various diseases is beyond the ambit of this review [10‐12]. In addition, various genes can cause both syndromic and non-syndromic IRDs; where milder hypomorphic variants in the particular gene cause non-syndromic IRD and null mutations in the same gene lead to additional systemic associations [13]. Therefore, genetic testing becomes extremely crucial in identifying syndromes early with occult systemic involvement or phenotypic variability [14, 15].

Table 1

Classification of inherited retinal dystrophies

Based on mode of inheritance

1. Autosomal dominant: Stargardt-like macular dystrophy (EVOVL4, PROM1), Autosomal dominant bull’s eye macular dystrophy (PROM1), Best macular dystrophy (BEST1), pattern dystrophy (PRPH2), Doyne’s honeycomb retinal dystrophy (EFEMP1), North Carolina macular dystrophy, Central areolar choroidal dystrophy (PRPH2, GUY2CD), Sorsby fundus dystrophy (TIMP3), Progressive bifocal chorioretinal atrophy, North Carolina macular dystrophy associated with deafness

2. Autosomal recessive: Stargardt’s disease, Fundus flavimaculatus, Autosomal recessive bestrophinopathies

3. X-linked: Rod-cone dystrophy (RPGR, RP2), Choroideremia, X-linked retinoschisis, Complete congenital stationary night blindness (NYX), Incomplete congenital stationary night blindness (CACNA1F), Blue cone monochromatism (OPN1LW/OPN1MW), Ocular albinism (GPR143), Alport syndrome, Norrie disease, Familial exudative vitreoretinopathy, Incontinentia pigmenti (IKBKG/NEMO), Aicardi syndrome, Fabry disease (GLA), Menkes disease (ATP7A), Danon disease (LAMP2), Mucopolysaccharidosis II, Hunter syndrome (IDS), Goltz syndrome/Focal dermal hypoplasia (PORCN)

4. Mitochondrial: Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome

Based on organelle involvement

1. Lysosomes: Hurler, Hurler-Scheie, Scheie disease; neuronal ceroid lipofuscinosis; spinocerebellar ataxia

2. Peroxisomes: Zellweger syndrome, Refsum’s disease, Neonatal adrenoleukodystrophy

3. Centrioles: FAM161A-associated retinitis pigmentosa

4. Mitochondria: Kearns-Sayre syndrome, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and MIDD syndromes (maternally inherited diabetes and deafness)

5. Cilium: Usher syndrome, Bardet-Biedl syndrome, Joubert syndrome, Senior-Loken syndrome, Alstrom syndrome

Based on functional loss

1. Rod-cone dystrophy

2. Cone-rod dystrophy

3. Cone dystrophy

4. Rod dystrophy

Based on the clinical course of the disease

1. Stationary: Congenital stationary night blindness, Achromatopsia, Blue cone monochromatism, Bornholm eye disease, Albinism, North Carolina macular dystrophy, Enhanced S cone syndrome, X-linked retinoschisis, Benign fleck retina, Retinitis punctata albescence

2. Progressive: Retinitis pigmentosa, Cone dystrophies, Cone rod and Rod cone dystrophies, Stargardt disease, choroidal dystrophies, Occult macular dystrophies

Syndromic IRDs

Alport syndrome, Norrie disease, Familial exudative vitreoretinopathy, Incontinentia pigmenti (IKBKG/NEMO), Aicardi syndrome, Fabry disease (GLA), Menkes disease, Syndromic retinitis pigmentosa

Based on region of involvement

1. Macula: Best vitelliform macular dystrophies, Autosomal recessive bestrophinopathies, Central areolar choroidal dystrophy, Doyne honeycomb retinal dystrophy, Stargardt’s disease/Fundus flavimaculatus, North Carolina macular dystrophies, Sorsby macular dystrophy, Pattern dystrophy, Doyne’s honeycomb dystrophy

2. Pan retinal: Bietti crystalline dystrophy, Choroideremia, Cone dystrophy, Cone rod dystrophy, Leber congenital amaurosis, Rod cone dystrophies—including Retinitis pigmentosa

# variable spatial distributions are known for these diseases

Based on layer of involvement

1. Vitreoretinal-X linked retinoschisis, Stickler syndrome, Wagner syndrome, Jansen syndrome, Familial exudative vitreoretinopathy, Weissenbacher–Zweymüller syndrome, Goldmann Favre syndrome, Norrie disease, Knobloch syndrome

2. Photoreceptor and Retinal pigment epithelium: Retinitis pigmentosa, cone dystrophy, cone rod dystrophy, Rod cone dystrophy, Leber congenital amaurosis, Achromatopsia, Fundus albipunctatus and other congenital stationary night blindness, Enhanced S cone syndrome

3. Retinal pigment epithelium: Stargardt disease, Pattern dystrophies (adult-onset foveomacular vitelliform dystrophy, butterfly-shaped pigment dystrophy, reticular dystrophy, multifocal pattern dystrophy simulating Stargardt disease and fundus pulverulentus), Best vitelliform macular dystrophy, Dominant drusen, Fundus flavimaculatus, Sorsby macular dystrophy

4. Chorioretinal—Choroideremia, Gyrate atrophy, Central areolar choroidal dystrophy, peripapillary choroidal dystrophy

# variable layers can be affected for these diseases

EVOVL4 elongation of very long chain fatty acids protein 4, PROM1 prominin 1, BEST1 bestrophin 1, PRPH2 peripherin 2, EFEMP1 epidermal growth factor-containing fibulin-like extracellular matrix protein 1, GUY2CD guanylate cyclase 2C, TIMP3 tissue inhibitor of metalloproteinase 3, RPGR retinitis pigmentosa GTPase regulator, RP2 retinitis pigmentosa 2, NYX nyctalopin, CACNA1F calcium voltage-gated channel subunit alpha1 F, OPN1LW/OPN1MW opsin 1, long-wave-sensitive/opsin 1, medium-wave-sensitive, GPR143 G protein-coupled receptor 143, IKBKG/NEMO inhibitor of nuclear factor kappa-B kinase subunit gamma, GLA alpha-galactosidase A, ATP7A ATPase copper transporting alpha, LAMP2 lysosomal-associated membrane protein 2, IDS iduronate 2-sulfatase, PORCN porcupine O-acyltransferase, FAM161A FAM161 centrosomal protein A, IKBKG inhibitor of nuclear factor kappa B kinase regulatory subunit gamma, NEMO NF-kappa-B essential modulator

Gene-Agonistic (Independent)/Nongenetic Therapeutic Prospects for IRD

Gene-agnostic therapeutic approaches aim to address the common pathways causing retinal degeneration, benefiting all patients with IRD regardless of their genetic mutations. These approaches offer potential functional vision rescue. We discuss key gene-agnostic strategies (Fig. 1).

Retinal Cell Replacement Therapies/Stem Cell Therapies

Before the era of molecular analysis of inherited conditions, such diseases were tackled with non-genetic approaches including various stem cell therapies—these aimed to replace the dysfunctional cellular pool containing the mutated gene with supplementation of healthy cellular pool. Cell therapy, a mutation-independent approach, can be performed even when the cells are completely damaged. Unfavorable outcomes and the advent of molecular genetics led to the redrawing of surgical approaches with a shift from cellular therapy to genetic manipulation (addition of the defective gene or editing of the mutated segment). This form of retinal regenerative medicine particularly deals with RPE or photoreceptor transplantation therapies, the rationale being twofold: (a) these cells easily integrate with the host retinal tissue and (b) they secrete neurotrophic factors for survival of cells. Photoreceptor transplantation, particularly of rod cells, is helpful in retinitis pigmentosa since this accounts for almost 90% of total photoreceptors in the eye [16]. The phase I/IIa clinical study (NCT02286089) on subretinal transplantation of hESC-derived RPE cells for patients with dry age-related macular degeneration (AMD) and geographic atrophy (GA) has shown promising results, with well-tolerated treatment and visual improvement in cohort 4 patients (10–22 letters). Imaging findings suggest the presence of transplanted RPE cells, highlighting encouraging structural changes. Further follow-up is needed to assess long-term efficacy and safety [17]. RPE transplantation is primarily aimed at treating Stargardt disease where the primary pathology is loss of RPE. Unlike that of photoreceptor transplantation, donor RPE cells need not integrate into the retinal neural network; however, correct polarization is critical. Table 2 highlights various clinical trials in retinal cell replacement therapies/stem cell therapies.

Table 2

Clinical trials in gene agonistic approaches

Approaches	Types	Trial number	Phase	Aim of study	Outcome
Photoreceptor transplantation	Stem cell suspension transplantation	NCT02320812	Phase 1/2 trial	Safety of a single, intravitreal injection of human retinal progenitor cells in retinitis pigmentosa	The cells were well tolerated
		NCT03073733	Phase 2b trial	Safety and efficacy of intravitreal injection of human retinal progenitor cells in adults with retinitis pigmentosa	Demonstrated some efficacy of human retinal progenitor cells delivery in high-dose patients (best corrected visual acuity improvement)
		NCT02464436	Phase 1/2 dose escalation study	Assessing safety, tolerability, and preliminary efficacy of subretinally transplanted human retinal progenitor cells via injection in retinitis pigmentosa	Trial still going on
		NCT04604899	Phase 2	Safety of repeat intravitreal injection of human retinal progenitor cells in adult subjects with retinitis pigmentosa	Trial still going on
		ChiCTR-TNRC-08000193	Phase 1 trial	Long-term safety of human retinal progenitor cell transplantation in patients with retinitis pigmentosa	No immunological rejection or tumorigenesis. Long-term safety and feasibility Significant improvement in visual acuity and increase in retinal sensitivity
	Structured retinal sheet transplantation	Japan registry of clinical trials ID: jRCTa05020002		Human induced pluripotent stem cell-derived retinal sheets transplantation in patients with advanced retinitis pigmentosa	Trial still going on
Retinal pigment epithelial transplantation		NCT01345006	Phase 1/2	Safety and tolerability trial to evaluate the effect of subretinal injection of human embryonic stem cell-derived RPE cells in patients with Stargardt’s macular dystrophy	Evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny
		NCT01469832	Phase 1/2	Safety and tolerability of subretinal transplantation of up to 200,000 human embryonic stem cell-derived retinal pigment epithelial cells with systemic immunosuppressive therapy for 13 weeks	Survival of viable transplanted human embryonic stem cell-derived retinal pigment epithelial cells
		NCT01625559	Phase 1	Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived RPE in Asian patients with Stargardt disease	No serious adverse events. Long-term safety, tolerability, and feasibility
		Ministry of Health of Turkey approval: 56733164/203	Phase 1	Safety of subretinal adipose tissue-derived mesenchymal stem cell (ADMSC) implantation in advanced-stage retinitis pigmentosa	Evidence of the short-term safety of ADMSCs in humans Ocular complications (choroidal neovascular membrane and epiretinal membrane) were reported
		NCT01625559	Phase 1	Safety and tolerability of MA09-human retinal pigment epithelial cells in patients with Stargardt’s macular dystrophy	No evidence of adverse serious safety issues Visual acuity improvement
		NCT02749734	Phase 1/2	Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5 years’ follow-up	Safe and tolerable. Increased visual function Visual function loss in two patients

Neuroprotection Approaches

Neuroprotective strategies, a mutation-independent modality, aim to target common stress pathways of the cells (photoreceptors or ganglion cells) and enhance the photoreceptor survival, irrespective of whether they target a primary causative or secondary/contributory pathologic process or the stage of the disease [18]. Neurotrophic factors are mostly small peptide molecules [glial cell-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor, and pigment epithelium-derived factor (PEDF)] that promote cell growth, proliferation, differentiation, and survival with either an autocrine or a paracrine effect; however, as a result of their shorter half-lives, they require frequent administration to attain desired therapeutic levels. However, adeno-associated virus (AAV)-mediated expression of neurotrophic factors can ensure stable transgene expression and therapeutic efficacy. In various animal models of retinal degeneration, morphologic and/or functional rescue of photoreceptors has been documented after treatment with different trophic factors [19]. Detailed discussion of studies is beyond the scope of this review. Strategies that target dysfunctional metabolism of photoreceptors which occurs during retinal degenerations include AAV8-mediated delivery of Txnip and subretinal rod-derived cone viability factor delivery [20, 21].

Pharmacologic Approaches

Visual function pathway dysfunction is the key cause for occurrence of IRDs. Photoreceptors and RPE play a major role in the visual cycle which is an enzymatic process where light falling on the retina is converted to an electrical signal and ultimately conveying the signal to the brain for image processing and perception [22]. The major substrate components and enzymes involved in the visual cycle are opsins, all-trans-retinal, 11-cis-retinal, retinol dehydrogenases, lecithin retinol acyltransferase (LRAT), the ATP-binding cassette subfamily A member 4 transport protein (ABCA4), and retinoid isomerohydrolase. Numerous pharmacological therapies have been studied to target these proteins and enzymes to restore or prevent progression in IRDs [23, 24]. Pharmacological drugs include by-products of vitamin A like oral retinoid therapies (9-cis-retinyl and 9-cis-β-carotene) and drugs that decrease the accumulation of excessive lipofuscin like ALK-001, isotretinoin, emixustat, VM200, and A1120 [23]. Orally administered 9-cis-retinyl acetate, 9-cis-retinyl succinate, and 9-cis-β-carotene are proven to help as by-products of the visual pathway. These by-products accentuate photoreceptor regeneration, antioxidant mechanisms, and reduce inflammation. Oral retinoid therapies are proven to be beneficial in LRAT and RPE65-deficient mice models and clinical trials in humans are ongoing [25, 26]. The outcomes of retinoid therapies were assessed by improvement in visual acuity and visual fields. Isotretinoin prevents lipofuscin accumulation by inhibiting 11-cis-retinol dehydrogenase. Studies have proposed that isotretinoin has a role in delaying the vision loss in IRDs associated with lipofuscin accumulation like Stargardt disease [27, 28]. Emixustat hydrochloride is a non-retinoid derivative which inhibits RPE65 function preventing toxic accumulation of A2E. Clinical trials have shown that oral administration of the drug is well tolerated in patients with Stargardt disease in three different doses (2.5 mg, 5 mg, and 10 mg). The efficacy was assessed in terms of rod b-wave amplitude recovery [29, 30]. VM200 is an orally administered aldehyde that prevents photoreceptor cell death by preventing formation of toxic A2E.

Optogenetics

The hypothesis of optogenetics involves transforming viable retinal cells, specifically ganglion cells, into artificial photoreceptors. These photoreceptors can respond to specific wavelengths of light projected by an optical device worn by the patient and generate electric signals transmitted to the brain, resulting in the perception of a binary image [31, 32]. Optogenetics with ChrimsonR differs from Luxturna-based gene therapy. While optogenetics is mutation independent, Luxturna is only suitable for RPE65-deficient cases. Optogenetics targets older patients with poor vision, while Luxturna targets the better eye in younger patients. Retinal function testing relies on EEG for optogenetics and ERG for Luxturna. Macular thickness is a concern with Luxturna because of subretinal injections, while optogenetics using intravitreal injections appears easier and safer in this regard. Mobility tests are used in Luxturna trials, while optogenetics focuses on indoor object perception tests. Optogenetics targets retinal ganglion cells, while Luxturna targets RPE cells. A study by Sahel et al. reported partial visual function recovery after optogenetics therapy in a patient who was blind with retinitis pigmentosa [31].

Retinal Prosthesis

Retinal prostheses are implantable electronic devices that are designed to stimulate sensation of vision by processing incoming light and transmitting the information in the form of electrical impulses to the remaining inner retinal layers for visual function. They aim to offer restoration of limited vision to people suffering from advanced stages of IRDs by replacing the function of the photoreceptors. Starting from the late 1980s, research in this field culminated in the first retinal prosthesis implantation in 2002 with phase I clinical trials for the Argus^® I, an epiretinal implant. The next-generation Argus^® II was approved for marketing in Europe after successful implantation in 30 participants [33]. The participants had bare or no light perception resulting from end-stage retinitis pigmentosa (RP).

In a recent trial, studying the post-approval long-term outcomes in a French population (prospective, multicenter, single-arm study) the 2-year data found benefits in improving participants’ daily activities. Visual benefit in daily activities was monitored with the Functional Low-vision Observer Rated Assessment (FLORA), and the final score at 2 years was the primary effectiveness outcome. In 17 participants who completed the study, statistically significant improvement was noted in tasks such as finding doorways, estimating the size of an obstacle, visually locating a place setting on a dining table, and visually locating people in a non-crowded setting (p < 0.001) [34].

Other than an epiretinal implant, interim trial data of a suprachoroidal prosthesis in four participants demonstrated safety and significant improvement in functional vision, activities of daily living, and observer-rated quality of life [35].

Challenges in the Treatment

Treating IRDs has historically posed significant challenges, with limited available methods to halt progression or reverse the pathology. Traditional classifications of retinal or choroidal dystrophies primarily focused on phenotypic diagnosis and prognosis, lacking therapeutic considerations. However, recent discussions at the Second Monaciano Symposium organized by the Monaciano Consortium addressed these challenges and identified priority areas for advancement [36, 37]. One of the key challenges discussed was the need to utilize natural history studies to guide trial design, allowing for a better understanding of the optimal timing for intervention and improving post-therapy outcomes. Developing meaningful pre- and post-therapy outcome measures was another crucial point, as these measures are essential for accurately assessing the effectiveness of treatments for patients with IRD. Standardizing validated outcome measures was emphasized to facilitate consistent evaluation and comparison of therapeutic interventions. Addressing inflammation associated with IRDs and gene therapy was identified as an important challenge, with efforts aimed at minimizing its impact on treatment outcomes. Establishing a pediatric action plan to address the specific needs and challenges of treating IRDs in children was also highlighted. Furthermore, improving patient guidance and counselling regarding participation in various studies and clinical trials was discussed to ensure that patients make informed decisions. Promoting transparency, accountability, and accessibility in the field of IRD research and treatment was emphasized as a crucial aspect. This involves fostering open communication, sharing research findings, and making treatments more accessible to patients. In addition to these priority points, there are several remote challenges in the treatment of IRDs. These include the lack of animal models with specific mutations, macular dystrophies (currently available animal models cannot fully mimic human STGD1), the involvement of many genes and different mutations in the pathogenesis of IRDs, the development of ideal vectors for gene therapy, and the need for widespread awareness and acceptability among vision scientists [38, 39].

Failed Therapies for IRDs and Emergence of Luxturna

IRDs have been the subject of research in cellular therapies, including autologous bone marrow-derived stem cells, human retinal progenitor cells, and embryonic stem cell-derived RPE, among others [40]. However, the field faced controversy when unregulated clinics in the USA began administering autologous “stem cells” for IRD therapy [41]. While cellular-based therapies have shown limited success, significant progress has been made in gene therapy using viral vector-based gene augmentation, exemplified by voretigene neparvovec (Luxturna), which provides hope for patients with Leber congenital amaurosis (LCA) having RPE65 mutation. The journey of successful gene therapy involved experiments in animal models before progressing to human trials. Overcoming obstacles beyond phase I trials included the development of standardized and exploratory functional outcome measures, addressing immune responses to readministration of gene therapy reagents, planning randomized controlled phase 3 studies, organizing multicenter trials, and securing a commercial sponsor [42].

Gene Therapy at the Bench

Targets for Genetic Therapy

Genetic defects can either be loss of function mutation or gain of function defects. Defects at the RPE level led to LCA/RP (RPE65 gene associated), RP (MERTK gene associated), and choroideremia (CHM gene). Defects at the photoreceptor level can result in achromatopsia (CNGB3, CNGA3, PDE6C, PDE6H, GNAT2, ATF6), X-linked RP (RPGR gene), and Stargardt disease (ABCA4), while disorder at inner retinal level is manifested as X-linked retinoschisis (RS1 gene). Targeting gene defects includes addressing a single mutation, multiple mutations in several genes, or even addressing missing or extra copies in a particular disease. Before approaching a disease using gene therapy, one should first identify the key protein, protein by-products, and pathways involved in the disease [43].

Various Strategies of Gene Therapy

Gene therapy (GT) encompasses deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)-based strategies, with gene augmentation and gene editing being the main DNA-based approaches. RNA manipulation involves messenger RNA (mRNA) transcript editing and correcting abnormal intron splicing using anti-sense oligonucleotide (AON) therapy. Gene augmentation is suitable for autosomal recessive diseases where the mutant allele leads to loss of function, and introducing a healthy allele can enhance functionality [44]. Gene editing at the DNA level has garnered immense focus in recent years owing to the introduction of CRISPR (clustered regularly interspersed short palindromic repeats)-based gene therapy [45, 46]. In fact, the first in vivo trials of CRISPR-based gene editing in the human body have been initiated for IRDs, specifically CEP290-mediated IRD. CRISPR (or more accurately CRISPR-Cas9)-based genetic engineering, also known as “genome surgery”, when used in vivo, uses endonucleases as molecular scissors to cleave at the chosen site of DNA nucleotides. Further, the DNA sequence of choice to correct the mutated sequence can then be inserted at the site of cleavage [47].

Vectors play a crucial role in delivering therapeutic genes to target cells. These vehicles carry the transgene, along with helper plasmids, and may include enhancer and promoter sequences. Commonly used viral vectors include adenovirus, AAV, and lentivirus, while non-viral vectors include naked DNA, oligonucleotides, and inorganic nanoparticles. The choice of vector is vital for the success of gene therapy [48, 49]. Choosing the right viral vector is a formidable task because of the constraints posed by the 4.7-kilobase (kb) limit of AAV vectors, especially in most of the genes responsible for IRD.

Modes of Ocular Administration

Ocular administration of gene therapy can be via intravitreal, subretinal, or suprachoroidal route. While the suprachoroidal and subretinal routes have the advantage of deposition of the vector close to the intended target, these are logistically difficult to achieve—requiring vitrectomy or specialized suprachoroidal delivery devices. Suprachoroidal delivery, in terms of complexity, shares similarities with intravitreal delivery and is a technique already in clinical use for treating conditions such as uveitides, as demonstrated by the use of Xipere (triamcinolone acetonide) [50]. The intravitreal route has the advantages of an in-office procedure; however, it has been associated with increased intraocular inflammation post-intervention and requirement of larger doses compared to the subretinal mode. Compared to other parts of the body, delivery of drugs is particularly challenging in the eye because of various ocular barriers like blood–aqueous barrier (ciliary nonpigmented epithelium), outer blood–retinal barrier (RPE), and inner blood–retinal barrier (retinal vascular endothelium) [51, 52].

On the other hand, the eye is considered ideal for gene therapy also for reasons like easy accessibility via injections and surgical interventions, immune-privileged status, presence of tight ocular barriers, assessment of retinal structure and anatomy post treatment with various imaging modalities, the fellow eye serves as a control.

Modalities of Gene Delivery

Gene delivery systems employ various modalities to introduce genetic material into host cells, each with its own set of advantages and limitations. Viral vector delivery systems, exemplified by adenoviral and AAV vectors, have distinct advantages and limitations. Adenoviral vectors exhibit good safety, efficient transduction, and a capacity to carry genes of around 30 kb. However, their use in retinal gene therapy is limited because of rapid clearance from pre-existing immunity. Second-generation adenovirus vectors with deleted early gene regions mitigate some issues but are not widely employed in retinal gene therapy. AAV vectors, on the other hand, offer a long duration of transgene expression, low risk of insertional mutagenesis, mild inflammatory response, and low possibility of germline transmission. AAV vectors have tissue-specific serotypes, enhancing their applicability in ocular gene therapies [53]. Recombinant AAV vectors, combining tropisms from multiple serotypes or employing dual/multiple vector strategies, address size restrictions and immune responses, leading to notable approvals for gene therapy products like Luxturna [54].

Non-viral gene delivery methods encompass physical, aptamer-based, electroporation, gene guns, ultrasound, and magnetofection. Physical delivery involves the injection of naked plasmid DNA, siRNA, mRNA, or miRNA, showing limited uptake due to quick degradation. Aptamer-based therapies, exemplified by Macugen, have fallen out of favor. Other physical methods like electroporation, gene guns, ultrasound, and magnetofection use physical means to deliver genes. Chemical methods, such as inorganic nanoparticles, lipid-based systems, and polymers, offer reduced immunogenicity, scalability, cost-effectiveness, and increased payload size. Inorganic nanoparticles and lipid-based systems have shown success in transferring target genes into retinal cells. Chemical methods like CK30-PEG DNA nanoparticles and lipid-based drugs have been studied for ocular gene therapy, while niosomes and polymer systems like chitosan, hyaluronic acid, PEI, PLGA, and PLL have been explored with potential benefits in terms of transfection efficiency and biocompatibility [55]. Overall, the choice of delivery method depends on factors such as transduction efficiency, duration of effect, immunogenicity, and therapeutic expression levels. Each method presents a unique set of pros and cons, emphasizing the need for tailored approaches based on the specific requirements of ocular gene therapy.

IRDs and Gene Therapy: Advantages and Challenges at the Bedside

The retina beyond the blood–retinal barrier is a relatively immune-privileged site and is suitable for intraocular procedures to effect gene therapy [45, 56, 57]. For IRDs, their monogenic pathophysiology makes them amenable to gene augmentation/editing. However, early success has been limited to early disease, relatively preserved photoreceptors, and younger subjects. Outcome measures can be titrated precisely with various imaging modalities. Gene therapy for LCA inspired hopes for other IRDs. However, it brings additional challenges of identifying genetic defects in different ethnicities and creating national IRD registries, training retinal surgeons and ocular geneticists, establishment of suitable visual tests for monitoring, and financial aspects of gene therapy.

Various Targeted IRDs and Ongoing Clinical Trials

Clinical trials in IRDs have exploded with active interest in gene therapy to quickly bring therapeutically active agents to the clinic. From 32 trials noted till October 2020, this number is on the rise with about 200 trials in different phases underway (till March 2023, Table 3). To just enumerate all the trials is a monumental task, let alone keep up with the trial results. Live registries that aim to clarify gene therapy trials should commence for researchers to easily look up and understand the status of a specific gene therapy for a particular gene target of an IRD. Table 4 illustrates the journey to US Food and Drug Administration (FDA) approval for Luxturna, serving as a compelling case study.

Table 3

Clinical trials in various inherited retinal diseases

Disease	Target gene	Vector/type	Starting year	NCT identifier	Phase	Status	Location(s)	Number	Outcome measures	Study title/link
Achromatopsia	CNGA3	rAAV8.hCNGA3	2015	2610582	1/2	Recruiting	Germany	14	Safety (AE). Number of participants with abnormal laboratory values and/or AEs that are related to treatment; efficacy measures. Number of participants with improved visual function	Safety and efficacy of rAAV.hCNGA3 gene therapy in patients with CNGA3-linked achromatopsia
	CNGB3	rAAV2tYF-PR1.7-hCNGB3	2016	2599922	1/2	Active, not recruiting	USA	32	Adverse events Visual acuity Light aversion Color vision	Safety and efficacy trial of AAV gene therapy in patients with CNGB3 achromatopsia (a clarity clinical trial)
	CNGA3	rAAV2tYF-PR1.7-hCNGA3	2017	2935517	1/2	Active, not recruiting	USA and Israel	24	Adverse events Visual acuity Light aversion Color vision	Safety and efficacy trial of AAV gene therapy in patients with CNGA3 achromatopsia (a clarity clinical trial)
	CNGB3 and CNGA3	AAV2/8-hCARp.hCNGB3 and AAV2/8-hG1.7p.coCNGA3	2017	3278873	1/2	Active, not recruiting	UK and USA	34	Incidence of AEs related to the treatment Improvement in the visual function Improvement in retinal function Improvement in quality of life	Long-term follow-up gene therapy study for achromatopsia CNGB3 and CNGA3
	CNGB3	AAV2/8-hCARp.hCNGB3	2017	3001310	1/2	Completed	UK and USA	23	Number of participants meeting the primary outcome defined as any of the below events occurring during the 6 weeks following administration, at least possibly related to the ATIMP, not surgery alone Improvements in visual function as assessed by visual acuity Improvements in retinal function as assessed by static perimetry	Gene therapy for achromatopsia (CNGB3)
	CNGA3	AAV2/8-hG1.7p.coCNGA3	2019	3758404	1/2	Completed	UK and USA	11	Number of participants meeting the primary outcome defined as any of the below events occurring during the 6 weeks following administration, at least possibly related to the ATIMP, not surgery alone Improvements in visual function as assessed by visual acuity Improvements in retinal function as assessed by static perimetry	Gene therapy for achromatopsia (CNGA3)
Choroideremia	CHM	rAAV2.REP1	2011	1461213	1/2	Completed	UK	14	Visual acuity Microperimetry, OCT, and fundus autofluorescence	Gene therapy for blindness caused by choroideremia
		AAV2-REP1	2015	2553135	2	Completed	US	6	Change in BCVA from baseline Change in retinal macular autofluorescence from baseline Changes in microperimetry from baseline Number of participants who experience an AE	Choroideremia gene therapy clinical trial
		rAAV2.REP1	2015	2077361	1/2	Completed	Canada	6	Number of patients with ocular and systemic AEs Changes in visual field Changes in visual function	An open label clinical trial of retinal gene therapy for choroideremia
		AAV2-hCHM	2015	2341807	1/2	Completed	USA	15	Safety and tolerability (assessed by physical exam, vital signs, laboratory changes over time, and AEs)	Safety and dose escalation study of AAV2-hCHM in subjects with CHM (choroideremia) gene mutations
		rAAV2.REP1	2016	2671539	2	Completed	Germany	6	BCVA in treated eye Absence of vector-related adverse reactions Fundus autofluorescence analysis	THOR—Tübingen choroideremia gene therapy trial
		AAV2.REP1	2016	2407678	2	Completed	UK	30	Change from baseline in BCVA in the treated eye Change from baseline in the central visual field in the treated eye as determined by microperimetry Change from baseline in the area of surviving RPE in the treated eye as measured by fundus autofluorescence, compared to the untreated fellow eye (control eye) after randomization of treatment to one eye or the other	REP1 gene replacement therapy for choroideremia
		AAV2.REP1	2017	3507686	2	Completed	USA and Germany	66	BCVA Ophthalmic examination assessment: IOP Ophthalmic examination assessment: abnormal slit lamp examination	A safety study of retinal gene therapy for choroideremia with administration of BIIB111
		AAV2.REP1	2017	3496012	3	Completed	USA, Canada, Denmark, Finland, France, Germany, Netherlands, UK	170	Percentage of participants with a ≥ 15-letter improvement from baseline in BCVA at month 12 as measured by the ETDRS chart Change from baseline in BCVA at month 12 measured by the ETDRS chart Percentage of participants with a ≥ 10-letter improvement from baseline in BCVA at month 12 measured by the ETDRS chart	Efficacy and safety of BIIB111 for the treatment of choroideremia
		AAV capsid variant (4D-R100)	2020	4483440	1	Active, not recruiting	USA	13	Frequency and severity of ocular and systemic AEs	Dose escalation study of intravitreal 4D-110 in patients with choroideremia
Leber congenital amaurosis 2	RPE65	AAV2-CBSB-hRPE65	2007	481546	1	Active, not recruiting	USA	15	Safety: standard ocular examination. Vision, hematology and serum chemistries, assays for vector genomes, reported subject history of symptoms and AEs	Phase I trial of gene vector to patients with retinal disease due to RPE65 mutations
		AAV2-hRPE65v2 (voretigene neparvovec-rzyl)	2007	516477	1	Completed	USA	12	Primary outcomes: safety and tolerability; secondary outcomes: include changes in visual function (subjective, psychophysical tests; objective, physiologic tests)	Safety study in subjects with Leber congenital amaurosis
		AAV2-hRPE65v2 (voretigene neparvovec-rzyl)	2010	1208389	1/2	Active, not recruiting	USA	12	Adverse events as a measure of safety and tolerability Visual acuity Visual field	Phase 1 follow-on study of AAV2-hRPE65v2 vector in subjects with Leber congenital amaurosis (LCA) 2
		AAV2-hRPE65v2 (voretigene neparvovec-rzyl)	2012	999609	3	Active, not recruiting	USA	31	Multi-luminance mobility testing (MLMT), bilateral FST testing: white light Multi-luminance mobility testing (monocular) Visual acuity	Safety and efficacy study in subjects with leber congenital amaurosis
		AAV2/5-OPTIRPE65	2016	2946879	1/2	Active, not recruiting	UK	27	Incidence of AEs related to the treatment Improvement in the retinal function Improvement in the visual function Improvement in quality of life	Long-term follow-up gene therapy study for Leber congenital amaurosis OPTIRPE65 (retinal dystrophy associated with defects in RPE65)
Leber congenital amaurosis 10	CEP290	QR-110 (antisense oligonucleotide)	2017	3140969	1/2	Completed	USA, Belgium	11	Frequency and severity of ocular AEs in the treatment and contralateral eyes Frequency and severity of non-ocular AEs Change in BCVA Change in FST	Study to evaluate QR-110 in Leber’s congenital amaurosis (LCA) due to the c.2991 + 1655A>G mutation (p.Cys998X) in the CEP290 gene
		AAV5 (AGN-151,587 or EDIT-101)	2019	3872479	1/2	Active, not recruiting	USA	34	Frequency of AEs related to EDIT-101 Number of participants experiencing procedural related AEs Incidence of dose limiting toxicities	Single ascending dose study in participants with LCA10
Retinitis pigmentosa, autosomal recessive	MERTK	rAAV2-VMD2-hMERTK	2011	1482195	1	Completed	Saudi Arabia	6	Systemic and ocular safety Visual acuity measurement FST	Trial of subretinal injection of (rAAV2-VMD2-hMERTK)
	PDE6B	AAV2/5-hPDE6B	2017	3328130	1/2	Active, not recruiting	France	17	Incidence of ocular and non-ocular AEs Improvement in visual function Improvement in visual fields Improvement in quality of life	Safety and efficacy study in patients with retinitis pigmentosa due to mutations in PDE6B gene
Retinitis pigmentosa, autosomal dominant	RHO	QR-1123 (antisense oligonucleotide)	2019	4123626	1/2	Active, not recruiting	USA	11	Incidence and severity of ocular AEs Incidence and severity of non-ocular AEs Changes in BCVA	A study to evaluate the safety and tolerability of QR-1123 in subjects with autosomal dominant retinitis pigmentosa due to the P23H mutation in the RHO gene
Retinitis pigmentosa, X-linked recessive	RPGR	AAV8-coRPGR	2017	3116113	1/2/3	Completed	USA, UK	50	Part 1: number of participants with DLTs Part 1: number of participants with TEAEs Part 2: percentage of study eyes with ≥ 7 dB improvement from baseline at ≥ 5 of the 16 central loci of the 10–2 grid assessed by macular integrity assessment (MAIA) microperimetry	A clinical trial of retinal gene therapy for X-linked retinitis pigmentosa using BIIB112
		AAV2/5-RPGR	2017	3252847	1/2	Completed	USA, UK	49	Incidence of AEs related to the subretinal administration of AAV2-RPGR Improvement in visual function Improvement in retinal function Improvement in quality of life	Gene therapy for X-linked retinitis pigmentosa (XLRP)—retinitis pigmentosa GTPase regulator (RPGR)
		rAAV2tYF-GRK1-RPGR (AGTC501)	2018	3316560	1/2	Recruiting	USA	42	Phase 1/2 dose escalation: number and proportion of AEs Phase 1/2 dose escalation: number and proportion of participants experiencing abnormal clinically relevant hematology or clinical chemistry parameters Phase 2 dose expansion: the difference in the proportion of responding eyes between treated and control eyes in low dose group and high dose group	Safety and efficacy of rAAV2tYF-GRK1-RPGR in subjects with X-linked retinitis pigmentosa caused by RPGR mutations
Retinitis pigmentosa, non-specific	ChR2 (optogenetics)	AAV2-Chop2 (RST-001)	2015	2556736	1/2	Active, not recruiting	USA	14	Number of participants with any grade 3 or greater AE considered related to RST-001	RST-001 phase I/II trial for advanced retinitis pigmentosa
		rAAV2.7m8-CAG-ChrimsonR-tdTomato (GS030)	2018	3326336	1/2	Recruiting	USA, France, and UK	15	The safety and tolerability of escalating doses of GS030-DP administered via a single IVT and repeated light stimulation using GS030-MD in subjects with non-syndromic retinitis pigmentosa Evaluate the treatment effect of GS030 as assessed by visual acuity Evaluate the treatment effect of GS030 as assessed by visual function	Dose-escalation study to evaluate the safety and tolerability of GS030 in subjects with retinitis pigmentosa
		AAV ChronosFP (BS01)	2020	4278131	1/2	Recruiting	USA	20	Number of subjects with AEs, changes in hematology/chemistry	BS01 in patients with retinitis pigmentosa
Stargardt disease	ABCA4	EIAV (SAR422459)	2011	1736592	1/2	Active, not recruiting	USA and France	27	The incidence of AEs Clinically important changes in ocular safety assessments Delay in retinal degeneration	Phase I/II follow-up study of SAR422459 in patients with Stargardt’s macular degeneration
Usher syndrome 1B	MYO7A	EIAV-CMV-MYO7A (UshStat)	2013	2065011	1/2	Active, not recruiting	USA and France	9	The incidence of AEs Clinically important changes in ocular safety assessments Delay in retinal degeneration	A study to determine the long-term safety, tolerability and biological activity of SAR421869 in patients with Usher syndrome type 1B
Usher syndrome 2	USH2A	QR-421a (antisense oligonucleotide)	2019	3780257	1/2	Completed	USA, Belgium, Canada, France	20	Incidence and severity of ocular AEs in the treatment and contralateral eye Incidence and severity of non-ocular AEs Change in DAC perimetry	Study to evaluate safety and tolerability of QR-421a in subjects with RP due to mutations in exon 13 of the USH2A gene
X-linked retinoschisis	hRS1	AAV8-scRS/IRBPhRS	2015	2317887	1/2	Active, not recruiting	USA	12	Retinal function Ocular structure Occurrence of AEs	Study of RS1 ocular gene transfer for X-linked retinoschisis
		rAAV2tYF-CB-hRS1	2015	2416622	1/2	Active, not recruiting	USA	27	Number of participants experiencing AEs Change from baseline in BCVA Change from baseline in schisis cavity size on OCT Change from baseline in b-wave amplitude in ERG responses	Safety and efficacy of rAAV-hRS1 in patients with X-linked retinoschisis (XLRS)

rAAV recombinant adeno-associated virus, CNGA3 cyclic nucleotide-gated channel alpha-3, CNGB3 cyclic nucleotide-gated channel beta-3, CHM choroideremia, REP1 Rab escort protein 1, BIIB111 investigational gene therapy, OPTIRPE65 optimization of retinal gene therapy for RPE65, LCA Leber congenital amaurosis, CEP290 centrosomal protein 290, QR-110 antisense oligonucleotide, rAAV2-VMD2-hMERTK recombinant adeno-associated virus 2 vector expressing MERTK gene, PDE6B phosphodiesterase 6B, QR-1123 antisense oligonucleotide, RPGR retinitis pigmentosa GTPase regulator, RPGR retinitis pigmentosa GTPase regulator, rAAV2tYF-GRK1-RPGR recombinant adeno-associated virus 2tYF vector expressing G protein-coupled receptor kinase 1 and RPGR, RST-001 retinoschisin, GS030 investigational product, BS01 investigational gene therapy, SAR422459 investigational product, RP retinitis pigmentosa, XLRS X-linked retinoschisis, Usher syndrome Usher syndrome type 1B, QR-421a antisense oligonucleotide, RS1 retinoschisin, rAAV-hRS1 recombinant adeno-associated virus vector expressing RS1 gene, SAR421869 investigational product, USA United States of America, UK United Kingdom, ATIMP investigational medicinal product, BCVA best corrected visual acuity, AE adverse event, FST full-field stimulus threshold, TEAE treatment-emergent adverse event, OCT optical coherence tomography, ERG electroretinogram, IOP intraocular pressure, ETDRS Early Treatment of Diabetic Retinopathy Study, DLTs dose-limiting toxicities, RPE retinal pigment epithelium

Table 4

“Luxturna”: journey to FDA approval, a case study (flowchart of timeline)

Date	Event
April 2012	Orphan drug designation
November 2012	Phase 3 clinical trials initiated
October 2015	First announcement of data from the first completed phase 3 trial
July 2016	Safety and efficacy data in the contralateral eye from a phase 1 study
October 2016	2-year efficacy and safety data from phase 3 study
January 2017	4-year efficacy and safety data announced from a phase 1 follow-on study
January 2017	Orphan drug designation
July 2017	Pivotal phase 3 clinical trial data published
August 2017	Study published confirming multi-luminance mobility test’s construct and content validity, reliability, and ability to detect change in functional vision
December 2017	FDA approves LUXTURNA^® (voretigene neparvovec-rzyl), the first gene therapy for a genetic disease in the USA
November 2018	EU approval LUXTURNA^® (voretigene neparvovec) becomes the first gene therapy for a genetic disease to be approved in both the USA and European Union
September 2019	4-year follow-up shows stable, persistent improvement in navigational ability and light sensitivity
December 2019	The first phase 3 trial outside of USA was initiated in Japan
June 2023	Japan approval LUXTURNA^® (voretigene neparvovec), with a phase 3 trial targeting Japanese patients
August 2023	Japan approval insurance reimbursement of LUXTURNA^® (voretigene neparvovec)

FDA Food and Drug Administration

Efficacy Assessment for Various Gene Therapy Trials and Setting Clinical Goals

Selecting various outcome endpoints to decide the efficacy is challenging in IRDs. Broadly, the various endpoints can be divided into functional (performance-based), structural, and subjective.

Functional Assessments: Performance-Based Endpoints

Clinically relevant functional outcome measures include assessment of visual acuity, contrast sensitivity, retinal sensitivity measurements, and electrophysiological tests. Although assessment of visual acuity assessment is meaningful and precise, it becomes less sensitive in IRDs where central cone function remains preserved until late in the course of the disease. It is important to note that this preservation of central cone function is not a universal feature across all IRDs. Similarly, the commonly used Pelli Robson chart is not an ideal measure of contrast sensitivity assessment in patients with a low threshold. Retinal sensitivity testing includes microperimetry and full field stimulus testing, the latter being extremely helpful in patients with low vision. Microperimetry has the advantage of shorter procedure time, large area of retinal coverage, and usefulness in pediatric patients [58]. Functional tests include microperimetry—proposed for ABCA4 clinical trials and decreased fundus autofluorescence (DDAF)—as a monitoring tool for interventions that aim to slow disease progression [59‐61]. Novel endpoint measures include multi-luminance mobility test (MLMT)—which measures ambulatory vision at light levels encountered in performing activities of daily living. It involves seven levels of standardized lighting conditions from 1 to 400 lx, and rating is based on completing the course at lowest light level with minimal or no errors [62]. An improvement in lowest light level required to complete the course is taken as the outcome measure.

Structural Assessments

Imaging modalities, especially high-resolution optical coherence tomography (OCT) combined with adaptive optics, have been utilized to correlate with health of photoreceptors, RPE, and monitor cones before significant decline has occurred [63‐66]. Specifically, fundus autofluorescence has been used to look at therapeutic outcome in Stargardt’s disease, in the form of leading front autofluorescence. Adaptive optics scanning light ophthalmoscopy (AOSLO) permits non-invasive cellular imaging in a way that helps to expand our understanding of IRDs [67]. Several parameters it assesses include cone density, peak cone density, Voronoi analysis of the regularity of the mosaics, and reflectivity [68].

Subjective Assessments

The best corrected visual acuity (BCVA) is not an ideal endpoint as it represents foveal cone-mediated function and it presents further difficulty in assessment in young subjects. Also, the change in BCVA was found to have low sensitivity when used for ABCA4 treatment trials [69]. Sometimes the observed functional and structural changes (even though statistically significant) may not translate into meaningful subjective improvement for the study participants. Various standardized questionnaires like NEI VFQ-25 and Brief Symptom Inventory have been built and authenticated to reflect different aspects of a patient’s life [70].

From Bench to “Park” Side: Challenges in Translating Bench Success to the Public Domain

Public health measures are vital to reduce population-wide morbidity. While IRDs are rarer than infectious and non-infectious diseases, their potential socioeconomic impact due to diminished productivity and quality of life is significant. As life expectancy increases and the working-age demographic shifts, early-life disability could hinder progress, particularly in communities with higher disease prevalence. Disability adjusted life years (DALYs) help in assessing the burden of disease, combining both early mortality and years of productive life lost as a result of a particular morbidity. Reports have suggested that patients with IRD have a significantly lower average health utility value compared with the normal population (0.58 vs. 0.8), causing profound impact across various aspects of life with the largest relative differences being the independent living, senses, and relationships dimensions [71]. Measuring visual acuity alone as a measure of quality of life may not capture the true quality of life impact as has been proven in previous studies [72]. One of the most crucial factors for assessing quality of life is mental health. In patients suffering from IRDs the emphasis on mental health well-being cannot be ignored [73]. When both economic costs and reduced well-being were considered, the impact of IRDs was noted to be substantial in a study conducted in the USA and Canada [74]. DALYs due to IRDs range from a lower bound of 3205 (Canada) to a high of 67,121 (USA), with a per person cost of well-being ranging from US$45,813 (USA) to CAN$51,147 (Canada) [74]. In a population-based study from rural South India by our group, a relatively high prevalence of 1 in 1000 and an incidence of 24.7/million per year was reported for clinically diagnosed “retinitis pigmentosa” [75]. This disorder was an important cause of incident blindness in that population [76]. The high prevalence could be ascribed to consanguinity (25% in rural and 33% in urban), being a major risk factor [77]. Genotyping is often unaffordable in developing nations and lacks widespread availability. Genetic counselling is underdeveloped because of a scarcity of skilled teams and specialists in IRDs. Genetic testing labs may surpass available ophthalmologists, making training for genetic counselling crucial. Low vision rehabilitation is essential to bridge therapeutic and rehabilitative gaps. Patient support groups and psychosocial counselling are crucial for addressing mental health needs of patients and families.

Appropriate awareness, screening, and management approaches can be designed only after careful consideration of the effectiveness of therapy, hence the need for viable therapeutic measures that can be coupled with easy accessibility and affordability to reduce the visual impairment burden from IRDs. An obvious challenge is the need to identify disease as early as possible, between the spectrum of preconception to early childhood before irreversible functional-structural damage develops. Unfortunately, the unaware population also faces the inability to afford the cure. Further the gap between patient expectations and real outcomes may be large at baseline and increases exponentially as the therapy is delayed. Collaborative efforts between governments and non-profit organizations can go a long way in this regard, and the setting up of specialized clinics with trained professionals can provide care for the sections of society bereft of options till now. Anti-vascular endothelial growth factor (VEGF) therapy’s success in neovascular AMD shows how overcoming costs and accessibility challenges can occur through broad healthcare provider adoption. This led to a breakthrough in conditions previously considered incurable, paving the way for intravitreal biological agents. Similar concerted efforts are needed to reduce patient financial burdens, including specialized insurance programs for affordable access to transformative treatments.

Conclusion

Gene therapy is emerging as a promising approach for inherited retinal diseases (IRDs), with ongoing trials reaching advanced stages. However, challenges such as high costs, early detection, genetic counselling, and managing post-therapy expectations need to be addressed. Advancements in viral vector research, including targeted cell-based delivery, hold potential for enhancing treatment efficacy. Optogenetics and pharmacological supplementation offer alternative options for severe visual loss in advanced IRD cases and may provide cost-effective solutions. These approaches can benefit a broader range of patients regardless of their specific genetic mutations, as long as viable retinal cells are present. Translational research is progressing with the development of specific capsids for targeted viral vector delivery and the selection of appropriate promoters to ensure effective transgene expression. Collaboration with genetic counsellors and clinics can help overcome barriers to access for patients seeking gene therapy. Besides gene therapy, upcoming therapeutic options such as optogenetics and light-sensitive molecules show promise in addressing advanced IRDs, challenging the notion of inevitable visual impairment and opening doors to the potential prevention of avoidable vision loss. The field of gene therapy in IRDs and these futuristic approaches signify exciting advancements with the potential to transform the landscape of visual impairment.

Declarations

Conflict of Interest

All authors, Anand Singh Brar, Deepika C Parameswarappa, Brijesh Takkar, Raja Narayanan, Subhadra Jalali, Sohini Mandal, Kaoru Fujinami, and Srikanta Kumar Padhy, have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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Titel: Gene Therapy for Inherited Retinal Diseases: From Laboratory Bench to Patient Bedside and Beyond
verfasst von: Anand Singh Brar
Deepika C. Parameswarappa
Brijesh Takkar
Raja Narayanan
Subhadra Jalali
Sohini Mandal
Kaoru Fujinami
Srikanta Kumar Padhy
Publikationsdatum: 19.12.2023
Verlag: Springer Healthcare
Erschienen in: Ophthalmology and Therapy / Ausgabe 1/2024
Print ISSN: 2193-8245
Elektronische ISSN: 2193-6528
DOI: https://doi.org/10.1007/s40123-023-00862-2

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Abstract

Introduction

Methodology

Classification of Inherited Retinal Degenerations

Gene-Agonistic (Independent)/Nongenetic Therapeutic Prospects for IRD

Retinal Cell Replacement Therapies/Stem Cell Therapies

Neuroprotection Approaches

Pharmacologic Approaches

Optogenetics

Retinal Prosthesis

Challenges in the Treatment

Failed Therapies for IRDs and Emergence of Luxturna

Gene Therapy at the Bench

Targets for Genetic Therapy

Various Strategies of Gene Therapy

Modes of Ocular Administration

Modalities of Gene Delivery

IRDs and Gene Therapy: Advantages and Challenges at the Bedside

Various Targeted IRDs and Ongoing Clinical Trials

Efficacy Assessment for Various Gene Therapy Trials and Setting Clinical Goals

Functional Assessments: Performance-Based Endpoints

Structural Assessments

Subjective Assessments

From Bench to “Park” Side: Challenges in Translating Bench Success to the Public Domain

Conclusion

Declarations

Conflict of Interest

Ethical Approval

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