Cell Signaling, Reinnervation and Metabolism in Kennedy Disease and Amyotrophic Lateral Sclerosis (ALS)

NCT05107349 | Recruiting

• 2 other identifiers: D201803442018-A03044-51
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurodegenerative disorder, usually leading to death from respiratory failure in 3-5 years. Riluzole, the only drug currently available, only modestly prolongs survival and does not improve muscle strength or function. In ALS, loss of functional motor neurons is initially compensated for by collateral reinnervation and strength is preserved. In the majority of ALS patients, as the disease progresses, compensation fails leading to progressive muscle weakness. Conversely, in long-term ALS survivors, slow functional decline is correlated with their ability to maintain a successful compensatory response to denervation over time. Compensatory collateral reinnervation is thus essential for functional motor preservation and survival, and elucidation of the molecular mechanisms involved is crucial to help identify new therapeutic targets. Energy metabolism and glucose homeostasis modifications also influence disease clinical course but the mechanisms by which they contribute to the progression of ALS are unknown. Weight loss is an independent negative prognostic factor for survival and, by contrast, ALS risk and progression are decreased in individuals with high body mass index and non-insulin-dependent diabetes mellitus. Insulin shares many common steps in its signaling pathways with insulin-like growth factor 1 (IGF-1), and is thus at the interface between glucose homeostasis regulation and maintenance of muscle mass. However, the contribution of insulin signaling to preservation of muscle innervation and function in ALS has never been investigated. With this study, we aim to determine the role of insulin signaling pathways in maintenance of collateral reinnervation and muscle function in ALS. We will also investigate the link with the disease-modifying effect of metabolic and glucose homeostasis perturbations, by identifying the contribution of metabolic profiles to preservation of skeletal muscle innervation and motor function in patients with ALS. For this purpose, we will determine the whole-body and skeletal muscle metabolic profiles of 20 patients with ALS and correlate these results to collateral reinnervation ability quantified on muscle biopsy specimens. For each patient, we will use both clinical and electrophysiological methods to evaluate motor function and motor neuron loss over time. Body composition, insulin secretion, insulin resistance level and serum concentrations of IGF-1 axis components will be determined. A motor point muscle biopsy will be performed for morphological analysis of neuromuscular junctions and quantification of innervation by confocal microscopy. Activation of insulin/IGF-1 canonical signaling pathways and metabolic pathways of glucose homeostasis will be quantified in muscle specimens. Skeletal muscle and whole-body metabolic parameters will be analyzed together and correlated with clinical assessment of motor function, electrophysiological data, and innervation quantification results. For comparison, 10 healthy subjects of similar age and 10 patients with spinal and bulbar muscular atrophy - a slowly progressive motor neuron disorder with maintenance of effective collateral reinnervation - will be used as controls. This study will be the first to address the question of the contribution of insulin signaling pathways and metabolic profiles in maintenance of muscle reinnervation and function in ALS patients. The molecular mechanisms identified will be new targets for future treatments promoting compensatory reinnervation and slowing disease progression in ALS. Ultimately, this translational project could have a significant therapeutic impact in disorders with muscle denervation and collateral reinnervation as a compensatory mechanism, such as spinal muscle atrophy or peripheral neuropathies.

Conditions

Amyotrophic Lateral Sclerosis; Kennedy Disease

Outcome Measures

Primary Outcomes (1)

• Quantification of neuromuscular junctions innervation

  Quantification of innervation by confocal microscopy will be performed by classifying neuromuscular junctions observed in each biopsy specimen according to the relationship between the intrasynaptic axonal branches and the postsynaptic membrane in four categories: "normal", "denervated", "partially innervated", or "reinnervated"

  At 15 days after inclusion visit

Secondary Outcomes (2)

• Level of the main components of the insulin/IGF-1 system

  12 months

• Correlations between metabolic profiles and muscle function

  12 months

Study Arms (1)

1

OTHER

Procedure: Muscle biopsy

Interventions

Muscle biopsy PROCEDURE

A motor point biopsy of deltoid muscle will be carried out at the time of inclusion using a standardized procedure, as routinely performed. Muscle samples will be removed from the deltoid muscle by open biopsy under local anaesthesia. The region containing NMJs will be determined by the small twitch provoked by the tip of the scalpel on the surface of the muscle fascicles.

1

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 18 to 80 (inclusive)
• Possible, probable (clinically or laboratory) or definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria (Brooks et al.,2000)
• Ten patients with Spinal-bulbar muscular atrophy (SBMA), aged 18 to 80
• Ten healthy subjects: Control muscle specimens (deltoid) will be obtained from 10 adult patients (aged 18-80) without neuromuscular disease, undergoing shoulder surgery for local joint or bone disease in the local department of orthopaedic surgery

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Association Française contre les Myopathies (AFM), Paris: collaborator
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (1)

Pitié-Salpêtrière Hospital

Paris, 75013, France

RECRUITING

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Bulbo-Spinal Atrophy, X-Linked

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Muscular Atrophy, Spinal; Heredodegenerative Disorders, Nervous System; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Gaelle Bruneteau, MD, PhD

  APHP - Hôpital Pitié-Salpêtrière

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gaelle Bruneteau, MD, PhD

CONTACT

0142162467; nathalie.cormand@aphp.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2021
• First Posted: November 4, 2021
• Study Start: December 12, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: February 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (1)