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.
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’.
Insulin
Insulin treatment for ALS is an intriguing area for future research. However, the risks of insulin administration are significant and potentially lethal. Currently, there is no clinical evidence to support its use in PALS. Therefore, we cannot endorse insulin as a way to slow, stop, or reverse ALS progression at this time.
Resveratrol
Resveratrol is a dietary supplement that likely activates SIRT1 cellular pathways and may alter the gut microbiome. These are interesting mechanisms that may potentially alter the progression of ALS and do confer benefit in animal models of one type of familial ALS; however, to-date, there have been no trials of resveratrol in PALS. Some trials in other populations show frequent gastrointestinal adverse events, including weight loss, and one trial showed a high risk of serious renal toxicity. Given the unknown benefit of resveratrol in PALS and the possible risks, we cannot recommend resveratrol as an ALS treatment at this time. We hope to see well-designed clinical trials of resveratrol and other SIRT1 modulators in the near future.
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Fecal Transplants
There is rapidly expanding evidence implicating alterations in the fecal microbiome in wide-ranging human diseases, including potential contributions via a gut-brain signaling axis in neurodegenerative and neuroimmunologic disorders. Proposed mechanisms such as immune modulation and the production of neurotoxins by clostridia or other microbiota could bypass an intact blood-brain barrier. To date, there are no data directly implicating the fecal microbiome in ALS, nor published case reports of FMT being tried in PALS. Data in other neurodegenerative and neuroimmunologic disorders are largely circumstantial, comprising a handful of published case reports. Therefore, ALSUntangled does not recommend FMT as a treatment for ALS at this time. However, it is plausible that the fecal microbiome plays a role in some neurologic disorders, including ALS. Given the lack of effective therapies and the relatively low cost and low risk of FMT – if performed by experienced clinical centers we support further investigations in this developing field. A reasonable next step would be a detailed molecular analysis of gut bacteria in ALS patients; certainly, these are the types of studies being advocated by the NIH Human Microbiome Project. If alterations are detected in the gut microbiome of ALS patients, a following step would be properly controlled studies in animal models, such as ALS mice. These studies could employ the same germ-free, and/or probiotic treatment regimens published in mouse models of EAE, Alzheimer’s disease, and obesity.