Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders

Discovery of therapeutics for Huntington’s Disease

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10182
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 399 800
Disease Focus: 
Huntington's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

The objective of the proposed research is to perform 3 independent hESC-based screens to identify drug candidates for Huntington’s Disease.

Impact

There are currently no effective treatments for HD. Combination of human isogenic HD-mutants, novel tools and technology will provide therapeutic solutions for this neurodegenerative orphan disease.

Major Proposed Activities

  • Screening of 2,000 natural compounds for hits that can rescue the HD germ layer phenotypic signature.
  • Screening of 2,000 natural compounds for hits that can rescue the HD early neuronal phenotypic signature.
  • Screening of 2,000 natural compounds for hits that can rescue the HD 'giant multinucleated neurons' phenotypic signature.
  • In vitro estimation of the potency and toxicity of the top 10 candidate compounds.
  • In vivo pharmacokinetics studies of the top 5 candidate compounds.
  • In vivo validation of candidate compounds in an HD mouse model.
Statement of Benefit to California: 

There are two main benefits for California: First, we will introduce a technology, which does not yet exist outside of my laboratory. This complements the mission of CIRM. Because our platform has a wider application than just modeling HD phenotypes, we anticipate the creation of new industries using these methods. Secondly, an estimated 40,000 Californians struggle with this incurable disease. Any improvement to their conditions will be of tremendous value for them, and their loved ones.

A tool for rapid development of clinical-grade protocols for dopaminergic neuronal differentiation of Parkinson’s Disease patient-derived iPSCs

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10067
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$677 160
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Develop a tool that facilitates rapid, cost effective development of optimized GMP-grade hPSC differentiation into functional DA neurons and apply this device to a cohort of PD patient-derived iPSCs.

Impact

Creating GMP-grade, functionally consistent phenotypes for DA neurons from each patient will significantly increase the likelihood of stem cell-derived DA neuron-based therapy for PD sufferers.

Major Proposed Activities

  • Develop a microfluidic device platform based on Scaled Biolabs methodology and approach that enables high-throughput optimization of a multistage, multifactor differentiation protocol.
  • Validate these new tools with the gold standard WA09 hESC line and the current best performing patient iPSC line using our research-grade DA neuronal differentiation protocol.
  • Transition research-grade protocol to GMP-grade protocol with gold standard WA09 hESC line and the current best performing patient iPSC line
  • Implement the tool to achieve optimized GMP-grade differentiation conditions for the generation of phenotypically and functionally equivalent DA neurons from eight PD patient iPSC lines.
  • Translate optimized GMP-grade differentiation conditions for each cell line to larger scale tissue culture plate/flask-based cultures and characterize using genomic analysis and electrophysiology.
Statement of Benefit to California: 

Thousands of Californians suffer from the degenerative effects of Parkinson's disease, a disease for which there is no cure. Our study seeks to develop a tool to accelerate the clinical assessment of a possible solution for PD sufferers, the production of neurons that can be used treat PD patients with cells derived from their own stem cells. The same approach may be applied to other diseases, such as diabetes and heart disease, to the benefit of many of the citizens of California.

A treatment for Zika virus infection and neuroprotection efficacy

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09649
Investigator: 
ICOC Funds Committed: 
$2 117 880
Disease Focus: 
Infectious Disease
Neurological Disorders
Zika virus
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

We propose to determine the impact of the Zika virus during human neurodevelopment and to test a FDA-approved therapeutic candidate to treat Zika infection.

Impact

A drug to treat/cure Zika infection and for neuroprotection.

Major Proposed Activities

  • To determine the molecular and cellular alterations caused by the Zika virus in the human developing brain and to validate a potential treatment for Zika infection.
  • To re-purpose a therapeutic drug to treat Zika infection and for neuroprotection using in vivo models.
  • To prepare and organize a clinical trial for Zika infection in a target population using a repurposed FDA-approved anti-viral drug.
Statement of Benefit to California: 

The recent outbreak of Zika virus prompted the WHO to declare a public health emergency of international concern due to the link between infected pregnant women and microcephalic babies. The virus is spreading quickly and cases of Zika was already reported in California. This proposal will test a FDA-approved drug repurposed to neutralize the virus deleterious consequences in human brain cells. The experiments are designed to learn about the long-term consequences of the virus infection.

CRISPR/dCas9 mutant targeting SNCA promoter for downregulation of alpha-synuclein expression as a novel therapeutic approach for Parkinson’s disease

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09610
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 931 589
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Discovery of a novel therapeutic candidate for Parkinson’s disease which modifies gene expression using human stem cell-derived neurons to halt the neurodegenerative disease process.

Impact

Stopping the neurodegenerative process of Parkinson’s disease is a critical unmet medical need. Our approach is based on novel gene engineering technology that modifies expression of key target genes.

Major Proposed Activities

  • Identification and engineering of therapeutic candidates that downregulate expression of test gene in human stem cell-derived neuronal precursor cells.
  • Measurement of target gene downregulation in human stem cell-derived neuronal precursor cells and neurons with assessment of phenotype rescue.
  • Testing downregulation of target gene using relevant pre-clinical model containing endogenous gene regulatory regions.
  • Development of a Target Product Profile for advancement of the therapeutic candidate for CIRM partnering opportunity: translational research projects (TRAN).
  • Preparation for stage appropriate regulatory meetings for subsequent CIRM pre-clinical application. Develop regulatory strategy with CIRM Clinical Advisory Panel.
Statement of Benefit to California: 

Estimated 36,000-60,000 people in the State of California are affected with Parkinson’s disease which is a neurodegenerative disease that causes a high degree of disability and financial burden for our health care system. This collaborative project will provide substantial benefits and values to the state of California and its citizens by developing new therapeutic candidates for the treatment of Parkinson’s disease enabled by stem cell technologies and gene therapy.

hNSC-mediated delivery of ApiCCT1 as a candidate therapeutic for Huntington’s disease

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09569
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 787 543
Disease Focus: 
Huntington's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

The therapeutic candidate is a human Neural Stem Cell that secretes a protein, ApiCCT1, that aids in the prevention of disease phenotypes, for application in treatment of Huntington's disease (HD).

Impact

No treatment currently exists that can slow or prevent the unrelenting progression of Huntington’s disease, a devastating brain disease, therefore a completely unmet medical need exists.

Major Proposed Activities

  • Generation of a Good Manufacturing Practice (GMP) grade lentivirus to deliver ApiCCT1 to stem cells.
  • Generation of a quality controlled bank of GMP grade human Neural Stem cells (hNSCs) that express a secreted form of the molecular therapeutic (ApiCCT1) and characterization of ApiCCT1 expression.
  • Test delivery of ApiCCT1 expressing hNSCs to the striatum of Huntington's disease mouse model and determine whether this stem cell candidate can provide neuroprotection.
  • Manufacture of a GMP grade human embryonic stem cell (hESC) bank with ApiCCT1 integrated into the genome at a safe harbor site. Cells will be characterized and expanded.
  • Test delivery of hESC-derived hNSCs expressing secreted ApiCCT1 to the striatum of rapidly progressing HD mice and determine whether this stem cell candidate can provide neuroprotection.
  • Test delivery of hESC-derived hNSCs expressing secreted ApiCCT1 to the striatum of slower progressing HD mice and determine whether this stem cell candidate can provide neuroprotection.
Statement of Benefit to California: 

The disability, loss of personal freedom and earning potential, and costly institutional care of Huntington's disease (HD) is devastating. Developing a candidate therapeutic for HD will benefit the State through new technologies and intellectual property resulting in possible job creation and revenues in new companies, in addition to the potential for substantial reductions in individual suffering, medical and care-giving costs.

Autologous cell therapy for Parkinson’s disease using iPSC-derived DA neurons

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09073
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 354 226
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Research Objective

Autologous human dopaminergic neurons derived from patient-specific induced pluripotent stem cells

Impact

Parkinson's disease

Major Proposed Activities

  • Characterize differentiation from all 10 patient cell lines
  • Characterize functionality of patient neurons matured in vitro
  • Immunogenicity assessment
  • Cryopreservation feasibility testing
  • Investigate dose response in vivo
  • Detect dopamine release in vivo
Statement of Benefit to California: 

Thousands of Californians suffer from the degenerative effects of Parkinson's disease, a disease for which there is no cure. There is hope, however, that stem cells could provide the key to providing long-term relief. Our study seeks to treat patients with cells derived from their own stem cells, a process which could be applied to other diseases such as diabetes and heart disease and could potentially be used to the benefit of many of the citizens of California.

MSC delivery of an artificial transcription factor to the brain as a treatment for Angelman Syndrome

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-09032
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 087 572
Disease Focus: 
Autism
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Research Objective

Mesenchymal stem cells will be used to deliver an artificial transcription factor to neurons in the brain to treat a genetic disease.

Impact

It could lead directly to a treatment for Angelman Syndrome, but the approach could be used to alter gene expression in almost any brain disorder. It could overcome the brain delivery bottleneck.

Major Proposed Activities

  • Prepare the MSC delivery system (month 1 – month 6)
  • Rescue and analysis of on-target molecular phenotypes in “YFP-mice” (month 6 – month12)
  • Rescue and analysis of the behavioral phenotypes in “AS-mice” (month 12 – month 24)
  • Analysis of the off-target molecular phenotypes in “YFP-mice” (month 18 – month 24)
Statement of Benefit to California: 

Brain disorders are responsible for more years lost to disability than any other medical condition. For example, autism spectrum disorder (ASD) in the US is estimated to affect 1 in 68 children. The need for effective treatments can not be understated. Molecular therapeutics pioneered to understand and treat rare single-gene disorders such as Angelman Syndrome will provide the tools and methods that will ultimately be used to address the more common complex brain disorders.

Scalable, Defined Production of Oligodendrocyte Precursor Cells to Treat Neural Disease and Injury

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-08982
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 848 462
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Research Objective

The goal of this proposal is to develop an optimized, scalable process to manufacture high quality oligodendrocyte precursor cells (OPCs) from human pluripotent stem cells for treating human disease.

Impact

OPCs have therapeutic potential for spinal cord injury, restoration of cognitive function after cancer radiation therapy, inherited demyelinating disease, and potentially multiple sclerosis.

Major Proposed Activities

  • To engineer human embryonic stem cell lines with fluorescent protein reporters to quantify differentiation into oligodendrocyte precursor cells (OPCs).
  • To use a high throughput system to screen thousands of cell culture conditions and thereby optimize a chemically-defined three-dimensional culture for differentiation into OPCs.
  • To validate the capacity of the differentiated oligodendrocyte precursor cells to remyelinate neurons in culture and in the nervous system.
  • To scale up this cell manufacturing system in a bioreactor for future translation towards preclinical and clinical studies.
Statement of Benefit to California: 

This proposal will accelerate the development of a stem cell therapy to treat patients with demyelinating conditions, a serious unmet medical need. Also, the PI has a strong record of translating research towards clinical development within industry, particularly within California. Finally, this project will expose young scientists within a large stem cell center to highly interdisciplinary training at the interface of science and engineering, thereby enhancing our California workforce.

A new phenotypic screening platform that identifies biologically-relevant targets and lead compounds for the treatment of Parkinson’s disease

Grant Type: 
Inception - Discovery Stage Research Projects
Grant Number: 
DISC1-10674
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$150 000
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

Demonstrate that our HitFinder™ library can be screened for phenotypic changes in A53T-IPSC-derived dopaminergic neurons and use a secondary handle to identify the targets responsible.

Impact

This technology combines phenotypic screening and target-ID eliminating the need to bias assays and/or screening libraries permitting application directly in iPSC-derived cells.

Major Proposed Activities

  • Prepare screening library including purchase of compounds and addition of chemical handles for target identification
  • Screen library for phenotypic changes in iPSC-derived engineered A53T-synuclein dopaminergic neurons: single point followed by dose-response
  • Large-scale preparation of compound-target complex in A53T IPSC-DA-neurons under conditions of phenotypic assay and confirm phenotypic change for target-ID.
  • Process scaled-up A53T-DA neurons and attach an affinity tag to the compound-target complex. Identify number of targets that reacted with the ligand (selectivity) and the identity of these targets.
Statement of Benefit to California: 

This technology has the potential for broad impact on patients. Immediately, compounds and targets identified from this screen can progress into a drug discovery program to identify new treatments for Parkinson’s disease (PD). PD is estimated to affect 36-60,000 Californians. Application of iPSC-derived neurons permits screening in patient-derived cells to determine if therapeutics/targets are relevant in all forms of PD (genetic and sporadic) and eventually expand to other diseases.

An exosome-based translational strategy to mitigate Alzheimer’s disease neuropathology

Grant Type: 
Inception - Discovery Stage Research Projects
Grant Number: 
DISC1-10079
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$179 911
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

These studies will determine whether stem cell derived exosomes (nano-scale vesicles) can be used to treat the symptoms of Alzheimer’s disease (AD).

Impact

Our stem cell-derived exosome therapy will provide a viable approach to ameliorate the relentless progression of AD that severely impacts quality of life for millions of patients and their families.

Major Proposed Activities

  • Evaluate whether exosome therapy can reduce the symptoms of early stage AD including anxiety, depression, and learning and memory.
  • Evaluate whether exosome therapy can reduce the symptoms of advanced stage AD including anxiety, depression, and learning and memory.
  • Determine whether exosome therapy can slow the appearance of AD related changes typically observed in the early stage AD brain.
  • Determine whether exosome therapy can reduce the appearance of AD related changes typically observed in the advanced stage AD brain.
Statement of Benefit to California: 

In the US, California has the most cases of AD, a burden on patients, their families, and the health care system. As such, AD is an unmet medical need that requires new therapies to improve disease management. This project tests a transformational idea—human stem cell derived exosome therapy. These studies will identify a novel stem cell-based strategy and a viable approach to impede the progression of AD and it’s symptoms that severely impact quality of life for patients and their families.

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