Today our medical research program includes the Tau Consortium, the Rainwater Prize Program, and several other initiatives, all of which are designed to accelerate the development of new treatments for those who suffer from tauopathies. Since 2009, the Foundation has invested more than $115 million in our medical research program. This accounts for more than 60% of all tau-related grantmaking by U.S. philanthropies over the last decade, including more than 75% of the funding provided for treatment development projects. We recognize that patients and families are counting on us. That’s why we act with urgency and with the patient in mind.
Basic Discovery Biology
Pure tauopathies (e.g., PSP) are diseases where abnormal tau appears to be the primary pathology, while in other tauopathies (e.g., Alzheimer’s), there may be other proteins that are aggregating in addition to tau. As part of normal function, proteins in the body fold into different shapes to perform specific functions. When these proteins are no longer needed, they are broken down and recycled by the cell. In many neurodegenerative diseases, mutations and other cellular events alter the normal folding process, and the misfolded proteins begin to accumulate.
The accumulation of tau is thought to disrupt normal cellular function and lead to the death of neurons. Due to its misfolded state being a consistent component of so many incurable neurodegenerative diseases, studying and potentially targeting tau dysfunction is critical for the development of new treatments in this field.
Progressive Supranuclear Palsy is a relatively rare disease, but it is no longer being overlooked by the pharmaceutical industry. The FDA’s orphan drug program helps to streamline the drug development process, which improves potential financial returns. And because it is a pure tauopathy, many scientists believe finding treatments for PSP may be an important step to curing a wide range of other neurodegenerative diseases.
Mechanisms of Tauopathies
To find better treatments, researchers need to better understand the diseases they are working to treat. Our funded researchers attempt to uncover the biological mechanisms that initiate neurodegenerative disease and identify pathways that could be targeted to prevent disease. This area of research covers the mechanisms behind tau protein production as well as tau propagation (i.e., how the toxic protein spreads from cell to cell along specific networks). We also have a strong research focus on the mechanisms that naturally clear tau, and how we might develop treatments to speed up the clearance of these toxic proteins or even prevent accumulation. A necessary component of studying these diseases in the lab is the development and use of relevant models that accurately depict the disease as it develops in humans. Researchers use these model systems to test potential therapies, look for molecular changes at different stages, and measure tau levels. These model systems allow for rapid hypothesis testing, thus making it possible to elucidate mechanisms of tauopathies like PSP that pave the way to effective treatments for patients.
Mechanism of Tau Normal Function v. Dysfunction
Tau Production (RNA Silencing) – These studies on the production of tau focus on lowering the overall levels of tau in the brain and spinal cord. A human clinical trial in Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) with an antisense oligonucleotide against another disease-causing gene, SOD1, has been completed and is the model for a similar trial in patients with tauopathies. The antisense oligonucleotide acts to decrease total tau production in the brain, thereby decreasing the amount of tau available to misfold.
Tau Propagation – Toxic tau aggregates may spread cell-to-cell along specific networks, in a prion-like fashion, leading to progressive brain dysfunction. Tau microdialysis, a new method to measure tau in the brain of active mice, has shown that neuronal communication rapidly increases tau in the space surrounding nerve cells in the brain. Investigators are using genome-wide association studies (GWAS) of the spinal fluid to look for tau “seeding” and any new genetic risk factors.
Tau Clearance (Autophagy & Proteasome) – These studies focus on removing toxic forms of tau from the brain by using the cell’s normal cleaning process (via autophagy, or the proteasome). If the process of tau is unable to remove toxic tau (or does it too slowly), abnormal concentrations of tau appear, injuring or killing the neuron. We have identified targets in the autophagy and proteasome pathways as potential drug targets to speed up the rate of tau clearance from cells. Various “molecular chaperones” have been identified that play an important role in escorting tau to its disposal systems.
Models and Technology
Technology and Model Generation
We enable our scientists to build models and technology that benefit researchers and are shared with the entire field.Amy Rommel, PhD Scientific Program Director
Animal Models – Animal models of tauopathies allow us to study the impact of turning on and off different parts of the cellular pathway, seeing which steps play the most significant roles in disease. We also use model systems to test potential therapies, look for molecular changes at different stages, and measure tau levels. These model systems allow for rapid hypothesis testing around disease mechanisms. Complementary models in the same animal allow us to test the difference between naturally occurring normal (wild type) variations and disease-causing genetic variations.
Stem Cell Models – Patient-specific induced pluripotent stem cell (iPSC) models allow us to replicate a specific patient’s disease in cells in a petri dish, which allows us to study the molecular changes and processes that occur, as well as quickly and safely test potential drug treatments. iPSCs created in the Tau Consortium carry several rare variants, including A152T, of the tau gene. Studying these cells with mass spectrometry allows the investigator to determine how much tau is produced and in what form. These cells can also be compared to other stem cells from someone with the same variant but no disease. The difference between the two people can illuminate any modifier effects of other genes or states (e.g., methylation, phosphorylation). iPSC models have already shown that A152T variation increased tau fragmentation and phosphorylation, both toxic, while correcting the mutation removes the tauopathy.
Drug Discovery and Translation
The Mission of the Tau Consortium is to accelerate the development of new treatments for tauopathies, such as Progressive Supranuclear Palsy, Frontotemporal Dementias, Alzheimer’s Disease, and other neurodegenerative diseases associated with neuropathological dysfunction of the tau protein. Pharmacological interventions that rescue pathological tau dysfunction, such as targeting aberrant tau hyperphosphorylation, modulating proteostasis mechanisms to remove abnormal forms of tau protein and modulating tau protein translation, hold promise as disease modifying therapies for tauopathies. Optimization of drug properties for brain penetration, regardless of the therapeutic modality (i.e. small molecules, antisense oligonucleotides (ASOs), proteolysis targeting chimera (PROTACs), antibodies, etc.) is crucial to attain pharmacological modulation of tau in the brain. Click here to learn more.
Genetic Markers of Disease and Clinical Response
Genomics – Whole-genome sequencing of large numbers of patients with progressive supranuclear palsy (PSP), A152T carriers worldwide, and healthy controls allows us to search for concurrent gene variations that either directly cause disease or impact the risk for developing PSP. Multidimensional analyses of genetic data allow us to identify genetic and epigenetic changes (e.g., methylation, phosphorylation) that may affect the risk for FTD spectrum disease.
Clinical & Biomarkers – As we prepare for clinical trials of potential therapies, we need to have accurate diagnoses to make sure the right people enter the clinical trials and that we have accurate measures of disease progression (e.g., protein levels in the blood or spinal fluid, imaging, pathogenic aggregates in cell culture medium). New techniques for measuring the health of specific networks of neurons in the brain have provided new insights to groups of patients. Now we want to know if the imaging can show the same changes occur in an individual as the disease progresses. Pathological studies of the brains of individuals carrying the A152T gene variation will allow us to determine how the genetic variation influences disease susceptibility. A clinical trial of a compound that improves microtubule function (important for cell structure), decreases abnormal tau, and improves thinking and movement is in the pipeline.
Other Clinical Programs
Progressive Supranuclear Palsy (PSP) Study – will, through interviews with patients and caregivers, learn more about the experience of people who have PSP and publish the information so more people can understand what it is like to live with PSP.
Learn more here: PSP Study FAQ
Through our partnerships we currently have the following open grant programs:
Tools and Resources
Our organization continues to seek out and create resources that could benefit the scientific, clinical and patient community. If you have a resource we should consider adding, be sure to contact us so we can learn more.
History of Tauopathy Research