Peter Hamley, Chief Scientific Officer of Samsara Therapeutics, on understanding and leveraging the body’s cellular recycling process – autophagy.
Autophagy biology has emerged as a ray of hope in addressing age-related diseases such as neurodegenerative disorders. Substantial effort in academia has been directed at advancing our understanding of the field and paving the way for ground-breaking therapies. But with genuine challenges in harnessing the power of autophagy and in developing effective therapies in this disease area, how close are we to really finding the first autophagy boosting drugs…?
The devastating impact of neurodegenerative diseases such as Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS), the most common form of Motor Neurone Disease (MND), cannot be overstated. According to the WHO, neurological diseases affect over a billion people globally and are the leading cause of disability and the second leading cause of death worldwide [1,2]. Incidence is increasing too, predominantly driven by population growth and aging. And, with no prospect of a cure, people who develop these conditions face a bleak future.
Justifiably, this disease area has been the subject of intensive research for many years and there have been some breakthroughs along the way, possibly offering hope for the development of new therapies. However, translating scientific breakthroughs into viable drugs for patients has been enormously challenging.
A common factor in many neurodegenerative diseases, thought to play a role in their onset, is the accumulation of toxic proteins within the cells. Hence strategies to remove or prevent this accumulation have been a key area of interest in the search for new therapies.
Just this year there have been some exciting new advances as new drugs for Alzheimer’s disease and ALS have been approved by the FDA. These drugs (Leqembi for Alzheimer’s and Tofersen for ALS/MND) work by selectively removing the toxic aggregated proteins. For AD, this is a protein known as b-amyloid, while for MND/ALS the corresponding protein is superoxide dismutase 1 (SOD1) (though unfortunately this protein is implicated in only 1-2% of all MND sufferers) [3]. The drugs selectively bind to and remove the protein aggregates, resulting in small but significant improvements in cognition (for Alzheimer’s patients) and overall survival (for MND patients).
It’s great that these new therapies have been shown to really work for patients, but they only lead to marginal improvements. Just removing the protein aggregates may not be enough to treat these complex and serious neurological diseases. Which begs the question, is direct removal of the toxic aggregate the most effective way to treat neurodegeneration anyway?
Other scientific researchers have spent the past decade examining whether harnessing and boosting the body’s natural methods of removing protein aggregation could actually be more efficient. They’ve been studying autophagy, a process that occurs in all human cells whereby membrane structures encircle cellular waste such as potentially toxic proteins, and then by fusing with the lysosome (the cell’s degradation machinery), recycle this waste for energy or as building blocks for new molecular structures. There is growing evidence to show that autophagic disruption or dysfunction is associated with a range of human disease including Alzheimer’s, Parkinson’s, liver and kidney diseases, cardiovascular disease and many other disorders.
In 2016, Japanese scientist Yoshinori Ohsumi won the Nobel Prize for his research into the mechanisms of autophagy. While it was previously known that inhibiting autophagy could be effective in treating some cancers, due to the fact that tumours are known to induce autophagy to survive, it has emerged more recently that boosting autophagy could in fact extend lifespan and counteract chronic, age-related diseases. And no, this does not result in more cancerous tumours as, unless you already have a tumour, boosting autophagy can also prevent their development.
Although research to broaden our understanding of the process of autophagy has attracted considerable investment it has, until now, failed to generate any new therapies, largely because the process itself is enormously complex.
Recent research into the drug rapamycin, which was originally discovered in 1972 by scientists examining a soil sample from Easter Island, has shown it has significant anti-ageing properties. The drug works by inhibiting a protein called mTOR, and mimics calorific restriction, which in turn stimulates many of the body’s emergency processes including autophagy. The challenge with rapamycin – and other therapies such as metformin that have also been found to influence autophagy – is that they impact a number of pathways in the body. This could potentially result in undesirable effects or safety challenges if used to boost autophagy, creating a significant problem for drug developers.
The rapamycin dilemma has prompted more expansive research into new drug candidates that solely target autophagy with fewer adverse effects. Due to the complexity of the process, there are potentially many different biologic targets that could stimulate autophagy.
Samsara is the only company in the world exclusively developing autophagy therapies to prevent and halt neurodegenerative disease. One of our areas of research focuses on Transient Receptor Potential Mucolipin 1 (TRPML1), a protein that is at the centre of the degradative machinery that is so important to the autophagy process. Our drug candidate SAM001, which will enter clinical trials at the end of this year, activates TRPML1. Early trials have shown it boosts or kick-starts the process of autophagy, and not only reduces the hallmark toxic protein aggregates but reduces overall damage to brain cells of people with Parkinson’s Disease and Amyotrophic Lateral Sclerosis (ALS), the most common form of motor neurone disease. These results have been replicated in mouse models too.
By boosting autophagy, we are getting closer to the cause of the disease – kick starting the body’s own degradation system to remove the proteins. At the same time, we are increasing the overall health of the cell, which has been compromised by the decline of autophagy in general and by the toxic protein aggregation. As a result, we would expect this holistic approach to accrue many more benefits in addition to those seen in the recently approved therapies selectively removing protein aggregation.
There are also other organisations looking at autophagy from different perspectives. Some are attempting to subvert or ‘take over’ the autophagy mechanism altogether by developing drugs that identify specific protein targets, bind to them and transport them to the lysosome for degradation. It is an ambitious goal that involves very complex molecules which are incredibly difficult to develop into viable drugs, particularly for neurodegenerative disorders – but it’s certainly an area worthy of further exploration.
Bringing a drug to market for any company is a challenging and expensive process, one that’s exacerbated when trying to develop a drug for neurogenerative conditions, due to the complexities of finding molecules that are able to cross the blood-brain barrier. Yet it is absolutely vital that R&D efforts in these areas continue, given that patients suffering these terrible diseases currently have no curative options.
Channelling the power of autophagy not only has the potential to solve some of humanity’s most obdurate and longstanding health challenges, but it also affords us an opportunity to increase healthspan for everyone. By boosting autophagy in animals, increases of up to 30% in lifespan have been observed. It is no overstretch to imagine that, in 20 or 30 years’ time, we could see people routinely taking autophagy-inducers to not only avoid the development of neurodegenerative diseases but to enable longer and more healthy lives – not just a ray of light for neurogenerative disorder sufferers, but a brighter future for everyone.
Peter Hamley, PhD, MD
Chief Scientific Officer of Samsara Therapeutics
Peter is a recognized leader in drug discovery, having spent 15 years at Sanofi, most recently as Global Head of External Innovation, Drug Discovery in Business Development. Prior to this, he led global high throughput medicinal chemistry, natural product and antibody drug conjugate departments across Germany, France, and the US, and has contributed to the advancement of many projects into clinical development across several therapeutic areas.
He started his career at AstraZeneca leading medicinal chemistry teams in the respiratory and inflammation disease areas. Prior to a postdoctoral position at the University of Pennsylvania, he obtained his PhD from the University of Cambridge, and a BSc in Chemistry from Imperial College London. He holds an MBA from the University of Bath.
Over his career in big pharma, he has been involved in hundreds of drug discovery projects, has executed external partnerships and has published numerous papers and patents including co-editing the textbook Small Molecule Medicinal Chemistry: Strategies and Technologies (Wiley).
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641502/
[2] https://www.who.int/news/item/27-02-2007-neurological-disorders-affect-millions-globally-who-report
[3] https://pubmed.ncbi.nlm.nih.gov/18268245/
