Quinolinones as a Novel Therapeutic Strategy in ALS
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal and severely debilitating neurodegenerative disease with no effective treatment. Despite 160 years of recorded history and the completion of more than 200 ALS clinical trials, there are no drugs available that can prevent the onset of ALS or at least significantly inhibit disease progression. The only two therapies available, riluzole and edavarone, unfortunately offer only modest survival benefits. This offers little hope for patients and their families and constitutes a major financial and emotional burden for society. Hence there is an urgent need to develop new, much more effective treatments for ALS. A wide variety of new drugs have been tested in animal models of ALS but ultimately failed to show benefit in human clinical trials (or have not yet been approved). However, many previous studies were based on an animal model (the SOD1 mouse) that we now know does not accurately represent most ALS, in that it lacks pathological forms of a protein called TDP-43, which is present in almost all human cases. Furthermore, our understanding of disease processes in ALS has increased significantly in recent years and much of our earlier knowledge was also specific to SOD1 forms of ALS. The global pharmaceutical company Astra-Zeneca recently examined why 147 of their drug discovery projects had failed, and the main reason was a lack of understanding of the basic disease mechanisms of these drugs. This highlights the importance of having accurate knowledge of the underlying mode of action of drugs on the disease process. Importantly, the mechanisms of action of both riluzole and edavarone remain unclear. Together, this highlights the importance of both (i) using the right disease models and (ii) understanding how drugs work at the molecular level, in developing new treatments for ALS. We have identified a new class of drugs that have potential as a new treatment for ALS. Importantly, these drugs are based on an accurate understanding of the underlying disease mechanisms. We have found that our drugs are highly effective in multiple disease models (neuronal cells in culture and zebrafish that develop ALS) and against four different misfolded proteins that cause ALS. This suggests that our drugs will be applicable to multiple diverse forms of ALS, caused by several different gene mutations based on SOD1, TDP-43, FUS, and CCNF. Importantly, as well as being effective in common genetic forms of ALS, we know they are effective against the TDP-43 pathology, which is common to 97% of ALS, including the most common non-genetic form, which represents 90% of all cases. Hence, this study will provide outcomes that are relevant to almost all ALS patients. A new drug candidate suitable for clinical testing in human ALS patients needs to satisfy specific and stringent criteria. It needs to be very selective for the drug target, to display protective activity in human neuronal cells, and it needs to produce the desired responses in animal models before it can be progressed into humans. This study has three main goals that aim to address these points. The first is to (i) identify the major protein that these drugs bind to in the cell, and thus develop a rapid way to confirm the effective targeting of the drugs and (ii) confirm that administration of these drugs is not toxic. The latter is very important because all drugs must pass very stringent standards of toxicity evaluation in animals and safety issues are dominant when identifying a clinical drug candidate. We will also validate our drugs in human neuronal cells, which is a resource few researchers have access to. The second is to make new derivatives of these compounds so that they have the best drug-like properties in human patients. This is also a top priority for drug candidates so that we can understand how a drug behaves in the body. This informs the exact dosage that is eventually delivered to patients, and wi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210224
Entities
People
- Julie D Atkin
Organizations
- Macquarie University
- United States Army