Key Information
ISR over-activation may play an important role in ALS pathogenesis, as supported by data from pre-clinical models and PALS. Several different ISR inhibitors have been tried in ALS models or inPALS with mixed results; but given the differents pecific actions of these, it is not possible to generalize across the whole class. ISRIB can attenuate parts of the ISR and has shown benefits in cell models of familial ALS. A group of PALS in Spain who are taking ISRIB report subjective improvements in some ALS-related symptoms, but objective evidence is lacking. Reported side effects are minimal, but no published trials of ISRIB exist,leaving questions about safety and tolerability unanswered. In addition, concerns remain about its solubility and human bioavailability. Currently,there is not enough information to support the regular use of ISRIB for treating ALS. Furthers tudies are required to evaluate its pharmacokinetics, safety, and efficacy in PALS.
Mechanistic plausibility
Mechanistic plausibility
Mechanistic plausibility - C
Mechanistic plausibility
Mechanistic plausibility
Mechanistic plausibility
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Grade A: Two or more peer-reviewed publications reporting benefits in well-designed studies.
Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Grade B: One peer-reviewed publication reporting benefits in a well-designed study.
Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Grade C: One or more peer-reviewed publication(s) reporting benefits in flawed studies.
Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Patient case reports
Patient case reports
Patient case reports
Patient case reports
Patient case reports
Patient case reports
Patient trials
Patient trials
Patient trials
Grade D: One or more peer-reviewed publications reporting benefits in a flawed trial.
Flawed trials means those in which there are identifiable problems with patient selection, randomization, blinding, controls or follow-up. These have ‘high or unclear risk of bias’ according to published criteria. Well-designed trials are those that have ‘low risk of bias’.
Patient trials
Patient trials
Risks (harms that occurred on this treatment)
Risks (harms that occurred on this treatment)
Risks (harms that occurred on this treatment)
Grade B (oral): More than 0% but less than10% of exposed patients experienced harms (no hospitalizations or deaths)
Grade D (intravenous): More than 0% but less than 5% of exposed patients experienced death or hospitalizations
Risks (harms that occurred on this treatment)
Risks (harms that occurred on this treatment)
Risks (harms that occurred on this treatment)
Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations
Grade F: At least 5% of exposed patients experienced death or hospitalization