Here is an interesting article on ALS and FTD, for two reasons.
- The first is that it tells about the multiple pathways that could lead to the same disease. In other words, when doctors speak of conditions when they should speak of phenotypes.
- The second reason is that it looks at astrocyte pathology, one of the multiple "glial" cell types that are nearly always absent in neurodegenerative studies.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases.
Consistently, pathological inclusions of the same proteins and mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, the authors focus on astrocytes, a heterogeneous population of glial cells that perform several functions for optimal central nervous system homeostasis.
- Firstly, they discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around neuroinflammation (1), atrophy/degeneration (2), and abnormal protein aggregation (3).
Furthermore, the scientists summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers.
Then the authors address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how they used these models to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics.
As astrocyte dysfunction is considered a consistent feature of the ALS/FTLD spectrum and contributes to the establishment of a neurotoxic environment, there is a need to explore the potential therapeutic interventions targeting astrocytes. This includes transplantation experiments, manipulation of gene expression, modulation of glutamate transporters, stimulation of antioxidant responses, and metabolic balance restoration.
Finally, they present the current clinical trials for ALS/FTD, restricting their discussion to treatments that modulate astrocyte functions, directly or indirectly.
Neural progenitor cells engineered to differentiate to astrocytes and to secrete GDNF were produced for a phase I/IIa clinical trial (NCT02943850) to test the safety of unilateral spinal cord injection in a small cohort of ALS patients. The study met the primary end-point for safety but showed only a small delay in motor function loss in the treated side, most likely due to an unanticipated minimal migration of the injected cells from the dorsal towards the lumbar spinal cord.
These overall encouraging results will be hopefully reinforced by the results of an analogous phase I/IIa trial from an independent ALS clinic (NCT03482050) and by an ongoing study designed to evaluate the injection of CNS10-NPC-GDNF in the motor cortex of ALS patients (NCT05306457), thus possibly corroborating the therapeutic neuroprotective power of healthy astrocytes.
Early genetic manipulations or viral-mediated gene therapy demonstrated that reducing the expression of a harmful protein, mutant SOD1s, in astrocytes slowed motor decline and prolonged survival in mouse models of ALS-SOD1. The success of these and several other studies aimed at silencing SOD1 in various CNS populations led to testing the therapeutic potential of SOD1 ablation in ALS-SOD1 patients. Regrettably, although a phase I/IIa clinical trial showed that the administration of an antisense oligonucleotide to lower SOD1 expression in ALS patients was safe, a subsequent study very recently failed to demonstrate that the intervention slowed disease progression.
Currently, ongoing clinical trials are not investigating formulations to deliver NRF2-pathway-stimulating compounds specifically to astrocytes but rather exploring the therapeutic potential of nutritional supplementations with such biological action to the entire CNS. More specifically, studies have been registered aiming at evaluating whether supplementation with curcumin (found in turmeric), a polyphenol that stimulates the NRF2 signaling pathway, could delay progression in ALS patients (NCT04499963; NCT04654689).
It would be very important to restore the metabolic balance in ALS/FTD astrocytes as it might halt neuronal death. Intriguingly, the results of a pilot clinical trial (NCT02288091) showing the safety of inosine supplementation to ALS patients have been recently published . Although the rationale for such study was to elevate blood concentration of uric acid, a known antioxidant whose levels correlate with slower progression rate and extended survival of ALS patients, we know now that inosine can also prevent astrocyte-derived motoneuron demise. Therefore, we can speculate that any potential therapeutic benefit arising from inosine supplementation might be mediated also by rescuing astrocyte metabolic dysfunction.
Similar considerations could be drawn about the compound CuATSM. The exact mechanisms of action of this drug are not yet known. Regardless, there are several clinical trials aiming at investigating its potential therapeutic effect in ALS (NCT04082832, NCT03136809, NCT04313166); these trials are perhaps prompted by CuATSM efficacy in ALS mouse models