Crystals and Fatty Acid Abnormalities Are Not Present in Circulating Cells From Choroideremia Patients

Radziwon, Alina; Cho, Woo Jung; Szkotak, Artur; Suh, Miyoung; MacDonald, Ian M.

doi:10.1167/iovs.18-25112

Cited by 4 publications

(4 citation statements)

References 28 publications

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“…Unlike Zhang et al, no significant differences in saturated FAs, monounsaturated FAs, or polyunsaturated FAs were detected in our cohort ( 14 ), except for a reduction of branched FA 17-methylstearate (i19:0). These results were in accordance to the study by Radziwon et al, who did not detect FA metabolism differences in a cohort of 9 CHM patients ( 15 ). Nervonic acid, the only FA altered in CHM patients in both studies, was not detected through UPLC-MS.…”

Section: Discussionsupporting

confidence: 93%

“…RBCs revealed increased levels of capric acid (C10:0), nervonic acid (C24:1[n-9]), and plasmalogen derivative dimethylacetal acid (16:0), as well as a decrease in eicosenoic acid (C20:1[n-9]) ( 14 ). A follow-up report refuted these findings, stating that no lipid abnormalities were detected in the plasma of 9 CHM patients, nor could crystal deposits be detected after transmission and scanning electron microscopy analyses of WBCs and RBCs, respectively ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Cunha¹,

Richardson²,

Tracey‐White³

et al. 2021

JCI Insight

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Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations in CHM , encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE), and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated; therefore, in this study, whole metabolomic analysis of plasma samples from 25 CHM patients versus age- and sex-matched controls was performed. Results showed plasma alterations in oxidative stress–related metabolites, coupled with alterations in tryptophan metabolism, leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, as well as imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chm ru848 zebrafish provided further evidence for dysfunction, with the use of fenofibrate over simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes potentially novel pathomechanisms and targets for therapeutic consideration.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Cunha¹,

Richardson²,

Tracey‐White³

et al. 2021

JCI Insight

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“…The protein product of CHML , known as REP2, appears to be able to largely compensate for the loss of REP1. Although a prenylation deficit of certain Rabs can be detected in several cell types of the body [29,36,37], a single report of a systemic, blood-related, clinical phenotype have not been substantiated [38,39] and loss of REP1 appears to cause cellular dysfunction and death that is limited to specific ocular tissues and manifest as a specific disease of the retina. Differential spatial expression does not provide an obvious answer, as both REP1 and REP2 are expressed ubiquitously.…”

Section: Choroideremia Genotypementioning

confidence: 99%

Molecular Therapies for Choroideremia

Cehajic-Kapetanovic

Barnard

MacLaren

2019

Genes

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Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, international research community has been engaged in conducting gene therapy trials for another more common inherited retinal disease known as choroideremia and with phase III clinical trials now underway, approval of this therapy is poised to follow suit. This chapter discusses new insights into clinical phenotyping and molecular genetic testing in choroideremia with review of molecular mechanisms implicated in its pathogenesis. We provide an update on current gene therapy trials and discuss potential inclusion of female carries in future clinical studies. Alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia.

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“…In males, chromosomal defects causing choroideremia has been associated with obesity, congenital deafness and developmental delay (21) and cleft lip and palate and severe developmental delay (20) whereas in female carriers, translocation between chromosomes X, 1 and 3 has led to choroideremia with ectodermal dysplasia (22). There are two reports in the literature regarding the presence (23) or absence (24) of intracellular crystals in lymphocytes and fatty acid abnormalities in serum and red blood cells in choroideremia patients compared to controls throwing conflicting evidence towards choroideremia being part of widespread systemic disease.…”

Section: Diagnosis and Genetic Testing In Choroideremiamentioning

confidence: 99%

Progress in the development of novel therapies for choroideremia

Cehajic-Kapetanovic

Patrício

MacLaren

2019

Expert Review of Ophthalmology

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Introduction-There are no currently approved treatments for choroideremia, an X-linked progressive inherited retinal degeneration that leads to blindness by middle age. Several treatment options are being explored, but with major advances in adeno-associated vector (AAV) gene replacement therapy that has reached phase III clinical trials.Areas covered-In this review we discuss new insights into the clinical phenotyping and genetic testing of choroideremia patients, that aid disease characterisation, progression and patient inclusion into clinical trials. Recent advances in in-vitro studies have resulted in the development of functional assays that can be used to confirm the diagnosis in challenging cases and to quantify vector potency for use in clinical trials. We review the progress in current gene therapy trials and some considerations towards gene therapy approval for the treatment of choroideremia. Lastly, we discuss developments in alternative therapies including optogenetics.Expert Commentary-AAV gene replacement therapy is the most promising treatment strategy for choroideremia, that has developed exponentially over the last few years with a phase III clinical trial now underway. Optogenetics is a promising alternative strategy that might be applicable in late stages of degeneration.

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Crystals and Fatty Acid Abnormalities Are Not Present in Circulating Cells From Choroideremia Patients

Abstract: This investigation failed to observe crystals previously reported in peripheral circulating blood cells derived from CHM subjects, and showed no significant fatty acid abnormalities, not supporting the view of CHM as a systemic disease.

Cited by 4 publications

References 28 publications

REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Molecular Therapies for Choroideremia

Progress in the development of novel therapies for choroideremia

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