The 2022 International Conference on Alzheimer’s and Parkinson’s Disease ended last weekend, but it reported on numerous research studies and insights into the diseases.
The 2022 International Conference on Alzheimer’s and Parkinson’s Disease held virtually and in Spain late last week and this weekend has ended, but it reported on numerous research studies and insights into the diseases. Here’s a look at just a few of those stories.
Cortexyme Offered New GAIN Trial Data on Moderate Alzheimer’s
Cortexyme presented new data from its Phase II/III GAIN trial of COR388 (atuzaginstat) to treat mild to moderate Alzheimer’s disease. The data described target engagement data showing the drug inhibited lysine gingipains, which demonstrated a 30% to 50% slowing in cognitive decline in participants with high P. gigivalis load. It also described numerical trends in traditional Alzheimer’s disease biomarkers, including phosphor-tau 181 and total tau.
“Our understanding of the impact of lysine gingipain inhibition on neurodegeneration and other Alzheimer’s disease markers continues to expand,” Michael Detke, MD, Ph.D., Cortexyme’s chief medical officer, said. “The evidence demonstrates our target — P. gingivalis — may play a key upstream role in both of these areas, and correlations between P. gingivalis biomarkers and clinical assessments show that our ability to inhibit this target potentially leads to improved patient outcomes.”
SQZ Biotechnologies Receives $2 Million Grant from NIH for Parkinson’s
SQZ Biotech was awarded a $2 million SBIR Phase II grant from the National Institute of General Medical Sciences, a National Institutes of Health division. The two-year grant will support the development of cell engineering approaches to reprogram a patient’s immune cells directly into dopamine-producing neurons. This will be a potential new therapy for Parkinson’s disease, marked by the death of dopamine-producing cells in the brain.
“Directly creating dopamine-producing neurons by reprogramming a patient’s own immune cells would be a major breakthrough and could support a new Parkinson’s disease treatment paradigm,” Jonathan Gilbert, vice president and head of exploratory research at SQZ Biotechnologies, said. “Unlike alternative allogeneic cell replacement approaches in development for Parkinson’s disease, by using a patient’s own cells, treatment might not require chronic immunosuppression. Moreover, in altering cell fate with RNA-based cell engineering methods, no changes to the genome are likely to occur that could carry long-term risks.”
The company’s Cell Squeeze technology may have broader applications than Parkinson’s disease because it is used to induce human pluripotent stem cells to create other cells via delivery of an mRNA encoding for a fate-specifying transcription factor.
Memory T Cells a New Target for Parkinson’s Therapies?
Researchers at La Jolla Institute for Allergy and Immunology discovered that Parkinson’s disease patients have a clear “genetic signature” of the disease in their memory T cells. Parkinson’s disease progresses as dopamine-producing neurons in the brain die, although what is causing the death is unknown. However, one clue is the dead cells contain clumps of the alpha-synuclein protein that has been damaged. Their research found that people with Parkinson’s disease have T cells that target alpha-synuclein early in the disease. This suggests a previously undiscovered possibility of an autoimmune component of the disease.
“Parkinson’s disease is not usually seen as an autoimmune disease,” said LJI research assistant Professor Cecilia Lindestam Arlehamn. “But all of our work points toward T cells having a role in the disease.”
One crucial gene observed in these T cells is LRRK2, which is associated with the familial form of Parkinson’s. This opens up potential new targets for treatment and prevention.
New Approach Decreases Brain Damage in PSP, Alzheimer’s and Related Diseases
Investigators at Washington University School of Medicine in St. Louis demonstrated that targeting astrocytes, specific immune cells in the brain, can reduce tau-related brain damage and inflammation — at least in laboratory mice. Dysfunctional astrocytes, whose job is to clean debris out of the brain and repair damage, have been associated with Alzheimer’s and other neurodegenerative diseases. The researchers identified high levels of Alpha2-NKA, a protein that drives astrocyte toxicity, in brain samples from people who died of progressive supranuclear palsy (PSP), Alzheimer’s and other tau-related neurodegenerative diseases.
Brain inflammation, in general, is believed to be a contributor to Alzheimer’s disease, and Gilbert Gallardo, PhD, senior author and an assistant professor of neurology at WU said “that inflammation is driven by non-neuronal cells in the brain, including astrocytes. Our study highlights that inflamed astrocytes are contributing to tau-associated pathologies and suggests that suppressing their reactivity may be beneficial in reducing brain inflammation and delaying Alzheimer’s progression.”
The researchers also tested the use of a heart drug, digoxin, which interferes with apha2-NKA activity. The drug worked on mice models of tau-opathies, both when they were beginning to develop tau tangles and when the tangles and damage were already established.
“The take-home message here is that suppressing the inflamed astrocytic state halts disease progression,” said first author Carolyn Mann, who was then a technician in the Gallardo’s laboratory. “This is important because experimental therapeutics for Alzheimer’s and related tauopathies have focused largely on clearing pathological proteins that have been implicated in neuronal dysfunction and death. But our study gives evidence that targeting inflamed astrocytes and brain inflammation may be the key to successfully treating such conditions.”
