Amyotrophic lateral sclerosis (ALS) is a God-awful disease, where patients progressively weaken and die because they aren’t strong enough to breathe, remaining mentally intact the entire time. A recent paper [ Science vol. 348 pp. 239 – 242 ‘ 15 ] showed that a drug already released by the FDA for treating hypertension — Wytensin (Guanabenz) was of benefit in a mouse model of the disease. So the drug is out there. If I were still in practice, I’d certainly give it a shot in my patients — off-label use be damned. Even better, enterprising organic chemists synthesized an analogue of Wytensin (Sephin1) which doesn’t lower blood pressure, but which still works in the mouse model.
Here’s why you shouldn’t get your hopes up too high. [ Nature vol. 4564 pp. 682 – 685 ’08 ] The work using SOD1 mutant mice (the mouse model of ALS mentioned above) is quite sloppy and nearly 12 drugs with benefit in mouse models have had no benefit in clinical trials. Minocycline which was effective in 4 studies in mice actually made things worse in a clinical trial of over 400 patients .
Now for a bit of background. Most cases of ALS aren’t familial, but a few are. One protein Superoxide Dismutase 1 (SOD1) was found to mutated in about 20% of familial ALS. It’s been studied out the gazoo, and some 140 different mutations have been found in its 153 amino acids in familial cases.
It’s hard to conceive of them all acting the same way, and literally thousands of papers have been written on the subject. It does seem clear that aggregated proteins occur in the dying neurons of ALS patients, but whether they are made mostly of SOD1 remains controversial (although it is present in the inclusions to some extent). Mature SOD1 is a 32 kiloDalton homodimeric metalloenzyme, in which each monomer contains Cu and Zn and one intrasubunit disulfide bond. It is one of the most abundant cellular proteins. It has a tendency to aggregate when overexposed.
The mouse results are impressive, as it improved established disease. In vivo, Sephin1 prevented the motor morphological and molecular defects of two unrelated protein misfolding diseases in mice (Charcot Marie Tooth 1B and ALS ! ! !). The mice had a mutant SOD1 (G93A). SOD1 mutants bind to Derlin1 on the the cytosolic side of the endoplasmic reticulum (ER) membrane blocking degradation of ER proteins causing ER stress. Very impressive ! ! ! !