The Drug Discovery Lab approach is based on the hypothesis that AD results from imbalances in an extensive array of networks. Therefore, rather than just identifying a single new drug, we believe a more comprehensive Systems Therapeutic Approach is needed that includes both pharmacological components (single drug or multi-drug combination) and nonpharmacological components to address the various network imbalances in AD.
Our aim is to identify and develop small molecule compounds as new therapeutics for AD. Our small molecule candidates may be NCEs (New Chemical Entities) or repurposed compounds.
- Compounds that have never been tested before
- One of our NCEs is currently undergoing pre-clinical trials in preparation for clinical testing
- Repurposed compounds are drugs already in use for other conditions.
- They are known to be safe and have well-characterized pharmacological effects
- The allow faster clinical development
- We are testing a repurposed compound in a clinical trial for Mild Cognitive Impairment (MCI), and hope to move toward a clinical trial for AD
F03 for MCI
- F03 is a repurposed drug originally approved for post-operative and chemotherapy-induced nausea and vomiting (PONV).
- It increases the sAPPα to Aβ ratio and is multifunctional, interacting with two brain cell receptor pathways.
- It is very safe, and enters the brain (passes the blood-brain barrier).
- Improved AD-like deficits in a mouse model of AD to a greater degree than currently approved drugs.
- It is currently in a clinical trial for the treatment of MCI in Australia.
Ongoing Drug Development
The Drug Discovery lab at UCLA is part of the Mary S. Easton Center for Alzheimer's Disease Research and in the Department of Neurology. It is run by experienced scientists, has cutting edge technology, and benefits from collaborations at UCLA and beyond with some of the most pre-eminent research groups in the world.
One of our unique capabilities is compound synthesis. Our ability to rapidly and cleanly synthesize the many compounds we design means we can test and improve these compounds at a rapid pace. We pride ourselves on our use of "Green Chemistry" to make our compounds (3).
The Drug Discovery Lab is first and foremost focused on finding new therapeutics for AD. The field of AD has rapidly expanded in recent years, and a number of physiological systems have been identified to be dysfunctional in AD. We attempt to identify potential drugs that might address imbalances in these systems.
Amyloid precursor protein (APP) is cleaved by the enzymes BACE and γ-secretase, which leads to the production of Aβ, which aggregates and damages neurons and is thus an important target in AD. Anti-Aβ therapeutics target increase clearance of Aβ from the brain or decrease the production of Aβ. Once area of focus in the DDL is decreasing Aβ production by inhibiting the enzyme BACE.
- Our goal is to find compounds that only affect the processing of APP by BACE without affecting other molecules processed by BACE.
- We screen compound libraries to identify compounds that decrease BACE activity.
- We improve compounds by making chemical variations (analogs).
In addition to being cleaved by BACE and γ-secretase to produce Aβ, APP can be processed by an enzyme called ADAM10, which leads to the production of a protein called sAPPα. Most APP is in fact processed by ADAM10. sAPPα is neurotrophic, reduces the production of Aβ, and is needed for the formation of connections (synapses) between neurons.
- Our goal is to find compounds that increase the amount of sAPPα produced in the brain.
- We have already identified two compounds that increase sAPPα: F03 and an NCE.
- We hope to find many more by screening the 200,000-compound small molecule library at UCLA.
Sirtuin 1 is a major longevity determinant that is found in the brain and body, and affects healthy aging.
- SirT1 is found to be lower in the blood serum of AD patients.
- We want to find compounds that normalize SirT1 levels, especially in more vulnerable individuals with the E4 form of the apolipoprotein gene.
Decreasing Stress Effects
Chronic stress is associated with a higher risk for AD by increasing a chemical modification (phosphorylation) of a protein called tau.
- Chronic stress is associated with a higher risk for AD.
- It increases ptau and neurofibrillary tangles, hallmarks of AD.
- We have a therapeutic that targets stress pathways and improves cognition in an AD mouse model
- We are improving this compound and will continue pre-clinical testing
Modifying the Inflammatory Response
Inflammation may occur in response to infection, injury, or Aβ plaques in the brain.
- Chronic inflammation is associated with a higher risk for AD.
- We have two "series" of compounds — each targeting a different pathway — in the early discovery stages targeting inflammatory pathways.
Inhibiting APP-C31 Production
In addition to BACE/γ secretase and ADAM10 cleavage, APP may be cleaved by an enzyme called a caspase to form a toxic molecule called APP-C31.
- C31 formation is increased during early AD and is associated with inflammation.
- We have identified several small molecules that inhibit the formation of C31, which we will be testing in animal models of AD.
Getting Into the Brain
It is difficult for most compounds to enter the brain because of the blood brain barrier (BBB). The BBB is created by cells surrounding the blood vessels in the brain and proteins specialized to keep toxic substances out of the vulnerable brain.
- We use pharmacokinetic studies to determine if a compound gets into the brain.
- For compounds that are not brain-penetrant, we have created using microfluidics small deformable nanovesicles (DNV) that can encapsulate drugs and potentially be used to deliver small molecule drugs, protein therapeutics, antibody therapeutics, mRNA and other molecules across the BBB and into the brain.
Window Into the Brain: Exosomes
Exosomes are membranous particles that are secreted by cells and contain proteins cellular components that reflect the physiological state of the cell.
- They can be found in body fluids, such as blood, saliva, and cerebrospinal fluid.
- We have the ability to isolate exosomes that come specifically from the brain.
- We are actively pursuing the use of neuron-derived exosomes to determine the level of alertness and to gain information regarding disease state in neurodegenerative disorders.
- We also hope to develop methods to use exosomes to follow responses to drug treatment.
Clinical Trial in a Dish
This new cutting-edge method can be used to test the effects of therapeutics in differentiated cells derived from pluripotent stem cells originiating from patients with different disease characteristics and genetics.
- Skin cells from patients can be turned into stem cells and then into neurons.
- These stem-cell-derived neurons can then be treated with different therapeutic compounds to test whether cells from different patients respond differently to the same therapeutic.
- Different compounds can be compared for neurons from the same donor.
- We can then tailor clinical trials of these compounds to include only patients whose stem-cell-derived neurons were responsive to the therapeutic
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