White Paper Issue 15: Are in vitro Neuronal Cells Models for ALS discovery?

Updated: May 30

Cells placed in laboratory culture, or in vitro, may be useful models for uncovering the biology of disease, exploring the pathogenesis of disease processes and discovery potential drug targets. Options include induced pluripotent stem cells (iPSCs) that can come from blood or skin. Cochlear, or epithelial nasal cells are possible sources of research material. The iPSCs are generated by reprogramming the somatic cells taken from an individual. These cells are like embryonic stem cells and can differentiate into all three germ layers and give rise to almost all cell types of the body. A considerable advantage of these cells over other cell sources is that these cells represent the genetics of the donor. A hope is that these cells can stratify patients by predicting a drug therapy response, especially for ALS.


There are no good models of ALS, in vivo or in vitro, that predict the success or failure of a proposed treatment for the disease. A possible reason that drugs fail to translate into clinically applicable therapeutic strategies for patients is that ALS is not a single disease, more appropriately ALS defines a group of diseases with some shared pathologies. Less than 10% of ALS cases are considered inherited, with a familial genetic cause underlying the disease. Familial ALS, fALS, can be a mutation that is inherited in a dominant monogenetic manner, dominant with incomplete penetrance, recessive, or X-linked. Non-familial ALS, called sporadic or sALS, represent the majority of cases. The cause of sALS is unknown. Yet, all ALS cases are considered genetic, but sALS patient’s present without a clear family history.


The clinical course of fALS and sALS are indistinguishable. Genetic causes such as the presence of a hexanucleotide repeat expansion in the C9orf72 gene can be found in both fALS and a small number of sALS patients. Suffice it to say, the ALS phenotype is highly heterogeneous and the interaction between genetic risks and exposure to various environmental risk factors are complex. Is this why drugs fail… the treatment population isn’t the intended target population for a drug?


An important goal for ALS researchers is discovering biomarkers that can be used to identify and stratify patients. One could use markers to identify a responder group for a specific treatment that would enhance finding an effective therapy. It is undeniable that studies involving a heterogeneous patient population in a context of such varied disease pathologies may mask the efficacy of certain drugs on a specific subset of patients, such as genetic forms of the disease or even a restricted phenotype. An often cited example is the positive effects of lithium carbonate in the ability to enhance the survival of ALS patients carrying the UNC13A mutation, but it was not effective in the general ALS population. The efficacy of lithium carbonate was hidden in studies until the association with UNC13A was made.


There are other examples of targeted effectiveness that are recognized. Only SOD1-ALS patients seem to benefit from SOD1 antisense oligonucleotide therapy, arimocolomol, and pyrimethamine. The obvious course of action to treatments lies in developing and using multiple different precision medicine approaches. Genetic markers identify the ability to modify disease (progression or pathology) and could be used for beginning patient stratification. More biomarkers are necessary.

One has to consider where to modulate disease. The pathology can be upstream or downstream in a particular pathway and then vary in the current state of the disease process. Also, one should recognize if the pathology is a primary or secondary effect of the disease processes due to ALS.


There is a need to know if a particular patients phenotype is that of a “slow” progressor or a “fast” progressor. A slow or fast progressor are terms related to onset of signs to the time of the diagnosis. In a clinical trial, a patient with slowly progressing disease placed in the control group may bias the study outcome and tag a therapy to be falsely labeled as ineffective. A patient with fast progressing disease, when placed in the treated group, may likewise bias the study outcome and label a drug as ineffective. A patient with fast progressing disease when placed in the control group may skew the results so that an ineffective drug may be falsely labeled as effective.


A genetic analysis for biomarkers include gene mutations and other disease-related sequences, like short structural variations, are useful evaluators, however other methods that can determine the of state of disease and speed of progression in a patient should be employed. Some in vitro evaluators are iPSCs sourced from skin, blood, or adipose tissue. Olfactory stem cells (OSC) may be useful, they are easily obtained from olfactory mucosa. Olfactory neural spheres (ONS) are clusters of progenitor or stem cells from olfactory mucosa and grown in suspension culture.


Perhaps an advantage of the olfactory neurons over the induced iPSCs are they maintain the chronological age of the patient. Easier to obtain, iPSCs revert to the nascent state and may lose some important traits that would be accessible from ONS. Hypoxic culture promotes dopaminergic-neuronal differentiation of the nasal olfactory mucosa. One would like motor neuro- like cells to interrogate.


As more researchers use the ONS cells and compare these results with iPSCs it is possible an in vitro model system to stratify specific patients will develop. It may be predicted that no single in vitro system, nor one biomarker, will be the Rosetta Stone for stratifying ALS patients. Such a complex disease may follow the course of other diseases that share pathologies across etiologies. As patients progress and live with ALS, it is important to reassess a repertoire of biomarkers that change in known dysregulated pathways.

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