As part of my ongoing research into areas of unmet need, I’ve decided to dig further into an area which I personally feel is both a challenging area of medicine (ALS) but also one in which the right time may have come in our biotechnology cycle to dramatically improve therapeutic options…
Quick intro into what ALS (Amyotrophic Lateral Sclerosis) is:
ALS is a neurological disease of unknown origin characterized by a selective degeneration and death of upper and lower motor neurons, initiating in mid adult life and almost invariably progressing to paralysis and death over a 1-5 year time. The majority of patients afflicted with ALS seem to have it in non-familial form.
About 95% of ALS patients are sporadic, whereas 5% are familial. In this group, approximately 15% are caused by mutations in the SOD1 gene (on chromosome 21)
Biological causation behind ALS disease:
Several potential mechanisms of motor neuron degeneration in ALS have been proposed. These include:
– the involvement of environmental and genetic factors
– autoimmune phenomena
– increased oxidative stress
– glutamate toxicity
– protein aggregation
– mitochondrial dysfunction
– cytoskeletal abnormalities
– impairment of axonal transport
– pro-apoptotic alterations
– Both Neurons and surrounding Glial cells are affected
However the cause of ALS is still unclear and the only current approved medication, Rilutek (riluzole) only extends average survival time by 2-3 months. So what are the most promising future targets for therapeutic development based on our latest understanding of ALS?
Promising potential treatment targets for ALS
- Glutamate toxicity – increasing neuronal reuptake or reducing Glutamate in the brain and cerebral spinal fluid (due to implication in Neuronal cell death) seems to be a promsing avenue and several potential therapeutics could assist. Cephalosporins and memantin have been tested and show some promise
- SOD1 familial – 15% of cases and a mutation in this gene is assumed to increase oxidative stress damage. One potential therapeutic, Edaravone is a free-radical scavenger is which has been shown to significantly reduce the loss of function in motor neurons (currently in PhIII testing). Anti-Sense SOD1 also significantly reduced decline in mouse SOD1 models.
- Apoptosis and ALS – Transcriptional dysfunction has been implicated in the pathogenesis of many neurodegenerative diseases including ALS. Valproic acid inhibits apoptosis, promising in SOD1 mice but not effective at doses used in epileptics in humans (perhaps its worth trying higher doses in humans?). Tauroursodeoxycholic Acid (TUDCA) may have also have an effect on ALS disease progression.
- Inflammation – may be a secondary response in ALS, inflammatory cascades contribute to neuronal cell death, Celastol a potent anti-inflammatory and antioxidant, showed improved motor function in humans.
- Neurotrophic factors – involved in the regulation of neuronal survival and differentiation and in maintaining neuronal structural integrity. In SOD1 G93 mice treatment with insulin-like growth factor (IGF)-1 or glial-cell-line-derived neurotrophic factor (GDNF) have beneficial effects on survival and motorneurons morphology, overexpression or administration of VEGF protects motor neurons from degeneration and prolongs mice survival
- Autophagy – reduced autophagy linked to neurodegeneration, therapeutics like Lithium may have an effect on increasing neuronal autophagy and have a neuroprotective effect but human clinical results are mixed.
- Neuronal Stem Cell replacement – Ultimately, neurodegeneration results in neuronal cell apoptosis and one potentially promising therapeutic option is neuronal stem cell replacement, several companies are currently working on neuronal stem cell replacement therapies (Neuralstem, Brainstorms and others) and promising results have been seen in mouse models but none yet reported in humans.
It’s important to note that most pre-clinical pharmacological studies failed to translate to ALS patients most likely due to the limitations of ALS mouse models, which carry the same mutation and are relatively homogenous, while ALS patients are genetically homogenous and only a small percentage have familial ALS. After a review of the literature, it seems there are several promising pathways to target for effective therapeutic development, however this has to be guided by both an understanding of the potential genetic variability in different forms of ALS and the disease stage in patients effected by ALS.