New avenues for rare disease treatment

Drugs that boost autophagy hold great promise in preventing and halting neurodegenerative disorders. By ramping up the cell’s waste disposal system, they stimulate the removal of the toxic proteins that are a hallmark of brain conditions such as Alzheimer’s disease and Parkinson’s disease. Now, scientists are harnessing the power of autophagy to make inroads into the treatment of rare peripheral diseases, many of which also have dysfunctional proteins at their heart.

Woman with Parkinson's holding her hand

Almost every one of us will know someone with a neurodegenerative disease such as Alzheimer’s or Parkinson’s.  Whether it is a friend, a family member or a work colleague, it is likely these conditions have touched your life in some way.  It is less common to know someone with a rare genetic disease; but while individually rare, collectively they have an enormous impact.

More than 7,000 rare diseases – conditions that affect fewer than 1 in 2,000 people – have been identified, and1 in 17 people will develop a rare disease in their lifetime, with children disproportionately affected.  Most of these conditions are genetic in origin and the majority have no effective treatment.1,2

Many, however, do have dysfunctional proteins at their core, and for these diseases, a new option is being explored: autophagy-boosting therapies.

A natural way to get rid of waste

Autophagy is our cells’ waste disposal system.  Cells all around the brain and body use it to remove unwanted debris, such as old proteins, break it down and reuse the parts. Membrane structures encircle the waste and then fuse with the lysosome, the cell’s degradation machinery, where the waste is recycled for energy or repurposed as building blocks for new molecular structures.

Autophagy in a hot topic in scientific circles; the number of papers that mention the process has risen almost exponentially since Yoshinori Ohsumi was awarded the Nobel Prize in 2016 for his research into its underlying mechanisms.  There is a growing body of evidence that any dysfunction or disruption in autophagy is associated with a wide range of disorders including cancer, cardiovascular disease, type 2 diabetes and neurodegenerative diseases.

The evidence that autophagy ‘gone wrong’ is a key driver of Alzheimer’s, Parkinson’s, and other neurodegenerative diseases in which toxic protein aggregates build up in the brain, is overwhelming and boosting autophagy is seen as an attractive treatment strategy.  The premise is simple: if you make autophagy work better, more of the toxic protein will be removed, be that the beta-amyloid plaques of Alzheimer’s or the clumps of alpha-synuclein in Parkinson’s.  This will, in turn, slow the progression of, or even halt, the disease. 

Research in the field is fast-paced and, fuelled by advances in stem cell technology which allow diseases to be modelled in a dish, is beginning to yield results, with several autophagy-boosting therapeutics now in development.  One of our drug candidates at Samara activates Transient Receptor Potential Mucolipin 1 (TRPLM1), a protein that’s at the centre of the degradative machinery that’s so key to autophagy.  We’ve shown that it boosts autophagy and reduces damage to brain cells taken from people with Parkinson’s and Amyotrophic Lateral Sclerosis (ALS), the most common form of motor neurone disease.  Symptoms were reversed in mouse models and a clinical trial is planned for later this year.3

The benefits of autophagy-boosting drugs aren’t limited to neurodegenerative diseases – the approach could be applied to any disease that is driven by toxic protein aggregation.  That includes countless rare peripheral diseases, including many for which there are currently no treatments.

Transforming rare disease treatment

Let’s look at CMT1A, a subtype of Charcot-Marie-Tooth disease, the most common inherited peripheral neuropathy. In those with CMT1A, over-production of a protein called PMP22 damages the nerves that supply the arms, hands, legs and feet, leading to muscle weakness or paralysis, problems with balance and loss of sensation.  Symptoms usually start in childhood before progressing slowly, there is no cure and treatment is limited to painkillers, physiotherapy, orthopaedic braces and the like.4

In highly promising work on animal models, we’ve shown that if you boost autophagy in these nerve cells, you can reduce levels of PMP22.  This restores movement and improves nerve condition, which should bring back sensation.5 This drug candidate is progressing towards the clinic, with phase 1 trials due to start within 18 months.

Another example is alpha-1 antitrypsin deficiency, a disease in which an abnormal form of the alpha-1 protein accumulates in the liver, where it can cause severe, sometimes fatal, damage. We know from our own work, and from the literature, that boosting autophagy can reduce levels of this rogue protein.

Other rare genetic conditions that will be in the grasp of autophagy boosters include lysosomal storage disorders, such as Gaucher disease and Pompe disease.  People with these conditions lack enzymes the lysosome needs to recycle waste. These are just a few examples, but the possibilities are numerous.

Gene therapy, of course, also holds great promise.  It has potential to not just treat, but cure, rare diseases, which is the holy grail of drug R&D. However, it’s a very new technology and there are various technical challenges, including issues with delivery, that still need to be overcome.

Autophagy boosters, in contrast, are conventional small molecule drugs. Small molecules have been the mainstay of the pharmaceutical industry for nearly a century, they are easy to deliver – they are often given orally – and our health systems have a lot of experience of working with them. Restoring autophagy also has the added benefit of improving overall cell health.  After all, if you restore the cell’s recycling system, you won’t just be removing the protein responsible for the rare disease but all sorts of other potentially damaging debris.

Boosting autophagy won’t be the only road to new treatments for rare genetic diseases but it is a vital one to take. By travelling along it, we won’t just develop new therapies for conditions for are currently untreatable, we’ll bring patients and their families hope of a brighter future.

Author bio: 


Peter Hamley, PhD, MBA

Chief Scientific Officer, Samsara Therapeutics

Peter is a recognised 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. England Rare Diseases Action Plan 2022.
  2. The building blocks to make rare disease treatments more common | Research and Innovation [Internet]. [cited 2023 Sep 5]. Available from:
  3. Data on file, Samsara Therapeutics Inc, April 2023.
  4. [Internet]. 2018 [cited 2023 Sep 5]. Charcot-Marie-Tooth disease. Available from:
  5. Data on file, Samsara Therapeutics Inc, October 2022.