Preclinical studies are performed on a number of organisms, which scientists call "animal models of the disease." This concept is very vague and can involve everything from immortalized cancer cells to nematodes or fish. The most serious work is done on several standardized and commercial mouse models. This makes it possible in theory to compare work between laboratories, although this remains difficult in practice.
However, commercial mouse models of disease are expensive and are almost useless for diseases like ALS, because the nervous system of mice is very different from the human nervous system.
However, in preclinical studies, scientists look for clues that a drug might be useful, but it is not yet possible to prove that a drug will be effective in humans.
One of the best things they can do at this stage is to show that a drug has a positive effect on several unrelated commercial animal models.
The endoplasmic reticulum (ER) is an important organelle in cells that is involved in protein conformation. This step occurs after protein synthesis by ribosomes and after conformation, the new protein will be sent to its final destination by the Golgi apparatus. Protein conformation requires energy, so when disease occurs, the ER may not be able to properly conform the new proteins.
The accumulation of unfolded proteins leads to ER stress, followed by an adaptive response via activation of the unfolded protein response (UPR). Since folded proteins require energy, the unfolded protein response significantly slows down the production of new proteins. This is a way to cope with temporary stressful events, but it is not sustainable, as a cell that does not produce proteins is in a kind of stasis and will die quickly. Indeed, prolonged cellular stress activates apoptosis signaling leading to cell death.
Several studies have shown that impaired endoplasmic reticulum (ER) proteostasis is a pathogenic feature of ALS/FTD. Several drugs targeting the UPR in ALS have been proposed (GSK2606414, ISRIB, Guanabenz, Sephin1, Trazodone, KIRA), but none seem to be effective in ALS at this point.
There are different strategies, one is to stop the prolonged deleterious UPR in the hope that somehow the stressor has disappeared and the cell is healthy again. Another, on the contrary, tries to force an unfolded protein response state on all cells in the hope that the cell will be able to clear the backlog of accumulated misfolded proteins. However, the involvement of the UPR and the mechanisms by which ER stress contributes to pathogenesis are not entirely clear and can have contrasting or even opposing effects. Contributing to this complexity is that the UPR is actually several mechanisms.
The transcription factor XBP1s has several roles, one of them being that of regulator of the unfolded protein response. In a new publication, scientists provide evidence of suboptimal activation of the UPR in mouse models of ALS/FTD under experimental ER stress.
They designed a genetic therapy so that nervous system cells in ALS/FTD mouse models express the active form of XBP1 (XBP1s). XBP1s expression improved motor performance and extended lifespan in SOD1 mutant mice, associated with reduced protein aggregation.
It is important to note that AAV-XBP1 administration also attenuated disease progression in mouse models of TDP-43 and C9orf72 pathogenesis. As noted at the beginning of this text, most preclinical work in a single animal model is a bit suspect, especially when the animal model is not standardized but performed by administering a chemical that affects the nervous system.
ALS SOD1 disease is probably very different from TDP-43 and C9orf72 diseases. As SOD1 is an anti-oxidant, a mutated SOD1 protein probably protect less neurons from metabolism by-products. TDP-43 protein has many roles but one is to repair DNA in pluripotent stem cell-derived motor neurons. Most ALS patients have misfolded, aggregated fragments of TDP-43 in cell's cytosol which is weird as normally TDP-43 should be in cell's nucleus where it could repair DNA. C9orf72 is different again, in this disease the cellular ribosomes produce the wrong proteins from correct RNA, a so-called frameshift effect.
It is not clear how an XBP1s drug could benefit these three variants of ALS. However, if this is confirmed in humans, it would be good news because today, only one drug benefits ALS patients (Tofersen), but it benefits less than 1% of them. Having a drug that would benefit most patients would be extraordinary.
But we are not there yet, a first step would be to understand the mechanism of action of this drug in ALS