Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium

Thompson, Debra A.; Iannaccone, Alessandro; Ali, Robin R.; Arshavsky, Vadim Y.; Audo, Isabelle; Bainbridge, James; Besirli, Cagri G.; Birch, David G.; Branham, Kari; Cideciyan, Artur V.; Daiger, Steven P.; Dalkara, Deniz; Duncan, Jacque L.; Fahim, Abigail T.; Flannery, John G.; Gattegna, Roberto; Heckenlively, John R.; Hèon, Elise; Jayasundera, Thiran; Khan, Naheed W.; Klassen, Henry; Leroy, Bart P.; Molday, Robert S.; Musch, David C.; Pennesi, Mark E.; Petersen‐Jones, Simon M.; Pierce, Eric A.; Rao, Rajesh C.; Reh, Thomas A.; Sahel, J; Sharon, Dror; Sieving, Paul A.; Strettoi, Enrica; Yang, Paul; Zacks, David N.

doi:10.1167/tvst.9.7.2

Cited by 71 publications

(57 citation statements)

References 145 publications

(162 reference statements)

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“…To the best of our knowledge, this is one of the longest longitudinal studies of ACHM patients with a mean follow-up period of more than 5 years. Delineating the clinical features and the natural history of ACHM is both relevant and timely, given that phase I/II gene supplementation trials aimed at patients with causative mutations in CNGA3 and CNGB3 are ongoing [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, these genes account for over 90% of ACHM cases, while CNGA3 and CNGB3 alone are responsible for 69% of cases [19]. Gene therapy trials are ongoing to correct the defects of CNGA3 and CNGB3 that encode, respectively, the αand β-subunits of the cone photoreceptor cyclic nucleotide-gated ion channel (NCT02599922, NCT03001310, NCT02610582, NCT02935517, NCT03758404) [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

Brunetti-Pierri

Karali

Melillo

et al. 2021

IJMS

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Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (−0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

Brunetti-Pierri

Karali

Melillo

et al. 2021

IJMS

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“…A meticulous and systematic review of complete CHM articles was performed. According to the Second Monaciano Symposium [ 53 ], clinically meaningful endpoints acceptable to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and used in CHM clinical trials are reported in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies

Abbouda¹,

Moosajee

2021

Medicina

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Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (−6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had −17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.

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“…Voretigene neparvovec‐rzyl (Luxturna) was approved by the FDA to treat patients affected with retinal degeneration due to pathogenic variants in RPE65 in 2017, and the first patient was treated in 2018 (Ciulla, Hussain, Berrocal, & Nagiel, 2020; Russell et al, 2017). Several other gene‐based treatments are currently in clinical trials, including gene augmentation for CNGA3 , CNGB3 , CHM , and RPGR ; CRISPR gene editing for CEP290 ; and oligonucleotide therapy for CEP290 , USH2A , and RHO (Thompson et al, 2020). The development of these gene‐dependent treatments highlights the importance of determining the specific genetic cause of disease in patients with IRDs.…”

Section: Development Of Gene‐based Treatments and Trialsmentioning

confidence: 99%

“…CRISPR gene editing for CEP290; and oligonucleotide therapy for CEP290, USH2A, and RHO (Thompson et al, 2020). The development of these gene-dependent treatments highlights the importance of determining the specific genetic cause of disease in patients with IRDs.…”

Section: Development Of Gene-based Treatments and Trialsmentioning

confidence: 99%

Genetic testing for inherited retinal degenerations: Triumphs and tribulations

Branham

Schlegel

Fahim

et al. 2020

American J of Med Genetics Pt C

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Inherited retinal degenerations (IRDs) are a genotypically and phenotypically diverse group of conditions. Great strides have been made toward identifying the genetic basis for these conditions over the last 30 years-more than 270 different genes involved in syndromic and nonsyndromic forms of retinal dystrophies have now been identified. The identification of these genes and the improvement of clinical laboratory techniques have led to the identification of the genetic basis of disease in 56-76% of patients with IRDs through next generation sequencing and copy number variant analysis. Genetic testing is an essential part of clinical care for patients affected with IRDs and is required to confirm the diagnosis, understand the inheritance of the condition, and determine eligibility for gene-specific treatments or clinical trials. Despite the success achieved in determining the genetic cause of these conditions, several challenges remain, which must be considered when providing genetic testing and genetic counseling to patients. For this reason, an integrated team of ophthalmic and genetic clinicians who are familiar with these challenges is necessary to provide optimal comprehensive care to these patients.

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Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium

Cited by 71 publications

References 145 publications

Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies

Genetic testing for inherited retinal degenerations: Triumphs and tribulations

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