Thought Leadership Articles

February 29, 2024

Treating the untreatable: Condensate science is bringing new hope in ALS and other rare diseases

Rare diseases are a core pillar of Dewpoint’s development portfolio. With condensates playing fundamental roles in cellular biology and as central nodes of dysfunction in disease, modulating condensates has broad applications which could prove to be game-changing across diseases with unmet medical needs such as ALS and other neurodegenerative and rare diseases.

This rare disease day, we took the opportunity to speak with our Head of Discovery Biology – US, Violeta Yu about the exciting progress we are making in ALS, where Dewpoint has just been awarded a Target ALS Foundation grant, and the potential for condensate science to transform the way we view and treat neurodegenerative diseases in the future.

Violeta is an eminent molecular pharmacologist with 25 years of drug discovery experience. In her career, she used innovative strategies – including condensate–targeted drug discovery, to screen, study, and progress potential therapies towards the clinic in Neuroscience, Oncology, Inflammation, and Metabolic Disorders.  Prior to joining Dewpoint, Violeta led the ALS discovery program at Amgen Inc.

You’re leading Dewpoint’s work in ALS, a notoriously difficult to treat disease area, where many have tried and failed to make progress, how has your approach been different?

It’s true that a treatment for ALS has been elusive, despite this being one of the more well known and studied rare diseases. One factor that has made it so hard to target is the diversity of the disease, only around 10% of patients have a genetically inherited defect while the remaining 90% of cases are sporadic and traced to a combination of genetic or environmental factors. In addition, many of the key proteins that play a role in the disease pathology, such as TDP-43, have been found to be very difficult to drug.

Condensate science has enabled us to take a different view to target the disease. Condensates are membraneless compartments that organize cellular material in time and space and regulate many biological processes. When condensates go awry, they can lead to disease. We call an aberrant condensate associated with a disease ‘condensatopathy’. Despite the genetic diversity between ALS patients, the majority – over 97% – share a common condensatopathy which causes TDP-43, a protein which normally resides in the nucleus to be sequestered and concentrate in cytoplasmic condensates. Research has shown this to be a key driver of disease both through toxic gain of function in the cytoplasm and loss of function in the nucleus.

At Dewpoint we are developing small molecule condensate modifying drugs (c-mods) that will repair the condensatopathy directly, allowing TDP-43 to move back into the nucleus to resume its function. In cellular and animal models of TDP-43 pathology, we have already been able to demonstrate the mitigation of some of the cellular changes induced by the aberrant TDP-43 protein inclusions, including alterations in gene activity and stress-induced damage. Just last month, we were honored to have been awarded a Target ALS Foundation Grant to continue our work in animal models, which will allow us to take great new strides towards bringing our therapy to patients.

 What is your hope for how your ALS treatment could benefit patients?

ALS is a devastating neurodegenerative disease that affects up to 20,000 patients in the US alone each year. Based on our cellular and animal models we have a real hope that our c-mod treatment may be able to reduce progression of ALS, by restoring neuron health through reducing TDP-43 cytoplasmic inclusions and improving TDP-43 function – we think it could be transformative.

But of course, the earlier we can treat people the better the results could be. Once TDP-43 has become aggregated and insoluble, it could be in a state where its function is unsalvageable, so if we can act early, we can stop sequestration in the cytoplasmic condensates and release the TDP-43 while it is still functional, rescuing the impact of TDP-43 loss of function as well as reducing the progress for TDP-43 toxic gain of functions that underlie ALS. In the future I hope we will have the ability to screen for a biomarker that can identify TDP-43 loss of function early. There is a recent discovery that TDP-43 loss of function is seen years before symptoms can be detected1 so if we could treat ALS that early we might be able to fight the disease before it causes any clinical symptoms at all.

With the c-mod approach having so much potential in ALS, do you think it could be used to treat other neurodegenerative and rare diseases?

Despite diseases having different clinical representations, we are seeing more and more that the same dysfunctional condensate is shared between them. The TDP-43 condensatopathy for example, is seen not only in ALS but also in FTD, Perry Syndrome, CTE, Inclusion Body Myositis and Alzheimer’s – so I think it’s highly possible that we could expect our TDP-43 condensate targeted c-mod therapy to benefit numerous patient populations. I’m excited that we are starting to explore some of these areas.

Now we have this innovative approach, of using condensates (which are composed of a mix of RNA and protein components that act together to modulate biological processes) rather than focusing only on single protein targets, we are finding many other condensatopathies that play key roles in rare and neurodegenerative diseases, so I hope that we will be able to expand our scientific approach and continue our work towards overcoming these devastating diseases which have until now been seen as untreatable.

What can be done to speed up the development of treatments for rare diseases by the industry as a whole?

The major challenge in the rare disease space is, I believe, a general lack of research and dedication in general. We lack animal models, biomarkers, established end-points and defined clinical measures. We also need to work more closely with doctors and patients. Because not much is known, patient diagnosis is delayed, or the early symptoms misdiagnosed. We miss opportunities to learn from patients or for patients to be involved in clinical trials. The small patient population size can make it difficult to get robust data in the clinic. I believe these diseases are not uncurable. More focus, research, education and investment across the board will be vital for overcoming rare diseases.

At Dewpoint we are taking the challenges of rare diseases seriously. We believe that condensate science holds the key to treating many of these diseases and so we are putting the full force of our knowledge, experience and AI-powered discovery platform into finding new treatments. We have been challenging scientific conventions, hypotheses and biases to come up with a novel approach in targeting condensates and I hope that this can lead us to develop compounds with great efficacy not just in translational models but also in the clinic. Today we are progressing the science at a lightening pace – I’m proud of the progress we’ve made, and I can’t wait to see the day when our drugs can make a real difference to patients.

1 • Irwin, K.E., Jasin, P., Braunstein, K.E. et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD. Nat Med 30, 382–393 (2024).

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