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13.7 Inherited Macular Dystrophies

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Box 13.6 Salient Features of Inherited Macular Dystrophies-2

Ocular phenotype Salient clinical signs Inheritance Gene/locus Malattia leventinese/

autosomal dominant drusen/Doyne honeycomb retinal dystrophy

Early adulthood onset; radial-oriented small drusen in temporal macula and around optic disc; FFA drusen show early discrete hyperuorescence; subretinal brous dysplasia;

AD EFEMP1

2p R345W

late-onset macular atrophy; CNVM; visual loss

North Carolina macular dystrophy (MCDR1)

Sorsby fundus dystrophy

Variable: small drusen-like deposits to large conuent, coloboma; CNVM ERG/EOG: normal

Late-onset; fourth-decade; phenotypic variations; night blindness

AD Duplication of PRDM13in

MCDR1 locus 6q16

AD TIMP3

22q12.3 reversed by Vit A; inability to discriminate shades of blue and yellow early sign; macular oedema; atrophy; haemorrhage, progressive chorioretinal atrophy; pigment proliferation; reticular pseudodrusen in retinal periphery; hypoautouorescent; OCT: subretinal deposits which are hyporeective on NIR;disease reversal with adalimumab

Central areolar choroidal

atrophy

Three phenotypes; pigment mottling in macula; photoreceptors

AD GUCY2D (17p13.1)

PRPH2 (6p21.1) degeneration followed by welldened RPE and ChC atrophy by 30–60years

Dominant cystoid macular oedema

CME in the second to fourth decade with good VA; perifoveal leakage on

AD 7p15–p21

FFA; high hyperopia; squint; later stages decrease in CME; progressive atrophy ‘beaten bronze’ macula; normal ERG

X-linked juvenile retinoschisis

Infancy or early childhood; only males; spoke wheel-like foveal schisis; peripheral retinoschisis and pigmentary changes in 50%; vascular occlusion; hyperopia; Mizuo

XLR RS1 (cell adhesion protein

expressed on

photoreceptors and bipolar

cells)

Xp22.13 phenomenon ERG: ‘a’ wave larger than ‘b’ wave

Adapted from Michaelides etal. [68] AD autosomal dominant, EFEMP1 EGF containing brulin extracellular matrix protein1, MCDR1 macular dystrophy retinal 1 (North Carolina), PRDM13 PR domain-containing protein 13, TIMP3 tissue inhibitor of matrix metalloproteinase 3, RS1 retinoschisin 1, ERG electroretinography

https://www.omim.org/entry/136900. Spaide [139]

https://www.omim.org/entry/215500, https://www.omim.org/entry/613105, https://www.omim.org/

entry/613144

https://www.omim.org/entry/153880

https://www.omim.org/entry/312700

381

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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders

mated prevalence of 1:4,000–1:10,000 people. However, a recent prospective population-based study in the UK found a low incidence ranging from 0.110 to 0.128 per 100,000 people at a median age of 27. Patients were evaluated with FAF and ERG [100]. It is an autosomal recessive disorder caused by variants in the ATP-binding cassette subfamily A type 4 gene (ABCA4) locatewd on the short arm of chromosome 1 (1p21–p22). In the autosomal dominant phenotype, a milder STGD is seen in older adults; the gene variants are ELOVL4 (6q14) and PROML1 (4p) [100]. ABCA4 is a transport gene involved in transporting/ipping the product of 11-transretinal (N-retinal phosphatidylethanolamine) from the luminal side of the outer segments to the cytoplasmic surface, where it is reduced to 11-trans retinol before reaching the RPE during phagocytosis. The protein has a similar role in the RPE. In the absence of the protein encoded by ABCA4 protein, there is an excessive collection of 11-cis-retinal and N-retinal phosphatidylethanolamine in the outer segments of the photoreceptors and RPE where these get oxidized, resulting in A2E accumulation (lipofuscin) [101].

This phenomenon starts in the retinal periphery and proceeds centrally, eventually involving the macula. Yellow ecks in the posterior pole characterize the fundus picture (Fig. 13.7). The ecks are hyperautouorescent on FAF imaging. On FFA, the most signicant sign is ‘dark choroid’ due to the obscuration of choroidal circulation by the lipofuscin deposits in the RPE.Over time, the yellow ecks caused by lipofuscin accumulation in the RPE cells undergo atrophy and appear as transmission defects on FFA and areas of decreased autouorescence on FAF imaging. Histopathological studies have also shown somewhat similar ndings. So long as the disease is conned to the retinal mid-periphery without atrophy, it is termed fundus avimaculatus. Eventually, central macular atrophy develops when it is termed STGD.In a retrospective analysis of 217 patients of STGD drawn from the US, the UK, and Europe, questionably decreased autouorescence (DAF) areas developed over a mean of 6years. However, those without denitive areas of DAF developed denitive areas of

DAF in 4.9years. Nearly 50% of the eyes will progress in less than 5 years. Areas of decreased autouorescence can be used to monitor the progression of the disease [102]. STGD has been classied based on the colour fundus pictures, ERG changes, and FAF imaging with either Heidelberg or Optos. More recently, it has been graded as type I, limited to central atrophy with or without ecks conned to the posterior pole (within 55°); type II, central atrophy with ecks outside the posterior pole; and type III, central atrophy extending outside the posterior pole and signicant extramacular ecks [103].

13.7.1.1 Treatment ofSTGD

STGD patients’ signicant challenge is a progressive decline in central vision, making physical activities like driving and reading difcult, which causes great mental stress [104]. Patients need counselling to accept the disease and encouragement to use magniers and electronic devices for reading. There is, as yet no approved treatment available for SGTD.

One of the signicant steps in the visual cycle is the isomerization of all-trans retinyl esters to 11-cis-retinol by RPE65, an isomerohydrolase. Blocking the RPE65 is expected to interrupt the visual cycle, stop the regeneration of rhodopsin, and thereby reduce the accumulation of toxic lipofuscin uorophore, A2E.Emixustat is a small molecule which blocks the activity of RPE65. Successful interruption of the visual cycle can be seen on ERG as the recovery of the suppressed rod b wave. In a multicentric controlled study, Emixustat 10mg oral was found to be biologically active and has paved the way for a phase 3 clinical trial [105].

Delayed dark adaptation is a known side effect of isotretinoin, a commonly used drug for acne. This prompted its use in a mouse model of STGD to successfully block A2E accumulation in the RPE [106]. However, there are no clinical reports to suggest its efcacy in humans.

A novel RPE65-61, a non-retinoid compound, led to slower chromophore regeneration after light bleach in a mouse model of STGD [107].

It is yet early days in cell replacement therapies. Human embryonic stem cell-derived RPE

13.7 Inherited Macular Dystrophies

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383

cells were implanted under the macula in 12 patients with STGD and were followed for 12 months but failed to show a benet [108]. Although successful in salvaging the photoreceptors in the animal models, in small human studies, the autologous or allogeneic RPE cells suspension or layered on biocompatible scaffolds, although found safe, had no proven efcacy [109].

13.7.2 Bestrophinopathies

Mutations in the Best1 gene are associated with ve distinct clinical phenotypes, namely (1) Best vitelliform macular dystrophy(BVMD); (2) Adult onset vitelliform macular dystrophy(AVMD); (3) Autosomal recessive bestrophinopathy (ARB); (4) Autosomal dominant vitreoretinochoroidopathy (ADVIRC); and (5) Autosomal dominant micro cornea rod-cone dystrophy staphyloma syndrome (ADMRCS). There is no treatment available for any of the bestrophinopathies as yet. We give here a brief outline of the three relatively common bestrophinopathies. For more detailed information, the readers may refer to a review on this subject by Johnson etal. [110].

13.7.2.1 Best Vitelliform Macular Dystrophy

Best vitelliform macular dystrophy (BVMD) is not an uncommon autosomal dominantly inherited macular dystrophy seen in early childhood. At least ve phenotypes are known to be caused by a heterozygous mutation in the Bestrophin gene (BEST1, VMD2) located on the long arm of chromosome 11 (11q12.3). https://www.omim.

org/entry/153700?search=Best%20vitelliform%20macualr%20 dystrophy&highlight=best%20dystrophy%20 macualr%20vitelliform.

The typical presentation is of an egg-yolk appearance of a lesion located in the macula of both eyes (Fig.13.8). A rarer phenotype which is a more multifocal variety is seen as autosomal recessive dystrophy. At the egg-yolk stage, the disease is largely asymptomatic. Later in the

years, the egg-yolk appearance changes to a pseudohypopyon-like, followed by a scrambled egg appearance and is later replaced by an atrophic pigmented scar. At this stage, the central vision is signicantly affected. The ERG studies are normal, but EOG studies show a reduced Arden ratio (light rise/dark trough ratio) usually less than 1.5. The normal Arden ratio is 1.85–

2.5 or more. The deposition of vitelliform material under the RPE causes the egg-yolk appearance. During the scrambled egg appearance, there is a disruption of the photoreceptors responsible for the visual symptoms [111]. Histopathological studies have shown a widespread accumulation of vitelliform material in the RPE cells and between Bruch’s membrane and RPE cells. A rupture of the RPE cells possibly allows this material to move into the subretinal space and damage the photoreceptors [112]. Five stages of BVMD are recognized. Stage 1, pre-vitelliform; stage 2, vitelliform; stage 3, pseudohypopyon; stage 4, vitelliruptive; stage 5, atrophic. Visual acuity is maintained up to stage 2 [113], with progressive decline. In stages 1–2, only a few eyes may show disruption in EZ and RPE, but practically all eyes in stages 3–5 show disruption of the outer retinal layers and RPE.Most stage 5 eyes show the absence of outer retinal layers. The vitelliform material is seen in stages 2–3 and is reduced after that [113]. A vitelliform space called the Best space is present under the NSRin all stages except after brosis from a secondary CNVM.

The subfoveal RPE-BM thickness is signicantly reduced from the pre-vitelliform to the vitelliform stage. In the pre-vitelliform stage, the zone between the RPE and the EZis thickened, which corresponds to the interdigitating zone (IZ). The EZ overlying the vitelliform lesion shows disruption. Over time, during the pseudohypopyon stage, the RPE is separated from BMwith a hyporeective space. During the vitelliruptive stage, it is difcult to distinguish the RPE, vitelliform material, and the photoreceptors [114]. The vitelliform material is hyperautouorescent on short wavelength FAF.

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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders

13.7.2.2 Autosomal Recessive Bestrophinopathy

Autosomal recessive bestrophinopathy (ARB), rst described by Burgess etal. [115], is an autosomal recessive disorder due to a homozygous or compound heterozygous mutation in the BEST1 gene located on chromosome 11(11q12). BEST1 gene is located on the basolateral aspect of the RPE cells and controls Cl (−) channel responsible for maintaining the cell volume. ARB is a null phenotype, i.e. there is a total loss of formation of the functional protein. Patients with ARB present in the rst decade of life with visual symptoms. One of the characteristic lesions in ARB is a collection of serous uid in the macula accompanied by a cluster of hyperautouorescent dots around the faint yellowish central lesion. On fundus examination, there are areas of atrophy of RPE and subretinal yellow-white dot lesions in the macula and periphery. On FAF, the areas of RPE atrophy appear dark, while the yellow-white lesions correspond to the hyperautouorescent dots. None of these patients shows vitelliform lesions, highly characteristic of the Best disease. The FFA shows increased transmission hyperuorescence suggestive of RPE atrophy. The SRF in the macula also shows hyperuorescence. There may be a central scar due to the development of the CNVM. On EOG, the light rise is absent or grossly reduced. Pattern ERG shows mild to severe reduction in amplitude. The ffERG show delayed implicit times and reduced amplitude. Many patients with ARB are hyperopes, have a shallow anterior chamber, and may develop angle closure glaucoma.

The severity of lesions on ultrahigh SD-OCT reects the severity of the clinical picture. In the perifoveal area EZ, cone IZ and rod IZ are preserved. However, in the area of serous uid, the cone IZ are missing, and the cone outer segments are elongated. Hyperreective dots appear in the cone’s outer segments. The more severe changes include the cone outer segments’ disappearance and the EZ’s disruption into fragments. The fragmented EZ is replaced by hyperreective dots that hang like icicles initially from the EZ.With the disappearance of the EZ, these dots appear to hang from the ELM [116].

13.7.2.3 Adult Onset Vitelliform Dystrophy

Adult vitelliform macular dystrophy (AVMD), also termed vitelliform macular dystrophy-3 or Adult foveomacular vitelliform dystrophy is an autosomal dominant dystrophy caused by a mutation in the RDS gene (PRPH2) located on the short arm of chromosome 6 (6p21). Patients become mildly symptomatic in the third to the fth decade. https://

www.omim.org/entry/608161?search=Adult%20 onset%20vitelliform%20macular%20 dystrophy&highlight=adult%20dystrophy%20 macular%20onset%20vitelliform.

These have also been grouped as pattern dystrophies and named depending on the pattern of pigment distribution. Pattern dystrophies can present with variable phenotypic heterogeneity. The pattern in the two eyes of the same patient or different members of the same family may be different. The most common pattern is a small one- third to one disc diameter, a variable-shaped egg-yolk-like lesion, which may have pigmentation in its centre (Fig. 13.9). There may be smaller paramacular eck lesions in addition. On FAF, the lesions are intensely hyperautouorescent. On FFA, the lesions show central hypouorescence and hyperuorescence at the margins. In more than one-half of the patients, the lesions may be asymptomatic or have only mild visual symptoms [117]. Unlike the signicantly reduced Arden ratio (light rise to the dark trough of electric potential) in EOGin Best disease, it is nearly normal in AVMD.The ERG is also normal. Patients have normal colour vision. Progression has been demonstrated on SD-OCT in AVMD, similar to the BVMD. The OCT shows subretinal hyperreective material, which is highly hyperautouorescent. With the development of the pseudohypopyon stage, the vitelliform material is sedimented inferiorly. The upper part of the lesion becomes hypoautouorescent and hypo reective on the OCT.There is variable hypo- reective space between the NSRand the RPE.Disruption of the EZ is seen early in the course of AVMD. Additionally, focal hyperreective nodules between BMand RPE are also seen [118].

13.8 Mitochondrial Retinal Dystrophies

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On histopathology, loss of photoreceptors and pigment migration into the NSRis seen. Besides, a chorioretinal adhesion in the centre of the lesion accounts for the hyperpigmented spot seen clinically in the centre of the lesion. A focal drusenlike lesion may be seen. There is no change in the ChClayer [119]. Histopathology also conrmed the presence of lipofuscin-laden RPE cells, a zone of RPE atrophy ringed by a zone of RPE hypertrophy and photoreceptor degeneration overlying the atrophic RPE.Ultraviolet uorescent microscopy has conrmed the presence of autouorescent material in the hypertrophic RPE and the overlying atrophic photoreceptor layer [120].

It has been proposed that the patients who present with AVMD and have a mutation in the BEST1 gene should be considered milder versions of the BVMD [110]. RPE aperture has been noted to complicate AVMD [121]. For detailed information on inherited macular dystrophies, readers may refer to a review by Michaelides etal. [68].

13.8 Mitochondrial Retinal

Dystrophies

Somatic mutations in mitochondrial DNA (mtDNA) are fairly common in normal people. The paternal mtDNA is lost during fertilization and plays no role. Mutations in the maternal mtDNA lead to a state wherein the normal mtDNA is mixed with the mutated DNA in all the

cells of the body tissues. This is called heteroplasmy. Various clinical phenotypes manifest depending upon the proportion of the normal and mutated mtDNA. It is a dynamic process, and clinical phenotypes will appear when the mutated mtDNA becomes more abundant than normal. In the eye, these manifest as macular dystrophies and are associated with systemic features. Diagnosing these dystrophies may pose a challenge especially if the systemic features are mildly manifested. Fundus examination may provide the rst clue to the existence of mitochondrial dystrophy. In type 1 macular dystrophy, the patients are asymptomatic and have discrete eck-like lesions that show hyperautouorescence surrounded by hypoautouorescence. There are disturbances at the level of the interdigitating zone (IZ) and the RPE on OCT. The ERG is normal at this stage.

In type 2, in addition to the ecks, sharp areas of chorioretinal atrophy (GA) appear in the paracentral macula which may be discontinuous or continuous and spare the foveal centre, along with peripapillary hypouorescence. The changes are limited to the posterior pole. The patients may or may not be symptomatic. The ERG is normal. In type 3, the changes are more widespread with granular lesions that extend beyond the arcades. The atrophic areas extend into the fovea. The photopic and scotopic ERG are subnormal [122]. Many of these syndromes have overlapping macular and systemic signs. The salient features of the mitochondrial dystrophies and others associated with systemic features are given in Box 13.7.

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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders

Box 13.7 Systemic Associations of Mitochondrial and Other Macular Dystrophies

Phenotype

MIDD

Salient features

Ocular Pattern macular dystrophy:

progressive lesions Buttery/reticular Punctate/pigmented dots/

Salient features Systemic

Diabetes; deafness; men and women are equally affected

Inheritance/gene/ locus

A point mutation in mtDNA TL1, A3243G

MT-TK; MT-TE continuous or discontinuous perifoveal circular areas of GA FAF shows HFA dots, OCT hyperreective deposits in RPE

MELAS

Pigmentary dystrophy as in MIDD; optic atrophy progressive external ophthalmoplegia

Onset before 20years; recurrent stroke-like episodes; lactic acidosis- muscle fatigue; and pain, vomiting; breathing issues;

Point mutation

mtDNA

MT-TL-1

A3243G

confusion; slow dementia

MERRF

Pattern dystrophy Chronic progressive external ophthalmoplegia

Onset young to adults; myoclonic jerks legs/arms/body; epilepsy; ataxia; myopathy;

A point mutation in

mtDNA

MT-TK

cardiomyopathy; hearing loss; muscle biopsy shows red-ragged bres

KearnsSayre syndrome

Onset before 20years Pigmentary retinal degeneration in

the macula On pathology, pigment hypertrophy and loss of pigment in RPE, FFA transmission hyperuorescence

Cardiomyopathy; microcephaly; short stature; hearing loss; cerebellar ataxia; seizures; sensory and motor neuropathy; muscle weakness; muscle biopsy shows red-ragged bres; lactic acidosis; increased CSF proteins

Most cases are

sporadic multiple

deletions in

mtDNA

MTTL1in AD

cases

Ptosis; progressive external ophthalmoplegia ERG: subnormal

Alport’s syndrome

Lenticonus, PSC; post polymorphous corneal dystrophy; small yellow- white ecks in the supercial perifoveal macula and

85% are male; haematuria; progressive renal failure; and hearing loss

Deletion of

COL4A5/COL4A6

on Xq22, gene for

collagen IV deeper ecks in the peripheral retina; giant macular holes

Aicardi’s syndrome

Circular 1/10–2 DD, white chorioretinal lacunae; symmetrical; bilateral, no pigmentation

Only in females; infantile exion spasms, agenesis of the corpus callosum; seizures; microcephaly; postural defects

XLD inheritance;

lethal in males

Xp22

due to costovertebral defects

SjögrenLarsson syndrome

Early childhoodhyperautouorescent glistening white dots and yellow pigmentary changes in the macula Photophobia; ERG/EOG normal

Source:

https://rarediseases.org/rare- diseases/

Ichthyosis of skin; low-grade mental disability; spastic paresis of legs; speech difculty; dental and osseous dysplasia

ALDH3A2 gene

17p11.2

• Fatty aldehyde

dehydrogenase

deciency

Bryan etal. [140], Ambonville etal. [141], Agarwal [142] MIDD maternally inherited deafness and diabetes, MELAS mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes, MERRF myoclonic epilepsy with red-ragged bres, MT-TL mitochondrially encoded transfer RNA leucine 1, MT-TK mitochondrially encoded transfer RNA lysine, COL collagen, DD disc diameter, XLD X-linked autosomal dominant, ALDH aldehyde dehydrogenase

Heteroplasmy exists. Mutated and normal mtDNA co-exists in the same cell. Symptoms appear when mutated

mtDNA is signicantly more than the normal mtDNA

All three syndromes frequently show overlap and may have similar pigmentary dystrophy

https://www.omim.org/entry/530000

13.9 Treatment ofInherited Retinal Disorders

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13.9 Treatment ofInherited Retinal Disorders

In the last nearly 30years, rapid advances in gene sequencing technologies have facilitated the identication of the genes responsible for many retinal and macular dystrophies. Animal models for several genetic disorders have been created to test the efcacy of various therapeutic interventions. More are still required for estimating optimal dosage. Many approaches are being tested in preclinical studies, including gene supplements, an antisense oligonucleotide (AON), gene editing (gene repair), cell therapy, neurotrophic factors, and optogenetics.

More recently, inducible pluripotent stem cells (iPSC) from patients and normal people have been used to create a 2-D cell culture of RPE and 3-D retina organoids to study the IRDs [123]. The iPSC and organoids that contain multilayered retinal structures can be used as a source of cells for cell replacement therapy. The iPSC derived from broblasts or the patient’s blood with IRD can be reprogrammed (repaired) using CRISPR-Cas9 editing technology. It has successfully corrected a pathological variant in CEP 290, a mutation responsible for a type of LCA and a gain of function mutation Pro23His rhodopsin (RHO) mutation responsible for autosomal dominant RP. The gene editing restored the mRNA transcription [124]. This approach prevents overexpression of the supplemented gene. Moreover, this approach can overcome limitations imposed by the size of genes the AAV vector can package. These cells can be used for autologous transplantation of cells [124].

13.9.1 Gene Supplement Therapy

Monogenic defects (caused by a mutation in a specic gene) cause nearly 80% of genetic disorders. These are the rst being targeted for gene therapy. The initial clinical studies in such patients involved gene supplemental therapy. Among all genetic disorders, the treatment of Leber congenital amaurosis (LCA) caused by mutations in RPE65 was the rst to complete

successful clinical trials leading to the FDA approval of the rst gene supplement therapy in December 2017. It involved an injection of an adeno-associated vector to package an RPE 65 gene, Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics), into the subretinal space. Recently, the three decade-journey of the genetics of IRD, gene therapy, selection and safety of vectors, and preclinical studies nally leading to the clinical trials were reviewed [125]. The subretinal injection of Luxturna has been found safe, and the maximum improvement was reached in 30days.

No adverse effects were noted, and the effect was maintained in 4 years of follow-up [126]. The success of this therapy has prompted a change in terminology that involves specifying the gene in the diagnosis of IRD so that specic information can be shared with all the stakeholders [127]. The term LCA2 has been changed to RPE65 retinopathy. The term gene therapy is no longer used. It is preferred to use ‘Gene augmentation’ or ‘Gene replacement’. More recently, microstructural and visual improvements were reported at day 30/45 and 6months following the subretinal injection of Voretigene-neparvovek in six children in biallelic RPE65 retinopathy. There was an increase in the central foveal ring macular thickness and the outer nuclear layer [128].

In a cohort of 18 eyes of 10 patients, progressive subretinal atrophy developed, although all eyes showed a consistent increase in the full-eld stimulus threshold. Scotomas were reported in three eyes related to the chorioretinal trophy [129]. In a real-world study of 27 eyes of 14 patients, there was an improvement in full-eld stimulus threshold, visual acuity, and the Goldmann visual elds in each eye. The main adverse effects were the rise in intraocular pressure in 59% of eyes, inammation in 15%, and vitreous opacities in 26%, which resolved over several months [130]. The 3-year follow-up of subretinal gene supplement therapy for ABCA4 mutant Stargardt’s disease found the treatment safe in the rst 22 cases of a ve-family cohort. However, six of the treated eyes showed progression of chorioretinal atrophy more than the control eyes. None of the patients had changes in

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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders

visual acuity, perimetry or ERG attributable to treatment. Subretinal injection involves raising a serous retinal bleb into which the vector carrying the gene is injected. In some patients, it may lead to RPE atrophy [131].

A phase1/2 trial of intravitreal rAAV2tYFCB- hRS1, a recombinant adeno-associated virus vector expressing retinoschisin (RS1) was tested in 22 adults and ve children suffering from X-linked retinoschisis. The adverse event noted was mild to moderate ocular inammation requiring immunosuppressive therapy; however, at 1-year follow-up, no measurable improvement was in any of the parameters [132].

13.9.2 Antisense Oligonucleotide

Treatment

Mutations in USH2-exon13 often cause Usher syndrome and non-syndromic RP. ProQR reported positive results in a phase 1/2 trial. QR-421a, an RNA therapy that skips the mutated exon13 and restores the usherin protein, was well tolerated and showed improved visual acuity, perimetry, and OCT parameters. https://

www.proqr.com/press- releases/ proqr- announces- positive- results- from- clinicaltrial- of- qr- 421a- in- usher- syndrome- and- plansto- start- pivotal- trials.

13.9.3 Optogenetics

even in moderate to severe RP [133]. Optogenetics involves programming the ganglion cells to express opsin, the photosensitive protein, by injecting a gene carried by an AAV vector into either the intravitreal or the subretinal space [134]. It has the potential to restore partial vision in patients who are blind. The rst successfully treated case of advanced RP with optogenetic technology was reported in 2021. This person, a 58-year-old blind, had been diagnosed with RP 40years previously and had only light perception vision. He was administered intravitreal injection of an optogenetic AAV vector (serotype 2.7m8) that encoded ChrimsonR (channelrhodopsin protein fused to the red uorescent protein tdTomat). Seven months after the treatment, he was given visual training using light stimulation goggles. The partial vision was restored in the treated eye [135].

In 2021, Nanoscope announced the successful optogenetic treatment of 11 RP patients, restoring clinically meaningful results at 52weeks of followup. https://nanostherapeutics.com/2021/06/03/

nanoscopes- optogenetic- gene- therapy- restoresclinically- meaningful- vision/.

Another phase 2 trial has enrolled 14 advanced RP patients who were administered a single intravitreal injection of RST001, a therapeutic optogenetic gene and the results are awaited.

https://clinicaltrials.gov/ct2/show/ NCT02556736. Bionic sight also reported suc-

cessfully treating four patients. First Four Patients In Bionic Sight’s Optogenetic Gene (https://globenewswire.com).

The current technologies can target only a specic gene through gene supplementation, antisense oligonucleotides or gene repair using CRISPR cas9 technology. However, the number of defective genes in IRD exceed 250 and targeting these specic genes in individual patients, although possible, is not a practical solution. One of the unique characteristics of IRD is the survival of the inner retinal cells and their circuits for a long time despite the complete loss of the outer retina. Nearly 30% of the ganglion cells and 78–88% of the inner nuclear cells are present

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