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View of the Different Approaches to Treating Irds Treating IRDs: Gene-Specific and Gene-Independent Approaches A review of the different approaches to treating IRDs. BY ALESSANDRO IANNACCONE, MD, MS, FARVO ith more than 300 disease- other approaches are necessary. Thus, this group of retinopathies is primar- causing genes mapped and gene/disease–independent treat- ily of the Leber congenital amaurosis more than 260 cloned,1 the ments (Figure 1B) are a top priority. (LCA) and early-onset retinitis pig- field of inherited retinal dis- This article reviews the state of IRD mentosa type, affecting a relatively eases (IRDs) has experienced treatment approaches. small group of patients with IRDs. Wtremendous advances over the past Thus, much work (and opportunity) is 2 decades. This vast genetic heterogene- GENE/DISEASE–SPECIFIC TREATMENTS ahead in the field for additional gene ity represents both a great opportunity The field of gene augmentation therapies to be tested in human clini- and a remarkable challenge. therapy (gene therapy for short) wit- cal trials and, one hopes, to become The identification of the causes of nessed a major breakthrough with approved treatments for patients with so many forms of IRD and the growing the US FDA approval of voretigene IRDs. A list of such trials is provided in body of knowledge of their functions neparvovec-rzyl (Luxturna, Spark Table 1 in alphabetical order, and the and underlying disease mechanisms Therapeutics) for RPE65-related reti- list is growing rapidly. have allowed the development of nopathies.2,3 Although this approval It should be emphasized that, exciting new gene/disease–specific created major momentum in the field, for gene therapy to be possible, treatment opportunities (Figure 1A). However, the development and deliv- ery to bedside of gene/disease–specific treatments for each of the genes identi- AT A GLANCE fied to date are daunting tasks that may s require decades for full implementation. The development and delivery to bedside of gene/disease–specific With exciting new treatments treatments for each of the IRD-related genes identified to date is a daunting now aimed at an even more granular task that may take decades. level—targeting not just specific genes s but, in fact, specific mutations—the Most gene therapy trials for IRDs rely on adeno-associated virus task at hand is expanded by several orders of magnitude. Furthermore, vector–based gene therapy and subretinal injection delivery. gene/disease–specific treatments rely s on persistent target cells and sufficient Efforts are underway to identify improved viral vectors that can achieve ade- visual function to permit efficacy. quate, widespread transfection through the intravitreal route and to develop For the many patients who are out- thin transvitreal cannulas that do not require vitrectomy. side of this window of opportunity, 16 RETINA TODAY | JULY/AUGUST 2019 RARE AND INHERITED DISEASES s Figure 1. Researchers are exploring two pathways for treating IRDs—one that directly addresses underlying genetic dysfunction (A) and one that seeks to address the downstream effects of genetic mutation (B). knowledge of the causal gene for each or areas to be treated must also be implement gene editing strategies.5,6 disease and in each patient is neces- chosen carefully, aiming for areas that For example, a “cut and remove” strat- sary, underscoring the importance display residual target cell integrity egy is being tested in the LCA-CEP290 of genotyping affected patients via and, ideally, measurable function. For Editas trial (Table 1). CLIA-certified diagnostic laboratories. example, there may be little to no Correction of the genetic defect At this stage of the gene therapy benefit in treating eyes with no mea- downstream of the DNA sequence era for IRDs, most trials rely on adeno- surable rod-mediated function if the by targeting messenger RNA (mRNA) associated virus (AAV) vector–based gene to be delivered is a rod-specific instead. In this approach, editing gene therapy and a subretinal injection one. Exceptions to this rule of thumb antisense oligonucleotides (eAONs) approach, as does voretigene. In most exist, however, and the RPE65-related of the ongoing trials, the aim is to retinopathies are a perfect example of deliver a copy of the normal gene into this. In these conditions, there can be a RETINA TODAY photoreceptor or retinal pigment epi- significant mismatch between function thelium cells using the AAV vectors. and structural integrity.4 ON THE ROAD This invasive approach requires a Other emerging strategies for gene full-fledged vitrectomy and retinotomy therapy include the following: This article is adapted from a lecture the to deliver the treatment subretinally. Gene editing using CRISPR/Cas9– author presented at the Duke Fellows A key limitation of this approach is based technology, in which clustered Advanced Vitreous Surgery Course in that it is not possible to deliver gene regularly interspaced short palindrom- April. The 2020 meeting will be held April therapy to the entire retina, but rather ic repeats (CRISPR) complexed with one or more areas must be chosen to a CRISPR-associated (Cas) nuclease 17-18, 2020, in Durham, North Carolina. receive the subretinal bleb that will can be used to create breaks in DNA Visit MedConfs.com for details. define the treated area. Thus, the area sequences that can then be used to JULY/AUGUST 2019 | RETINA TODAY 17 s RARE AND INHERITED DISEASES TABLE 1. ONGOING GENE/DISEASE–SPECIFIC TREATMENT TRIALS Disease Gene/Mutation Sponsor NCT Numbera Treatment Method Route of Administration Achromatopsia CNGA3 AGTC NCT02935517 rAAV2tYF vector–based Subretinal CNGA3 MeiraGTx NCT03758404 rAAV2/8 vector–based Subretinal CNGB3 AGTC NCT02599922 rAAV2tYF vector–based Subretinal CNGB3 MeiraGTx NCT03001310 rAAV2/8 vector–based Subretinal Choroideremia CHM1/REP1 NightStar/Biogen NCT03507686 rAAV2 vector–based Subretinal NCT03496012 NCT03584165 Leber congenital amaurosis CEP290 Editas/Allergan NCT03396042 CRISPR/Cas9 gene editing Subretinal p.Cys998X mutation CEP290 ProQR NCT03140969 Editing antisense Intravitreal p.Cys998X mutation oligonucleotides RPE65 Spark Therapeutics NCT03602820 rAAV2 vector–based Subretinal RPE65 MeiraGTx NCT02946879 rAAV2 vector–based Subretinal Retinitis pigmentosa, autosomal PDE6B Horama NCT03328130 rAAV2/5 vector–based Subretinal recessive RLBP1 Novartis NCT03374657 rAAV8 vector–based Subretinal Retinitis pigmentosa, X-linked RPGR AGTC NCT03316560 rAAV2 vector–based Subretinal RPGR NightStar/Biogen NCT03116113 AAV8-RPGR vector–based Subretinal Stargardt disease ABCA4 Sanofi NCT01367444 Lentivirus vector–based Subretinal Usher syndrome type 1B MYO7A Sanofi NCT01505062 Lentivirus vector–based Subretinal Usher syndrome type 2A USH2A exon 13 ProQR NCT03780257 Editing antisense Intravitreal oligonucleotides X-linked retinoschisis RS1 AGTC NCT02416622 rAAV2 vector–based Intravitreal RS1 National Eye Institute NCT02317887 rAAV vector–based Intravitreal a www.clinicaltrials.gov. are used to correct the target defect in theory, reach any part of the retina multiple specific treatments for each after DNA transcription but before capable of responding to therapy. gene to be able to treat all patients. translation so that the resulting pro- Although the latter approach has Nonetheless, there is now published tein is normalized or greatly improved inherent advantages—namely, its evidence that eAON-based technol- compared with the mutated version ease of administration and panretinal ogy is delivering measurable benefits thereof. This strategy is being used in reach—the effects of the treatment to LCA-CEP290 patients after a single the ProQR trials (Table 1).7 diminish over time because incorrect injection.7 Another trial, for Usher At present, CRISPR/Cas9–based mRNA continues to be produced syndrome type 2A, has begun, and technology relies on the same AAV by the mutated DNA of the patient. more are planned for the relatively vector–based approaches as current Therefore, repeated periodic injections near future. gene therapies, whereas eAONs are are needed. Also, this technology is Disease-specific trials, unlike small molecules that can be injected currently mutation- or exon-specific, gene-specific trials, are aimed at tack- intravitreally. Thus, they can, at least meaning there is a need to develop ling mechanisms or circumventing 18 RETINA TODAY | JULY/AUGUST 2019 RARE AND INHERITED DISEASES s TABLE 2. ONGOING DISEASE/MECHANISM–SPECIFIC TREATMENT TRIALS Disease Gene/Mutation Sponsor NCT Numbera Treatment Method Route of Administration Leber congenital amaurosis LRAT, RPE65 QLT/Aegerion NCT01014052 Synthetic 9-cis-retinal Oral NCT01521793 Stargardt disease ABCA4 Acucela NCT03772665 Emixustat Oral ABCA4 Alkeusb NCT02402660 Deuterated vitamin A Oral ABCA4 Moran Eye Center NCT00346853 4-methylpyrazole (4-MP, Antizol) Oral ABCA4 Iveric Bio** NCT03364153 Zimura (complement C5 inhibitor) Intravitreal injection a www.clinicaltrials.gov. b Also ongoing in geographic atrophy. TABLE 3. GENE/DISEASE–INDEPENDENT TREATMENT TRIALS Disease Sponsor Trial Numbera Treatment Method Route of Administration Nutritional Approaches Retinitis pigmentosa Wilmer Eye Institute, Johns NCT03063021 N-acetyl-cysteine (NAC) Oral Hopkins University Stargardt disease Catholic University of the Sacred NCT01278277 Saffron Oral Heart, Rome Stem Cell–Based Treatments Retinitis pigmentosa JCyte NCT03073733 Dissociated human retinal progenitor Intravitreal injection cells (hRPC) ReNeuron NCT02464436 Human retinal progenitor cells (hRPC) Subretinal transplant
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