Discovery profiling and bioinformatics analysis of serum microRNA in Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE)

Levene, Michelle; Enguita, Francisco J.; Bax, Bridget E.

doi:10.1080/15257770.2018.1492138

Cited by 3 publications

(5 citation statements)

References 31 publications

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“…The Regulatory agencies are now recognising the need for flexibility in the review of therapies for rare diseases and may consider approving a therapy based on a surrogate endpoint or biomarker as these can provide better objective measures of clinical benefit. Based on the identification of a number of dysregulated miRNAs in the serum of patients with MNGIE compared to age and sex matched healthy controls, Levene et al are examining the application of a miRNA panel as a surrogate end-point biomarker in parallel with a clinical trial of EETP [157].…”

Section: Clinical Efficacy Endpointsmentioning

confidence: 99%

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Pacitti¹,

Levene²,

Garone³

et al. 2020

Prime Archives in Genetics

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Mitochondrialneurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterised by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

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Section: Clinical Efficacy Endpointsmentioning

confidence: 99%

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Pacitti¹,

Levene²,

Garone³

et al. 2020

Prime Archives in Genetics

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show abstract

“…The Regulatory agencies are now recognizing the need for flexibility in the review of therapies for rare diseases and may consider approving a therapy based on a surrogate endpoint or biomarker as these can provide better objective measures of clinical benefit. Based on the identification of a number of dysregulated miRNAs in the serum of patients with MNGIE compared to age and sex matched healthy controls, Levene et al are examining the application of a miRNA panel as a surrogate end-point biomarker in parallel with a clinical trial of EETP (Levene et al, in press).…”

Section: Treatment Optionsmentioning

confidence: 99%

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

et al. 2018

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

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“…The discovery that miRNAs are detectable in extracellular biofluids has raised much interest in their potential as early non-invasive biomarkers for diseases. Studies reporting alterations in miRNA expression profiles in patients with muscular and neurological disorders led us to conduct a feasibility study in patients with MNGIE [27,34,35]. In this study we reported a significant dysregulation of 82 miRNAs in the serum of patients compared to age and sex matched healthy controls, however, a critical limitation of this study was the small number of patients recruited (n =5).…”

Section: Discussionmentioning

confidence: 82%

“…From the discovery phase it was noted that 10 of the 14 upregulated miRNAs and 7 of the downregulated miRNAs were previously identified in our published feasibility study [27]. Although unsupervised clustering analysis of the discovery data revealed a natural separation between healthy control and patient serum samples, and showed that the miRNA profile within the healthy control group was similar, it exhibited a greater variability in MNGIE samples, based on pairwise Euclidean distances.…”

Section: Discussionmentioning

confidence: 97%

“…The absence of validated outcome measures to quantitate MNGIE disease progression and determine the effectiveness of potential therapies led us to investigate whether a panel of miRNAs could serve as a potential biomarker for MNGIE. Our previously reported feasibility study showed that compared to age and sex matched healthy controls, there was significant dysregulation in a number of miRNAs in the sera of patients with MNGIE [27]. To further explore the clinical applicability of circulating miRNAs as biomarkers of MNGIE, we report here an expanded miRNA expression profiling study comprising four phases, with each phase recruiting different cohorts of patients and healthy controls.…”

Section: Introductionmentioning

confidence: 99%

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Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

Mencias

Levene

Blighe³

et al. 2021

IJMS

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.

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Discovery profiling and bioinformatics analysis of serum microRNA in Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE)

Cited by 3 publications

References 31 publications

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy

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