Personalized First-choice Antidepressant Selection Technology.

Funding Type: 
Early Translational III
Grant Number: 
TR3-05669
ICOC Funds Committed: 
$0
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 
The lack of any biological or genetic predictors of clinical utility of specific medication for Major Depressive Disorder (MDD) results in random first choice and costly systematic follow-up assessment. Given the lifetime prevalence in the US estimated at 17% this empirical approach translates into millions of people going through months of ineffective medication increasing the morbidity and the cost of treatment (in 2000 the burden of depression in US was ~$83 billion). Here we propose a reliable in vitro test to predict the best existing drug for the new patients with MDD. Recent genetic studies suggested that genetic determinants are responsible for variable response to antidepressant. Therefore we put forward an in vitro assay based on the patient-derived neurons to measure and classify the variable response to antidepressant. We combined a state of the art techniques and entirely novel computational algorithms to build a reliable in vitro diagnostic platform to predict the best 1st choice antidepressant for each patient with MDD. In the future, this approach could be adapted to other psychiatric disorders.
Statement of Benefit to California: 
The lack of any biological or genetic predictors of clinical utility of specific medication for Major Depressive Disorder (MDD) results in random first choice and costly systematic follow-up assessment. Here we propose a reliable in vitro test/diagnosis methodology to predict the best existing drug for the new patients with MDD. An effective, straightforward, and understandable way to describe the benefits to the citizens of the State of California that will flow from the stem cell research we propose to conduct is to couch it in the familiar business concept of “Return on Investment”. The novel therapies and reconstructions that will be developed and accomplished as a result of our research program and the many related programs that will follow will provide direct benefits to the health of California citizens. In addition, this program and its many complementary programs will generate potentially very large, tangible monetary benefits to the citizens of California. These financial benefits will derive directly from two sources. The first source will be the sale and licensing of the intellectual property rights that will accrue to the state and its citizens from this and the many other stem cell research programs that will be financed by the CIRM. The second source will be the many different kinds of tax revenues that will be generated from the increased bio-science and bio-manufacturing businesses that will be attracted to California by the success of the CIRM.
Progress Report: 
  • Introduction: Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective; a drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. This is the overall goal of this application.
  • Year One Progress: Using a novel drug discovery paradigm, we have made a very potent drug called J147 that is exceptionally effective in rodent models of AD and also stimulates neurogenesis in both young and very old mice. Very few, if any, drugs or drug candidates are both neuroprotective and neurogenic, particularly in old animals. In the first year of this application we harnessed the power of hESCs and medicinal chemistry to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. Using iterative chemistry, we synthesized over 200 new compounds, tested them for neurogenic properties in ES-derived neural precursor cells, assayed their ability to protect from the amyloid toxicity associated with AD, and determined their metabolic stability. All of the year one milestones we met and we now have the required minimum of six compounds to move into year two studies. In addition, we have made a good start on the work for year two in that some pharmacokinetics and safety studies has been completed.
  • This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.
  • Introduction: Over 6 million people in the US suffer from Alzheimer’s disease (AD). There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective; a drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human embryonic stem cells (hESCs) as a screen to identify neurogenic compounds, we have shown that it is now be possible to identify and tailor drugs for therapeutic use in AD. This was the overall goal of this application, and to date we have made outstanding progress, making a drug that is both neurogenic for human cells and has therapeutic efficacy in a rigorous mouse model of AD.
  • Year 2 Progress: Using a novel drug discovery paradigm based upon human stem cell derived nerve precursor cells, we have made a very potent drug called CAD-31. CAD-31 potently stimulates neurogenesis in human cells in culture and in mice, and prevents nerve cell death in cell culture models of toxicities associated with old age and AD. Very few, if any, drugs or drug candidates are both neuroprotective and neurogenic, particularly in animals. In the first year of this project, we harnessed the power of hESCs and medicinal chemistry to develop CAD-31. All of the Year 1 milestones were met. In Year 2 we completed all of the required pharmacokinetics and safety studies on the six best compounds synthesized in Year 1. Of those six, one compound, CAD-31, was the best in terms of medicinal chemical, pharmacokinetic, neuroprotective and neurogenic properties. This compound underwent extensive testing for safety and passed with flying colors. It was then put into an AD mouse model where it stimulated neurogenesis, prevented behavioral deficits and some of the disease pathology. All Year 2 milestones were completed. In Year 3 of the project we will determine if CAD-31 is able to reverse AD symptoms in old AD mice that already have the disease. This is the most clinically relevant model of AD since therapies can only be initiated once the disease is identified.
  • This work has produced a novel AD drug candidate that is developed based upon a set of assays never before used by pharmaceutical companies. It presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure. This work could lead to a paradigm shift in drug discovery for the treatment of neurodegenerative disease.

© 2013 California Institute for Regenerative Medicine