Progress in the development of novel therapies for choroideremia

Cehajic-Kapetanovic, Jasmina; Patrício, Maria I.; MacLaren, Robert E.

doi:10.1080/17469899.2019.1699406

Cited by 19 publications

(7 citation statements)

References 49 publications

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“…Other examples are pathogenic variants identified in disease genes implicated in achromatopsia [ 30 ], choroideremia [ 31 ], Stargardt disease (STGD1), X-linked retinitis pigmentosa and other IRD [ 33 , 34 ] that are eligible for the huge range of clinical trials being undertaken currently [ 12 – 14 ]. Specifically, rare and recurrent deep-intronic pathogenic variants (total: 355) in ABCA4 associated with STGD1 in ~10% of cases allow the design of novel RNA splice modulation therapies using AONs [ 35 – 37 ].…”

Section: Main Textmentioning

confidence: 99%

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Black

Sergouniotis

Sodi

et al. 2021

Orphanet J Rare Dis

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Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

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Section: Main Textmentioning

confidence: 99%

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Black

Sergouniotis

Sodi

et al. 2021

Orphanet J Rare Dis

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“…Choroideremia is one such inherited retinal degeneration where gene augmentation is being tested in multi-institutional gene therapy clinical trials . Choroideremia is an X-linked degeneration caused by variants in the CHM gene, which encodes Rab escort protein 1 (REP1), a protein thought to be involved in membrane trafficking .…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6] Choroideremia is one such inherited retinal degeneration where gene augmentation is being tested in multiinstitutional gene therapy clinical trials. [7][8][9][10][11][12][13][14][15][16][17][18] Choroideremia is an X-linked degeneration caused by variants in the CHM gene, which encodes Rab escort protein 1 (REP1), a protein thought to be involved in membrane trafficking. 19,20 Variants in CHM lead to progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choroid.…”

mentioning

confidence: 99%

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Morgan

Vergilio

et al. 2022

JAMA Ophthalmol

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Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells. OBJECTIVE To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTSThis longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 10 10 vector genome per eye) or high-dose (1 × 10 11 vector genome per eye) AAV2-hCHM. Analysis began February 2015. MAIN OUTCOMES AND MEASURESThe macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point. RESULTSNine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM-injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment-related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO.CONCLUSIONS AND RELEVANCE Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.

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“…Although there are currently no approved treatments for CHM, a number of gene therapy trials are in progress. 6 Current trials are focused on affected male patients, but one wonders whether such therapy may also be appropriate for female carriers who are significantly or asymmetrically affected like our patient.…”

Section: Discussionmentioning

confidence: 99%