It's 2025, Happy New Year!
Since late 2018 this blog has comments on research on ALS, Parkinson's, and Alzheimer's diseases. My goal initially was to write a post every two days, with newly published research on Pubmed as input. This goal was impossible to reach because there is an immense activity but little valuable research on these topics.
Most articles are produced with an optic where quality is not important as long it's obscured by jargon. As publishing an article cost anywhere between $1000 and $4000, this is an incredible waste of money. Another aspect is that the articles about drugs' effects on immortalized cells, worms, or fishes, do not provide any hint that a drug might be useful for humans.
At a minimum such research to apply to humans must use animal models that are as large as humans and with a similar central nervous system. Only upper primates fit these requirements and the cost and ethics aspects are that kind of research almost never happen.
So I will try for a few months to write posts that briefly talk about publications that I feel have some merit.
Let's go!
A medical case report recounts that an ALS patient was given a GLP1-inhibitor (a category of drugs including Ozempic). Indeed the "case" deteriorated quickly. Sometimes patients make bad encounters in white coats.
Some good news came for ALS patients with a familial form. More than half of familial ALS cases are due to a nasty dysfunction in the mechanism that produces proteins. This study explores a novel approach to combat C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) using a CRISPR-Cas13-based RNA-targeting system. C9ORF72 mutations contribute to those diseases through three mechanisms: loss of C9ORF72 protein function, RNA toxicity from repeat-containing transcripts, and toxicity from dipeptide repeat (DPR) proteins. Current therapies, such as antisense oligonucleotides (ASOs) and miRNAs, face limitations, including transient effects and suboptimal targeting. The researchers developed RfxCas13d, a compact CRISPR-Cas13 variant, to target and degrade the pathogenic G4C2 repeat RNA in cellular and animal models. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeats without affecting normal C9ORF72 levels.
Another study demonstrates the potential of a CRISPR-CasRx-based approach for targeting both sense and antisense C9orf72 repeat transcripts. ASOs for the G4C2 repeat RNA developed by Wave Life Sciences and Ionis Pharmaceuticals and Biogen failed to show a benefit in human trials. Though the exact reason for this remains unknown, these ASOs targeted only the G4C2 (sense) repeat RNA and were thus presumed to not affect the G2C4 (antisense) transcript. This last study has the same overall goal as the first one but it targets both sense and antisense C9orf72 repeat transcripts. Yet the First study's RfxCas13d is a multiplexable enzyme. Thus, it has also the capacity to simultaneously target both the G4C2 (sense) and G2C4 (antisense) repeat RNAs from a single vector. Indeed there is a long road to transform these findings into efficient drugs, but it's a step in the right direction.
In younger, healthy cells, the "normal" metabolic process is typically oxidative phosphorylation (OXPHOS), which occurs in the mitochondria. Healthy cells maintain a slightly alkaline intracellular pH (around 7.2 in the cytoplasm). However, during aging, cells may shift towards glycolysis (a process common in senescent cells), where the cytoplasm, not mitochondria consumes glucose to produce ATP with lactic acid as a side product. As neurodegenerative diseases are, in most cases, diseases of aged people, one layperson would expect that the cell shift in metabolism from mitochondria to cytoplasm and subsequent acidification are of the utmost importance. Unfortunately, it is not, and as usual, when scientists have no idea about something, they tell that this shift in aging metabolism is due to a combination of multiple factors. Joyal Xavier and colleagues wanted to understand the mechanisms associated with TDP-43 aggregation. TDP-43 expressing cell lines were exposed to either an acidic environment, a neutral environment, or sodium arsenate. Asparaginyl endopeptidase (AEP) has been implicated in the misfolding and aggregation of TDP-43 and other proteins implicated in neurodegenerative diseases because it is an enzyme that can cleave proteins in toxic fragments. They have observed the localization of TDP-43 in the mitochondria under normal pH conditions. However, under acidic conditions and after sodium arsenate exposure, they observed an increase in TDP43 levels in the mitochondria and nucleus. Alternatively, they observed a decrease in TDP43 in the mitochondria and nucleus following treatment with an asparaginyl endopeptidase inhibitor. My conclusion is that not much has been learned, yet it is a neglected research avenue that has some potential.