Neurodegeneration, lysosomal dysfunction and autophagy

There is a desperate need for novel therapies that can prevent the progressive neurodegeneration in debilitating diseases of ageing, such as Alzheimer’s, Parkinson’s and Huntington’s Disease.  Research in this area has a long history, but the progress so far has been frustratingly slow.  However, with a greater understanding of the underlying biological processes, and the realisation that these processes may be similar in each disease, there are signs that breakthroughs could be on the horizon. At Samsara Therapeutics, we think we have a unique contribution to make in this area.

The amyloid beta (Aβ) hypothesis has driven Alzheimer’s research for the past twenty years.  The recent landmark – but controversial – FDA approval of Biogen’s monoclonal antibody, Aduhelm (aducanumab) has brought this hypothesis sharply into focus because the drug, which reduces the occurrence of extracellular Aβ protein “plaques”, has question marks in terms of its ability to arrest cognitive decline.

Meanwhile in Huntington’s Disease (HD), which features progressive motor decline due to mutated Huntington’s protein (Htt), pharma companies have been trying to reduce the mutated Htt with RNA-based therapies.  There have been some setbacks in this area recently with Pfizer’s recent demonstration that reducing the Htt in patients’ brains makes (at best) no difference (1). And in Parkinson’s Disease, (PD), a similar hypothesis, that the aggregation of α-synuclein is causing the disease, is driving companies to pursue strategies that selectively remove this protein.

We at Samsara think that the Aβ amyloid plaques in Alzheimer’s Disease (AD) are likely to be a symptom of the process, not the cause.  In fact we’d go further and say that this symptomatic approach is “shutting the stable door after the horse has bolted”.  Even in HD and PD, Htt or a-synuclein levels are unlikely to be the single driver of the diseases.  What should be more effective to really slow down the progress of these neurodegenerative disorders is to go directly to the source of the problem. We believe by restoring cellular autophagy we can prevent the underlying cause of the disease rather than merely trying to affect symptoms.

The first major clue that autophagy is central to these diseases (2) is the observation that in each disease, the disease cell’s ability to undergo autophagy is compromised.  Intriguingly the type of dysfunction is different between each disease, and can be different within each disease.  In some cases we can identify the exact mutation in a gene that is associated with the lysosomal dysfunction (for example mutations in APP or PSEN in AD, or LRRK2, GBA or PINK1 in PD), though why the association leads to dysfunction is unknown.  In HD autophagy inhibition is less clear cut, but there is some evidence that one function of Htt is to act as a part of the autophagy machinery (a cargo receptor), so a mutation leads to breakdown of this machinery (3).  The fact that so many different origins can lead to the same basic issue is overwhelming evidence that autophagy going wrong in these diseases is a key driver.

Furthermore, there is a clear link between progressive lysosomal dysfunction and protein aggregation, since the lysosome is the cell’s main method for clearing these aggregates. Which comes first – the dysfunction or the aggregation – is hotly debated in the literature (4). Whatever the order of events, we believe this is likely to be a vicious cycle of degeneration – the more there are of these toxic protein aggregates, the more lysosomal/autophagy dysfunction there will be, and thus the harder it is for the cell to clear the protein aggregates.  On top of this cycle, just as in analogous peripheral rare genetic diseases, a reduction of the cell’s capacity to undergo autophagy will interfere with other important cellular processes, driving more dysfunction and cytotoxicity.

Therefore, rather than merely reducing the levels of amyloid plaques once they have formed, we believe that by restoring autophagy to the neurons, we will tackle the protein aggregate formation at a much earlier stage or even prevent it from happening in the first place, disrupting this vicious cycle.  And this will give the additional benefit of restoring a vital cellular process. By tackling the origin of the problem, our approach is likely to be disease modifying.

What we’ve seen in our results so far is that in cellular models of PD our m-TOR independent autophagy inducers are more effective at clearing protein aggregates and protecting cells from death than known compounds in current clinical trials which are suspected to work via autophagy induction.  We have shown that our compounds induce autophagy in the brain, and we are now testing these results in animal models of neurodegeneration.   Moreover, the encouraging physical and pharmacological properties of our compounds point to a good chance of success for our unique approach.

References

1. Sheridan. Questions swirl around failures of disease-modifying Huntington’s drugs. Nature Biotechnology 2021, 39, 650
2. Boland et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov 2018, 17, 660
3. Martinez–Vicente et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s Disease. Nat Neurosci. 2010 13(5): 567
4. Nixon & Yang. Autophagy Failure in Alzheimer’s Disease – Locating the Primary Defect. Neurobiol Dis. 2011, 43, 38