Molecular Therapies for Choroideremia

Cehajic-Kapetanovic, Jasmina; Barnard, Alun R.; MacLaren, Robert E.

doi:10.3390/genes10100738

Cited by 22 publications

(14 citation statements)

References 63 publications

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“…[70][71][72] In choroideremia the preserved central retinal island reveals a unique autofluorescence pattern of sharply demarcated edges. [73] In RPGR X-linked RP it has been recently shown that the hyperautofluorescent ring correlates nicely with retinal regions that have lost the EZ, but still retain the ELM. [74] The decrease in the extent of the ELM and EZ, observed in the patient featured in Fig.…”

Section: 22mentioning

confidence: 99%

Monitoring progression of retinitis pigmentosa: current recommendations and recent advances

Menghini

Cehajic-Kapetanovic

MacLaren

2020

Expert Opinion on Orphan Drugs

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Introduction-Retinitis pigmentosa (RP) is the most common form of inherited retinal degenerations with an estimated prevalence of 1 in 4,000 and more than 1 million individuals affected worldwide. With the introduction of the first retinal gene therapy in 2017 the importance of understanding the mechanisms of retinal degeneration and its natural progression has shifted from being of academic interest to being of pivotal for the development of new therapies. Areas covered-This review covers standard and innovative diagnostic techniques and complementary examinations needed for the evaluation and treatment of RP. It includes chapters on the assessment of visual function, retinal morphology, and genotyping. Expert Opinion-Monitoring the progression of RP can best be achieved by combining assessments of both visual function and morphology. Visual acuity testing using ETDRS charts should be complemented by low-luminance visual acuity and colour vision tests. Assessment of the visual field can also be useful in less advanced cases. In those with central RP involvement measuring retinal sensitivity using microperimetry is recommended. Retinal morphology is best assessed by OCT and autofluorescence. Genetic testing is pivotal as it contributes to the pathophysiological understanding and can guide clinical management as well as identify individuals that could benefit from retinal gene therapy.

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Section: 22mentioning

confidence: 99%

Monitoring progression of retinitis pigmentosa: current recommendations and recent advances

Menghini

Cehajic-Kapetanovic

MacLaren

2020

Expert Opinion on Orphan Drugs

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“…[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.…”

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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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“…Therefore, we speculate that CHML overexpression might even have an adverse impact on disease progression. This observation could be relevant during selection of subjects to be enrolled in clinical trials, as well as in the follow-up of experimental therapy on disease progression [49,50].…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription

Fioretti

Iorio

Lombardo

et al. 2021

Genes

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Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy due to deficiency of the CHM gene product, i.e., Rab escort protein isoform 1 (REP1). To date, gene therapy for CHM has shown variable effectiveness, likely because the underlying pathogenic mechanisms as well as genotype-phenotype correlation are not yet fully known. Small nucleotide variants leading to premature termination codons (PTCs) are a major cause of CHM, but about 20% of patients has CHM gene deletions. To improve understanding of the disease mechanisms, we analyzed molecular features of seven deletions involving the CHM gene sequence. We mapped the deletion breakpoints by using polymerase chain reaction, sequencing and array comparative genomic hybridization; to identify rearrangement-promoting DNA sequences, we analyzed genomic architecture surrounding the breakpoint regions. Moreover, in some CHM patients with different mutation types, we measured transcript level of CHM and of CHML, encoding the REP2 isoform. Scattered along the whole CHM gene and in close proximity to the deletion breakpoints we found numerous repeat elements that generate a locus-specific rearrangement hot spot. Unexpectedly, patients with non-PTC variants had increased expression of the aberrant CHM mRNA; CHML expression was higher than normal in a patient lacking CHM and its putative regulatory sequences. This latest evidence suggests that mechanisms regulating CHM and CHML gene expression are worthy of further study, because their full knowledge could be also useful for developing effective therapies for this hitherto untreatable inherited retinal degeneration.

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Molecular Therapies for Choroideremia

Cited by 22 publications

References 63 publications

Monitoring progression of retinitis pigmentosa: current recommendations and recent advances

Monitoring progression of retinitis pigmentosa: current recommendations and recent advances

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

Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription

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