How good are our animal models of ALS? Are they predictive of effectiveness in humans?

I am not an expert (I am a retired R&D telecom engineer) but here is my take:

* As for cancer, there are several (many?) ALS variants. The first gene to be associated with ALS was SOD1 G93A allele in 1993. It stayed the only ALS gene known until 2006. That was a curse for research as ALS with SOD1 origin is less than 2% of total cases, and even for SOD1 there are dozens of mutations associated with ALS, some with 6 months of life expectancy, others with 20 years.

* Most commercial animal models are SOD1 G93A mice [0]. The G93A mutation represents roughly only 0.4-1.4% of all ALS cases worldwide, yet it is the most used animal model!

SOD1 G93A ALS models are also the less costly animal models.

* I think another important thing is that ALS starts often in hands (split hand phenomena) and targets skeletal muscles. But humans' nervous system for hands is very special, only shared with other upper primates. Other mammals like mice have an interneuron between the upper and lower motor neuron for hands. We do not, there is a direct connection between upper and lower motor neurons, reflecting the importance of manipulation for humans. Therefore for me, we can't prove with mice at pre-clinical stage, that a drug is efficacious or not (many drugs have some efficacy in animal models, but none in humans).

* Some publications pretend they can use individual cells, fishes, or nematodes as animal models. That's laughable, it's ignoring the importance of anatomy and physiology. We are complex animals, our hormones, our immune system, and our metabolism are important to understanding ALS. The proof of that is that ALS patients who have the best life expectancy have a BMI of 27.

* Other publications pretend to make their own animal models with some chemical, like BMAA, a neurotoxin found in certain cyanobacteria. Those publications smell bad behavior for me.

If you want to buy a mice model of ALS:

[0] https://www.jax.org/jax-mice-and-services/preclinical-resear...