Reacción a ""Promising" new strategy for ALS using stem cells created from patients"

The study is solid and based on research conducted on cells derived from iPS [induced pluripotent stem] cells from patients with this mutation in the VAPB gene. This approach has its limitations, as it is an artificial recreation of what occurs in vivo, but it is a good approximation for elucidating mechanistic aspects.

This study highlights three things:

1. That ALS is not a homogeneous entity from a pathophysiological point of view and that, in this case, the fundamental role leading to motor neuron neurodegeneration lies in the connections between the mitochondria and the endoplasmic reticulum (MAMs).
2. That there is, as a consequence of the dysfunction of these structures, an alteration in the integrated response to stress.
3. That this may lead to therapeutic approaches with inhibitors of this IRS such as ISRIB or similar. In this regard, there are previous studies by Spanish researchers (Bugallo et al.) that already pointed in this direction.

The limitations stem from the model. The authors study this in derived motor neurons, assuming that this disorder occurs in vivo in these cells, ignoring the possibility that similar mechanisms may exist in glial support cells. It would be important to analyse the effect of the mutation in muscle and glial cells to see the effect through conditioned mutation in a single cell line in other animal models.

This finding opens the door to developing drugs with this target and also to attempting to analyse in a clinical context the weight of this mechanism in cases of sporadic ALS in order to stratify patients in trials. Unfortunately, in sporadic ALS, various mechanisms converge, and we do not know the individual weight of each of them and their chronological sequence in specific patients, which makes it difficult to establish a therapeutic plan adapted to the real context of each patient. To advance precision medicine in ALS, we must be able to weigh the real situation of each patient using biomarkers linked to each mechanism.