Study of miRNA Expression Pattern as Diagnostic and Prognostic Biomarker in Amyotrophic Lateral Sclerosis (MIRSLA)

Etude de l'Expression Des Micro-RNA Comme Biomarqueur Diagnostic et Pronostic Dans la Sclérose Latérale Amyotrophique

The principal goal is to demonstrate that a specific pattern of microRNA (miRNA) expression can be correlated with the definite diagnostic of Amyotrophic Lateral Sclerosis (ALS). The investigators will use biological sample (from muscle biopsy, Cerebrospinal Fluid (CSF) and blood sample) collected in three control populations: definite ALS patients according to El Escorial diagnostic criterion, control patients without any neurological disease having an orthopedic surgery for shoulder disease, and control patient explored for peripheral neuropathy and myopathy. A second goal will correlate the miRNA pattern to the severity and/or progression rate of the motor neurons define as the progression rate of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score/year.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis; ALS
• Intervention / Treatment: Other: Clinical evaluation; Procedure: Muscular biopsy; Procedure: Lumbar puncture; Procedure: Blood sampling; Procedure: Muscular biopsy; Device: Cervical spinal cord and brain MRI; Other: Neurological assessments; Procedure: Neuro-muscular biopsy and lumbar puncture; Procedure: Blood sample

Detailed Description

Amyotrophic Lateral Sclerosis is an adult-onset neuro degenerative disease leading to muscle wasting, palsy and death due to respiratory failure within 3 to 5 years. The only effective drug (Riluzole) increases the life expectancy for about three months, knowing that on average, the diagnostic is given after a delay of one year in France. The identification of new biomarkers for early diagnostic is therefore of fundamental importance. This could improve the treatment efficacy but also give important clues about the prognostic, the rate of evolution and overall help identify new targets for future therapeutics. The investigators' goals are to find specific miRNA patterns expression associated to ALS in humans and use those patterns as diagnostic and prognostic tools.

miRNA are non-coding small fragments of RNA that binds mRNA and can down regulate their expression. In humans, around 700 miRNA have been so far identified. The role of miRNA in human pathology is well established in various types of cancer, but recent works have emphasize their role in neuro degenerative diseases and their expression profile can considered specific for Alzheimer, Parkinson and Huntington diseases. Very few data are currently available about their expression pattern in ALS. Previous studies have however shown that down regulating of some miRNA in spinal cord Moto neurons can trigger an ALS-like clinical phenotype. A more recent work on transgenic murine model SOD1 G93A has demonstrated the role of the specific miRNA206 in regulating the re-innervation processes at the neuro-muscular junction. Mi206 have the ability to promote the re-innervation process and therefore to slow the disease progression.

This research aimed to study the expression of more than 700 miRNA in four different groups (20 patients per group): ALS patients, normal control having a shoulder surgery during which they will have a muscle (deltoid) biopsy, patients explored for peripheral neuropathy with a blood sample, a lumbar puncture for CSF examination and neuro-muscular biopsy and patient explored for myopathy with a blood sample, a lumbar puncture for CSF examination and a muscular biopsy. The ALS group will be followed up every 4 months with ALSFRS scoring and blood sample and a second CSF sample only at M12. miRNA pattern expression will be compared and considered significant for a 2-fold change.

• Study Type: Observational
• Enrollment (Actual): 5

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33000
    • Chu de Bordeaux

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients suffering from ALS, neuropathy, myopathy or control subjects having a shoulder surgery during which they will have a muscle (deltoid) biopsy

Description

Inclusion Criteria:

For ALS patients:

• Age between 45 and 70 years old
• Patients with definite criteria of ALS according to revised El Escorial criterion (1998).
• ALS Patients with a clinical motor impairment of the limbs +/- impairment of the bulbar muscles.
• Patients with a clinical motor impairment on the deltoid muscle (MRC score<5)

For control patients:

• Age between 45 and 70 years old
• Patients having an orthopedic surgery of the shoulder with a normal neurological examination
• Patients having a peripheral neuropathy with a motor component needing a biological blood sample, a lumbar puncture for CSF examination and a neuro-muscular biopsy for complete diagnostic
• Patients having a muscular myopathy needing a biological blood sample and a deltoid muscle biopsy for complete diagnostic.
• Patients affiliated to a governmental health plan
• Clear and loyal consent form written and signed by the patient and the investigator ( before any exam and at least the day of inclusion)

Exclusion Criteria:

• Patients not eligible for a muscle biopsy (anti-coagulation, anti aggregation or blood coagulation pathologies)
• Patients not eligible for lumbar puncture (anti-coagulation, anti aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site).
• ALS patient with isolated bulbar symptoms
• Patients with a clinical syndrome of ALS-plus associating extra-pyramidal symptoms, cerebellar or spino-cerebellar syndromes autonomic disorders or ocular palsy.
• Patients with marked cognitive impairments (MMS<24/30 or BREF<14/18)
• Pregnant or breastfeeding women
• Patients with any neurological or non-neurological disorders interfering with the ALSFRS score
• Patients who could not express their consent
• Patients in emergency situation
• Patients under guardianship or judicial protection
• Pace maker, cochlear implant
• Spinal cord compression or trauma
• Spine surgery
• Spinal deformity
• Claustrophobia
• Metallic foreign body
• Pregnancy
• Vital capacity < 50 %

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ALS Patients	Other: Clinical evaluation; Clinical evaluation using MRC scale, Norris bulbar scale, ALSFRS score and respiratory evaluation ( Vital Capacity, PiMax and SNIP) at M0, M4, M8, M12; Procedure: Muscular biopsy; Muscular biopsy at M0; Procedure: Lumbar puncture; Lumbar puncture at M0 and M12; Procedure: Blood sampling; Blood sampling at M0, M4, M4, M8 and M12; Procedure: Muscular biopsy; Muscular biopsy for patient explored for myopathy; Device: Cervical spinal cord and brain MRI; ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion
Control patients suffering from neuropathy	Device: Cervical spinal cord and brain MRI; ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion; Other: Neurological assessments; Neurological assessments (MRC score and cognitive scales: MMS and BREF); Procedure: Neuro-muscular biopsy and lumbar puncture; Neuro-muscular biopsy and lumbar puncture for patients explored for peripheral neuropathy; Procedure: Blood sample; Blood sample for qRT PCR, detection and quantification for miRNA
Control patients suffering from myopathy	Procedure: Muscular biopsy; Muscular biopsy at M0; Procedure: Muscular biopsy; Muscular biopsy for patient explored for myopathy; Device: Cervical spinal cord and brain MRI; ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion; Other: Neurological assessments; Neurological assessments (MRC score and cognitive scales: MMS and BREF); Procedure: Blood sample; Blood sample for qRT PCR, detection and quantification for miRNA
Control subjects; control patients without any neurological disease having an orthopedic surgery for shoulder disease	Procedure: Muscular biopsy; Muscular biopsy at M0; Procedure: Muscular biopsy; Muscular biopsy for patient explored for myopathy; Device: Cervical spinal cord and brain MRI; ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion; Other: Neurological assessments; Neurological assessments (MRC score and cognitive scales: MMS and BREF); Procedure: Blood sample; Blood sample for qRT PCR, detection and quantification for miRNA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
miRNA expression	miRNA expression pattern in ALS patients compared to control patients.	At inclusion (day 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
miRNA evolution	Evolution of miRNA expression level in blood and CSF of ALS patients	12 months after inclusion
miRNA expression pattern in different ALS patients compared to control patients predictive of the clinical phenotype and of the progression of the disease.		Day 0 (inclusion)
Difference in diffusivity parameters of MRI	Difference in diffusivity parameters of MRI between ALS subjects and control groups	At inclusion (Day 0) and 8 month after inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Anne-Cécile WIELANEK-BACHELET, MD, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 17, 2014
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 22, 2015

Study Registration Dates

• First Submitted: November 18, 2013
• First Submitted That Met QC Criteria: November 21, 2013
• First Posted (ESTIMATE): November 25, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 5, 2018
• Last Update Submitted That Met QC Criteria: November 2, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: ALS; biomarker; miRNA; monocentric observational study
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: CHUBX 2012/13