There has been a recent surge in articles about the Integrated Stress Response (ISR) in neurodegenerative diseases. The hypothesis suggests that the ISR, a cellular mechanism for managing stress, becomes excessively prolonged in these conditions. Several refinements of this idea have been proposed, such as the notion that protein misfolding occurs because the endoplasmic reticulum cannot properly process proteins during ISR, leading to the accumulation of misfolded proteins in the cytoplasm, which causes various problems. For example, TDP-43 proteins fail to fold correctly and cannot be transported to the nucleus, where they play critical roles in DNA repair and virus defense.
In this blog, we have discussed this topic multiple times, including the Inflectis Sephin1/IFB-088 drug.
One such article about ISR is ALSUntangled #80, which discusses a drug called ISRIB (Integrated Stress Response Inhibitor).
Several ISR inhibitors have been identified, including Guanabenz, IFB-088, Salubrinal, and ISRIB. Some of these drugs, like Guanabenz, have significant side effects, making them less suitable for long-term and widespread use.
The outcomes of ALSUntangled are usually predictable; they tend to indicate that any drug they evaluate has limited interest for ALS. However, this time, it feels different, possibly because the two main authors, Javier Mascias Cadavid and Anna Mena Bravo, are from Spain.
They discuss ISRIB and how it was informally tested by 42 ALS patients in Spain, who reported subjective improvements and no side effects.
There are additional publications exploring whether ISRIB could be a promising treatment for ALS.
They say that ISR might be the culprit in a rare subtype of ALS, which is caused by a mutation in VAPB gene. The authors suggest that ISRIB might be useful.
What should we consider about all this? Maybe we should ask why scientists are searching for new drugs instead of focusing on compounds of drugs that have already shown some effects. Perhaps everyone wants to get rich, so they avoid exploring drugs that can't be patented.
For example, nobody has research on the benefits of Meclofenoxate in ALS in the last 50 years! A recent publication suggests it might be useful in Parkinson's disease.