Recent developments in therapeutics that selectively target protein accumulation in neurodegenerative diseases are rightly being celebrated for the potential benefits they offer in areas of high unmet patient need. But are these new therapies truly disease modifying or are they simply addressing the symptoms of a deeper problem? Are there other perhaps related strategies that could go a step further and bring greater benefits for patients afflicted with neurodegenerative disorders? Dr. Peter Hamley, Chief Scientific Officer at Samsara Therapeutics, explores.
Dr. Peter Hamley
Major developments in the treatment of neurodegenerative diseases have been hitting the headlines with the FDA approval of lecanemab (Leqembi) for Alzheimer’s and tofersen (Qalsody) for amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND), along with the announcement of promising data in Alzheimer’s for the experimental drug donanemab.
All three of these therapeutics work on the principle that dysfunctional proteins play a role in the changes to the brain that result in these debilitating diseases. Donanemab and lecanemab are monoclonal antibodies, developed to remove the toxic build-up of amyloid proteins associated with Alzheimer’s. And, in ALS/MND, tofersen works by interrupting the formation of mutated superoxide dismutase 1 (SOD1) proteins that accumulate in much the same way.
Donanemab and lecanemab have been shown to reduce the progression of Alzheimer’s by 35% and 27% respectively and are being heralded as proof of the long-held, and much scrutinised, theory that removing amyloid aggregates can slow cognitive decline.
But, while these drugs are undoubtedly a step in the right direction, they all offer only moderate benefits. Tofersen is only suitable for 2% of the ALS population that have the SOD1 mutation and in real terms, the impressive sounding 35% slow-down in progression offered by donanemab equates to a maximum seven-month delay in the loss of memory and thinking.
This is great progress but also highlights the importance of keeping our foot on the gas in the race to find more effective treatments. For example, by looking deeper into the natural biology of our cells and capitalising on some of the processes involved in neurodegenerative decline we could garner wider holistic benefits. Autophagy is a powerful case study to demonstrate the efficacy of this approach.
Autophagy is the cell’s self-cleaning and waste disposal system. Membrane structures encircle cellular waste such as potentially toxic proteins, and by fusing with the lysosome (the cell’s degradation machinery), recycle this waste for energy or as building blocks for new molecular structures.
In many neurodegenerative diseases, including Parkinson’s and Huntington’s diseases as well as Alzheimer’s and ALS/MND, protein accumulation appears to go hand-in-hand with dysfunctional autophagy. This results in a vicious cycle; dysfunctional autophagy reduces the ability of neurons to clear proteins; more proteins accumulate and this further hampers the autophagy process. Cell health deteriorates until eventually the cells die, disrupting important neural connections in the brain.
Though the type of autophagic dysfunction varies between these different diseases, and even within the same disease, the fact that the issue of protein accumulation arises from so many different starting points is overwhelming evidence that autophagy ‘going wrong’ is a key driver in neurodegenerative diseases.
Importantly, this also suggests that protein aggregation may be, in some or all cases, a symptom of these conditions, not the cause, making therapeutic approaches that target direct protein removal akin to “shutting the stable door after the horse has bolted”. Instead, a more effective method for reducing the progression of neurodegenerative disorders is to go directly to the source of the problem, preventing the underlying cause of the disease by correcting the autophagy dysfunction rather than merely trying to remove the end product.
Restoring or boosting autophagy in neurons kick-starts the cell degradation system into clearing the protein backlog, while at the same time improving the overall health of the cell and restoring its functionality. The beauty of this holistic approach is that the general improvements in cell health it delivers, should translate into benefits beyond what can be achieved solely by selective protein removal, since autophagy is so important to the health of the cell, by recycling and renewing all unwanted components. So, by restoring autophagy in neurons we hope to be able to tackle protein accumulation at a much earlier stage or even prevent it from happening in the first place.
These are complex biological processes to decipher and progress has been a long time in the making but compelling evidence in support of this approach is growing. Autophagy-boosting therapies are now in development and demonstrating promising results in reducing cell damage and reversing the symptoms of neurodegenerative diseases in cell and animal models (data on file, Samsara Therapeutics Inc, April 2023). The first, our own candidate SAM001, will begin clinical trials for Parkinson’s and ALS/MND early next year.
It doesn’t stop there. It is becoming clear that dysfunctional autophagy plays a role in countless other diseases including fibrosis, cardiovascular diseases, metabolic disorders and many rare genetic disorders. For all of these conditions and particularly those where there are few or no disease modifying therapies, further exploration of the role of autophagy in their development is crucial. It might just be the key to unlocking therapeutic breakthroughs that could deliver much greater benefits that truly transform the lives of patients and their families.