JMIR Publications

ABSTRACT

Background:

Respiratory impairment is a major concern in amyotrophic lateral sclerosis (ALS), shortening survival and lowering quality of life. One therapy with promise to delay respiratory decline in ALS is acute intermittent hypoxia (AIH) consisting of alternating periods breathing mildly hypoxic (~9-12% O2) and normoxic (21% O2) gas. AIH stimulates spinal, serotonin-dependent neuroplasticity in rodent models, conferring functional benefits in diverse physiological systems without detectable pathology. However, in rodent models, AIH-induced neuroplasticity is constrained by distinct signaling cascades initiated by spinal adenosine.

Objective:

We propose to investigate a therapeutic strategy to delay breathing compromise in those living with ALS by combining a selective adenosine 2A receptor (A2A) inhibitor (istradefylline) with AIH. The fundamental hypothesis guiding this proposal is that a single AIH trial after pretreatment with istradefylline (IST) enhances respiratory neuroplasticity versus AIH or sham intervention.

Methods:

We propose to evaluate resting breathing, respiratory strength, and participant-reported symptoms, in adults living with ALS after combined istradefylline plus AIH. A mixed within and between subject study design incorporates 4 test sessions, separated by ~2 weeks (+/- 5 days). Testing conditions include single sessions of: AIH + IST, AIH + placebo, sham AIH (i.e., normoxia) + placebo, and sham AIH + IST. Safety and feasibility will be characterized using the rate of adverse events, changes in vital signs, and participant-reported breathing sensations (Aim 1). Neuroplasticity of breathing and motor function will be evaluated as changes in resting breathing, voluntary respiratory strength, respiratory control, and maximal pinch force (Aim 2).

Results:

As of January 2025, 10/16 subjects with ALS and 5/16 control subjects completed study procedures. Recruiting is ongoing, and the final subject will complete the study by December 2025. Publication of results is expected by the end of 2026.

Conclusions:

These aims will provide crucial data regarding preliminary safety and feasibility of this paired intervention, and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS. Clinical Trial: This trial was registered in the ClinicalTrials.gov database on 22 April, 2022 (registration number: NCT05377424).