Stress granules are the body’s way of repairing itself. For example, if you hit your head, your body goes immediately into repair mode and creates stress granules to make the repairs. Normally, when the damage is repaired, the stress granules disperse. This is a process that usually takes 10-15 minutes. But, if you have a mutation or the stress granules are diseased, it makes them “stickier.” They build up and become persistent. This is the pathology that’s found in most neurodegenerative diseases.
The location of the persistent stress granules determines the symptoms. Accumulation in the spinal cord results in motor dysfunction and ALS, while accumulation in the hippocampus causes memory loss and Alzheimer’s disease.
Our team tested over 75,000 different compounds and identified a number that could eliminate stress granules. This is especially exciting news for patients because it has the potential to give them something close to their old lives back, nothing that any of the sufferers of ALS or Alzheimer’s currently dare to hope.
While there is agreement among the scientific community that stress granule proteins are the cause of ALS in more than 90% of patients and an estimated 50% of Alzheimer’s patients, we are the only company doing drug discovery and development to eliminate persistent stress granules. This breakthrough could turn around years of disappointment in ALS and Alzheimer’s research.
Before the discovery of TDP-43 stress granules, researchers spent 20 years studying SOD1, the first gene discovered that caused ALS. The problem was that SOD1 only occurs in 2% of patients with ALS. Despite many attempts, none of the trials targeting SOD1 was successful in finding an effective therapy for ALS.
For Alzheimer’s disease, the field has been focused on trying to break up the plaques. Until now, scientists have only known that the plaques and tangles accumulate, they haven’t known how or why, or why they are bad. For the first time, the stress granule provides a user’s manual for understanding the biology of how tangles form.
Aquinnah has been awarded five peer-reviewed grants, two from the ALS Association, two from the National Institute of Health (National Institute of Neurological Disorders and Stroke) and one from the Massachusetts Life Science Center. Our approach has also garnered interest and support from major pharmaceutical companies, including AbbVie, Pfizer and Takeda Pharmaceuticals.
The compounds Aquinnah discovered measure up against the most exacting standards: They are potent, orally bio-available in small doses, and can get past the blood brain barrier, a critical factor that hasn’t always been tested by others in the field.
We are currently conducting animal trials. Human trials are scheduled to begin in the next 2-3 years. Once in human trials, we should know in just one year if the drug is effective because ALS is such a rapidly progressing disease. Once the drug is proven successful in ALS patients, clinical trials will begin for Alzheimer’s disease.
Both Dr. Larsen and Dr. Wolozin are very optimistic about the future of neurodegenerative diseases. The discovery that the molecules in stress granules are the building blocks of neurodegenerative disease provides a new foundation for not just one, but potentially
many new therapies.
Historically, of all the branches of medicine, the study of neurology has the most unknowns and the fewest treatments, however, Dr. Wolozin believes that is about to change. Scientists have been studying the molecular mechanisms of these diseases for 30 years. It's important to remember that progress moves in increments. For example, it took a long time to go from the invention of the telephone to the iPhone. Drug development also takes time, but can make similar dramatic leaps forward.