Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse modelResearch in context
Anne-Sophie Montero,
Ilyes Aliouat,
Matthieu Ribon,
Michael Canney,
Lauriane Goldwirt,
Samia Mourah,
Félix Berriat,
Christian S. Lobsiger,
Pierre-François Pradat,
François Salachas,
Gaëlle Bruneteau,
Alexandre Carpentier,
Séverine Boillée
Affiliations
Anne-Sophie Montero
Sorbonne Université, Neurosurgery Department, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Advanced Surgical Research Technology Laboratory, Paris, France; Sorbonne Université, GRC 23, Brain Machine Interface, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Ilyes Aliouat
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Matthieu Ribon
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Michael Canney
Carthera, Lyon, France
Lauriane Goldwirt
AP-HP, Pharmacology Department, Hôpital de Saint-Louis, Paris, France
Samia Mourah
AP-HP, Pharmacology Department, Hôpital de Saint-Louis, Paris, France
Félix Berriat
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Christian S. Lobsiger
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Pierre-François Pradat
AP-HP, Centre de Reference Maladie Rare SLA, Neurology Department, Pitié-Salpêtrière Hospital, Paris, France
François Salachas
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; AP-HP, Centre de Reference Maladie Rare SLA, Neurology Department, Pitié-Salpêtrière Hospital, Paris, France
Gaëlle Bruneteau
AP-HP, Centre de Reference Maladie Rare SLA, Neurology Department, Pitié-Salpêtrière Hospital, Paris, France
Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Corresponding author.
Summary: Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Methods: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models. Findings: Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation. Interpretation: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells. Funding: Fondation pour la Recherche Médicale (FRM). Investissements d’avenir ANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d’étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).
