Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03573466 |
| Other study ID # |
P171004J |
| Secondary ID |
2018-A00573-52 |
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 10, 2019 |
| Est. completion date |
May 25, 2023 |
Study information
| Verified date |
February 2022 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Denervation of neuromuscular junctions (NMJs) and initial compensatory reinnervation is the
earliest pathological event in various motor neuron disease models, occurring far before
motor symptom onset. In patients harboring genetic mutations responsible for Amyotrophic
Lateral Sclerosis (ALS), identification of early, pre-symptomatic, NMJ pathological events
and compensatory mechanisms could lead to the development of new treatments to prevent motor
functional impairment.
The aims of our study are thus:
1. To investigate and characterize early, presymptomatic, defects of NMJ morphology in
pre-manifest C9ORF72 or SOD1 mutation carriers;
2. To investigate and quantify reinnervation at the level of NMJs in these subjects;
3. To identify muscle molecular dysregulated pathways involved in the development of NMJ
alterations and the development / maintenance of compensatory collateral reinnervation.
Description:
The neuromuscular junction (NMJ), where the axon terminal connects the motor endplate of the
muscle fiber, is the first structure affected in various Amyotrophic Lateral Sclerosis (ALS)
rodent models. In these models, NMJ denervation and initial compensatory reinnervation are
the earliest pathological event. These NMJ morphological defects occur far before changes can
be seen at the level of motor neuron cell bodies and motor symptom onset. In these rodent
models, there is thus a "latency phase" of the disease.
In ALS patients, the onset of symptoms is believed to occur when approximately 50 to 80% of
motor neurons are lost and it has been suggested that the disease may have a prolonged
preclinical period. After clinical onset of the disease, the existence of striking NMJ
morphological defects and compensatory reinnervation of endplates has been shown in muscle of
ALS patients, but their occurrence at the presymptomatic stage has never been investigated.
As in animal models, at the subclinical onset of the disease, efficient reinnervation of NMJs
could compensate for the loss of motor neurons and subjects would remain free of any motor
symptom. As the destruction of NMJs progresses, compensation would become ineffective,
leading to progressive muscle weakness and clinical onset of the disease. Identification of
early, pre-symptomatic, NMJ pathological events and compensatory mechanisms could thus lead
to the development of new treatment strategies to prevent motor functional impairment.
In human, the "latency phase" of the disease can be investigated in pre-manifest ALS mutation
carriers. Indeed, in a population of asymptomatic carriers of C9ORF72 or SOD1 mutations (two
of the main genes associated with familial ALS), a dysregulation of circulating microRNAs has
been found long before the estimated time window of disease symptom onset.
The objectives of the PRE-ALS study are:
Primary objective: to investigate and characterize early, preclinical defects of NMJ
morphology in muscle specimens from pre-manifest C9ORF72 or SOD1 mutation carriers;
Secondary objectives:
- to investigate and quantify reinnervation at the level of NMJs in these subjects; and
- to identify muscle dysregulated pathways involved in the development of NMJ alterations
and the development / maintenance of compensatory collateral reinnervation.
For this purpose, ten subjects with mutations in one of two major ALS-associated genes -
C9ORF72 and SOD1- free from any motor symptom, will be included in the study. These subjects,
diagnosed on the basis of presymptomatic DNA tests performed in the context of familial ALS
or familial frontotemporal dementia linked to C9ORF72 expansion (C9-FTD), will be recruited
from the Paris ALS center (Dr Salachas) and the Reference Centre for Rare Dementias (Dr Le
Ber). Subjects harboring mutations in the C9ORF72 gene with only moderate cognitive
impairment may also be included if they are free of motor involvement after neurological
examination.
Subjects will be clinically and neurophysiologically followed-up during 18 months after
inclusion in the study:
- Muscle strength will be measured by manual muscle testing according to the grading
system of the Medical Research Council;
- Functional motor impairment will be assessed using the widely used revised ALS
Functional Rating Scale (ALSFRS-R), a 12-item scale that rates the performance of
activities of daily living;
- Motor neuron loss will be evaluated using Motor Unit Number Index (MUNIX), a validated
method to assess number and size of motor units in ALS patients.
A muscle biopsy will be performed to investigate potential morphological defects at the level
of NMJs. The morphology of NMJs will be analyzed using confocal microscopy after
immunostaining and collateral reinnervation will be quantified for each subject. Dysregulated
intracellular signaling pathways potentially implicated in preclinical structural defects of
NMJs and / or reinnervation will be investigated in parallel.
To date, the PRE-ALS study will be the first to investigate preclinical changes of NMJs in
presymptomatic ALS mutation carriers and to identify muscle compensatory mechanisms allowing
preservation of motor function. This work should pave the way to identification of new
therapeutic strategies in order to prevent the occurrence of strength loss in ALS mutations
carriers and limit muscle wasting in sporadic ALS patients.
