Therapeutic approach of repeated transient blood-brain barrier opening in amyotrophic lateral sclerosis.
Ce projet est porté par la Fondation Sorbonne Université – Sorbonne Université – APHP.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons leading to extensive muscle paralysis and ultimately death from respiratory failure in 3-5 years. There is a critical unmet need for effective, disease-modifying therapies in ALS, with to date only three FDA-approved drugs showing only a modest clinical effect. Neuroinflammation is one of the key mechanisms that have been implicated in the pathogenesis and progression of ALS but, to date, systemic administration of general immune modulators has failed to show any efficacy, suggesting that targeted immunoregulation may be required. Overall, the blood brain barrier (BBB) is a barrier to drug delivery to the central nervous system (CNS) contributing to the difficulty of developing effective treatments for ALS. There have been recent advances in the field of gene therapy with the development of ASOs targeting major ALS causative or disease modifier genes. However, ASOs do not cross the BBB and their administration requires frequent intrathecal injections with a significant burden on patients, families, and society.
Low intensity pulsed ultrasound can be used to transiently disrupt the BBB without tissue damage to enhance drug penetration.
Preclinical research performed at our institution founded that inALS mouse model (B6.Cg-Tg(SOD1*G93A)1Gur/J), the Blood spinal cord barrier repeated disruption using a 1 MHz ultrasound transducer is safe anddemonstrated a survival advantage in mice treated with ultrasound alone vs untreated mice (178.5 vs. 166.5 days, p=0.018). Analysis of glial cell immunoreactivity and lymphocyte infiltration suggested that the beneficial effect of US could act through immune cell modulation. These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy, and suggest implication of immune cells (Montero et al, ebioMedicine, in press)
Ultrasound-induced BBB disruption can also modulate the immune response in the central nervous system and may then be therapeutic by itself in ALS by stimulating innate and cellular immune responses.
The SonALS clinical trial will be the first-world to evaluate repeated transient BBB disruptions (9 sessions) in the upper motor neuron and adjacent supplementary motor cortex area with no concomitant drug administration over a prolonged period (6 months) in early stage ALS patients.
This is a proof-of-concept, single-arm, single-center clinical trial
- to assess the safety of the procedure (phase 1, n=12) and
- to explore the efficacy of the procedure (phase 2a, n=23) on neurofilament light (NfL) blood levels (biomarker for neurodegeneration and clinically validated prognostic biomarker for ALS). As Secondary efficacy objectives, BBB transient opening will be confirmed by MRI and blood biomarkers ( Nfl, S100β, Aquaporin-4 and NSE) and efficacy on Disease progression over 26 weeks will be evaluated by motor function (ALSFRS-R score, Muscle strength), Cortical excitability of the treated hemisphere utilizing the threshold tracking transcranial magnetic stimulation (TMS) technique , QOL, Overall Survival (OS) defined as time from baseline to death. Additionally, Overall Survival of US treated patients will be compared to a control group from an external placebo control arm from PRO-ACT international database.
- This BBB opening highly innovative strategy has the potential to change the current neuroprotective management of ALS by modulating neuroinflammation, leading to prolonged survival and milder impairment of motor function as we noticed on preclinical SOD1 models.
- For the participants in the SonALS study, the procedure could have an individual benefit by being neuroprotective in itself through modulation of neuroinflammation and lead to prolonged survival and milder impairment of motor function
- Safety evaluation of such a procedure has the potential to change current management of ALS by allowing future systemic drug administration that do not normally cross the BBB such as gene therapies, antibodies, antisens therapies, …
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