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

Amyotrophic Lateral Sclerosis Clinical Trial

— MIRSLA  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01992029
• Other study ID #: CHUBX 2012/13
• Status: Terminated
• Start date: June 17, 2014
• Est. completion date: October 22, 2015

Study information

• Verified date: November 2018
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: October 22, 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 70 Years

Eligibility

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 %

Related Conditions & MeSH terms

• ALS
• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

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
• Lumbar puncture
Lumbar puncture at M0 and M12
• Blood sampling
Blood sampling at M0, M4, M4, M8 and M12

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
• Muscular biopsy
Muscular biopsy for patient explored for myopathy
• Blood sample
Blood sample for qRT PCR, detection and quantification for miRNA

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

Locations

Country	Name	City	State
France	CHU de Bordeaux	Bordeaux

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bordeaux

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	miRNA expression	miRNA expression pattern in ALS patients compared to control patients.	At inclusion (day 0)
Secondary	miRNA evolution	Evolution of miRNA expression level in blood and CSF of ALS patients	12 months after inclusion
Secondary	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)
Secondary	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