Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-12130
Investigator: 
ICOC Funds Committed: 
$249 968
Disease Focus: 
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

We propose to investigate the transplantation of pluripotent stem cell derived microglia as a potential therapy for the devastating neurological disease; Adult-onset leukoencephalopathy (ALSP/HDLS).

Impact

The most immediately impacted condition will be ALSP. However, further examination of the safety of human microglial transplantation will have broad implications for many neurodegenerative disorders

Major Proposed Activities

  • We will differentiate the human embryonic stem cells line ESI-017 into micoglia, the primary immune cell of the brain.
  • We will assess the purity of stem cell derived microglia by examining multiple markers for microglia and stem cells. We aim to achieve greater than 99% purity.
  • We will utilize single cell RNA sequencing as a sensitive method to determine whether any contaminating pluripotent stem cells remain following microglial differentiation.
  • Using specialized mice that develop ALSP pathology and allow human cells to be transplanted, we will engraft human microglia into the brain.
  • We will allow mice to age for 3 months and then use a series of tests to examine the impact of micorglial transplantation on motor and cognitive function.
  • We will examine the impact of human microglial transplantation on ALSP-associated neuropathologies. We will then report our results and schedule a discussion with the FDA.
Statement of Benefit to California: 

Adult-onset leukoencephalopathy (ALSP) is a neurological disease that effects patients during the prime of their lives. Although rare, ALSP represents the clearest example of a ‘microgliopathy’, a disorder that affects microglia, the immune cell of the brain. As microglial dysfunction is implicated in virtually all neurological disorders, the examination of stem cell-derived microglia to treat ALSP could provide important insight into many of the neurological diseases that affect Californians.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-11165
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 553 923
Disease Focus: 
Dementia
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Research Objective

Develop stem cell-based therapy to treat dementia

Impact

There are no treatments for dementia. If successfully achieved, this study will lead to a cure of a familial
 form of dementia in the elderly population.

Major Proposed Activities

  • Develop a robust human stem cell-derived microglial platform for cell-based therapy
  • Determine short-term safety and efficacy of engrafted human microglia in wildtype mice
  • Determine short-term efficacy of engrafted human microglia in FTD mouse models
  • Determine long-term efficacy of engrafted human microglia in FTD mouse models
Statement of Benefit to California: 

The proposed research will benefit the State of California and its citizens because of the potential to cure 
a major form of dementia in the elderly population. With the fast aging population in California, more and
 more Californians are diagnosed with neurodegenerative dementias. 
There is an urgent need to develop a treatment or cure for these devastating conditions. Success of our 
study will address this urgent medical challenge of our modern society.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-11070
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 827 576
Disease Focus: 
Autism
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Research Objective

We will use human patient induced pluripotent stem cell (hiPSC)-based models to screen for a drug that activates a transcription factor critical to the treatment of Autism Spectrum Disorder (ASD).

Impact

Our goal is to develop a small molecule to treat Autism Spectrum Disorder (ASD), which currently affects 1/68 children born in the USA. Currently, there is no effective treatment.

Major Proposed Activities

  • Assay Development for Drug Screening: Generate and characterize "disease-in-a-dish" models using hiPSCs generated from MEF2C Haploinsufficiency Syndrome patients, a form of ASD (month 1 - month 6).
  • High-throughput Screening: Screen for hit-to-lead compounds that upregulate MEF2 activity by reporter-gene assay (month 3 - month 9).
  • Efficacy Evaluation of Hits: Evaluate candidate therapeutics using ASD patient hiPSC-derived neurons (month 10 - month 18)
  • Drug Optimization - 1) Perform additional SAR and optimization, and 2) Perform additional CNS permeability studies and initial PK (month 18 - month 24).
  • Develop a Target Product Profile (month 21 - month 24). 1) Using the standard CIRM form, a TPP will be formulated for treatment of the MEF2C Haploinsufficiency Syndrome (MCHS) type of ASD.
  • NA
Statement of Benefit to California: 

Recent studies show that MEF2C activity not only affects MCHS but also other forms of ASD because MEF2C drives the activity of other ASD-related genes. Thus, while we are developing a treatment for the MCHS form of ASD, in fact MEF2 activator drugs may prove effective for a much large group of ASD patients. ASD is now reported to occur in 1 in every 68 births in both CA and the USA, so the benefit to the ASD community is potentially immense.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10753
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 575 613
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 

Research Objective

This project generates new cGMP compliant tissue educated human neural stem cell lines, paired with in vivo pre-clinical proof of concept testing, and development of a predictive in vitro profile.

Impact

Identification of new cell lines with in vivo efficacy testing to enable efficient translation to chronic cervical spinal cord injury, an area of significant unmet medical need.

Major Proposed Activities

  • Derivation of new human neural stem cell lines
  • In vitro characterization of human neural stem cell lines
  • Construction of an in vitro cell line profile that can discriminate in vivo efficacy potential
  • In vivo analysis of human neural stem cell line efficacy after transplantation into spinal cord injured mice
Statement of Benefit to California: 

The impact of this research includes generation of new CD133-enriched tissue-educated cGMP compliant human neural stem cell lines, which have demonstrated capacity for translation into the clinical for multiple neurological disorders, and development of a profile that can relate in vitro expression analyses from these cells under growth and differentiation conditions to in vivo efficacy. Both of these are critical steps for effective translation.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10714
Investigator: 
ICOC Funds Committed: 
$2 096 095
Disease Focus: 
Neurological Disorders
Stroke
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

Research Objective

This cell line will target recovery in ischemic white disease, a progressive dementing condition with no current therapy by developing a new stem line, iPS-glial enriched progenitors (iPS-GEPs).

Impact

This cell line will target tissue repair and recovery in ischemic white disease/vascular dementia, a chronically progressive and dementing condition with no current therapy.

Major Proposed Activities

  • Efficacy. 1) Determine most efficacious iPS-GEP line; 2) Test efficacy in chronic white matter stroke; 3) Test efficacy for transplant location; 4) Test dose response; 5) Test efficacy in aged mice
  • Mechanism of Action. 1) Determine cell intrinsic vs extrinsic effects; 2) Identify expression profile of iPS-GEPs during tissue repair; 3) Identify molecular systems that produce recovery of function
  • Assay Development.: 1) Qualify identity, purity, safety and stability assays for iPS-GEPs
  • Biomarker Development. 1) Develop structural MRI biomarker of iPS-GEP repair of damaged white matter; 2) Develop resting state MRI biomarker of enhanced brain connectivity
Statement of Benefit to California: 

Stroke is the leading cause of adult disability. White matter stroke occurs in the connecting areas of the brain. This entity is up to 30% of all stroke and the second leading cause of dementia. There is no therapy for this disease. White matter stroke damages the specialized cells that support brain connections, glial cells. The proposed studies develop a specifically tailored stem cell therapy for tissue repair in white matter stroke, an induced pluripotent glia cell.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10665
Investigator: 
ICOC Funds Committed: 
$2 100 581
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

We propose to utilize human neural stem cells to form neuronal relays across sites of severe SCI, restoring function across the site of spinal cord injury.

Impact

We will develop a specific type of neural stem cell that is best suited for repairing the injured spinal cord.

Major Proposed Activities

  • In Vitro Assessment of GMP-compatible H9-scNSC Batches.
  • In Vivo Assessment of GMP-compatible H9-scNSC Batches.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 1: T10 moderate contusion.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 2: T3 severe compression.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 1: C5 moderate contusion.
  • FDA Pre-pre IND Meeting.
Statement of Benefit to California: 

Spinal cord injury (SCI) affects approximately 300,000 people in the U.S., with more than 11,000 new injuries per year. This research plan will examine a novel therapeutic strategy for SCI. Neural stem cells will be generated from human embryonic stem cells and grafted into animal models of SCI. We predict neuronal relays will form across a SCI lesion site that will mediate behavioral recovery. These studies will form the basis for clinical translation for the treatment of spinal cord injury.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10525
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 616 536
Disease Focus: 
Epilepsy
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

A stem cell-derived nerve cell therapy to minimize seizures in people with epilepsy

Impact

Many people with epilepsy have uncontrolled seizures that can be life threatening and adversely impact quality of life and independence. A cell therapy could help those not responsive to drugs.

Major Proposed Activities

  • Transplant a nerve cell therapy made with clinically compatible methods into a mouse model of epilepsy to reduce seizures and understand how the cells function in the brain
  • Transplant a nerve cell therapy made with clinically compatible methods into a rat model of epilepsy to reduce seizures and understand how the cells function in the brain
  • Work to cryopreserve the nerve cells and see if they are the same in a dish before and after freezing
  • Transplant the cryopreserved nerve cells into the mouse brain to see if they are the same before and after freezing
  • Characterize different batches of the nerve cells to show they are the same and then compare with data from transplantation studies to see what cell characteristics are most important for activity
  • Prepare for a meeting with the FDA to present a well-informed development plan based on the data obtained in Activities 1-5
Statement of Benefit to California: 

Approximately 370,000 adults in California live with epilepsy. They have spontaneous seizures that are unpredictable, uncontrollable, and very disabling, impacting health and their degree of independence. One-third of people with epilepsy do not respond to anti-epileptic drugs and brain resection is their best treatment option. Better treatments for seizures could improve the quality of life for people living with the chronic disease and decrease the lost wages and productivity to California.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10195
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 671 213
Disease Focus: 
Neurological Disorders
Traumatic Brain Injury
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

We propose to discover the optimal human neural stem cell candidate for traumatic brain injury. 4 hNSC products (2 ES derived & 2 fetal) will be compared with TBI/vehicle controls, & then each other.

Impact

Traumatic brain injury (TBI) affects more Americans than brain, breast, colon, lung and prostate cancer combined ! There are no approved stem cell therapies for TBI, we hope to change that.

Major Proposed Activities

  • Obtain 2 GMP grade human ES cell lines.

    Obtain 2 GMP grade human ES cell lines.

  • Expand/sort ESCs to hNSC and produce sufficient quantities to transplant into 18-20 ATN rats at a dose of 500K per animal.
  • Test each ES derived hNSC line in an CCI animal model of TBI for efficacy on four different tasks, two for memory and two for emotional changes.
  • Obtain 2 GMP grade human fetal cell lines.
  • Expand fetal lines to hNSC and produce sufficient quantities to transplant into 18-20 ATN rats at a dose of 500K per animal.
  • Test each human fetal derived hNSC line in an CCI animal model of TBI for efficacy on four different tasks, two for memory and two for emotional changes.
Statement of Benefit to California: 

1.7 million American’s experience a Traumatic Brian Injury (TBI) leading to hospitalization (200,000 Californians), at a cost to society of $76.5 billion each year (~$9.3 billion to California). TBI can result in permanent cognitive and emotional deficits. Transplantation of human neural stem cells (hNSCs) could lead to improvements in learning & memory, or emotion that could significantly change a patient’s quality of life and have considerable economic impact to the people of California.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10188
Investigator: 
ICOC Funds Committed: 
$2 206 291
Disease Focus: 
Infectious Disease
Neurological Disorders
Zika virus
Human Stem Cell Use: 
Adult Stem Cell
iPS Cell
Public Abstract: 

Research Objective

Our objective is to utilize human iPSC-derived neural and ocular cells to identify growth attenuated and non-pathogenic Zika virus vaccine candidates that can prevent congenital ZIKV disease.

Impact

Currently, there are no therapies or vaccines available against ZIKV for human use. The human iPSC technology provides a unique opportunity to test the growth and virulence of vaccine candidates.

Major Proposed Activities

  • Generating recombinant Zika viral vaccine candidates by genetic engineering.
  • Assessing the growth and virulence of vaccine candidates in iPSC-derived neural and ocular cells.
  • Characterizing vaccine virus growth and immunogenicity after various routes of administration in adult mice.
  • Evaluating the safety of vaccine candidates in newborn mice.
  • Immunization of female mice to limit ZIKV induced congenital disease during pregnancy.
  • Assessing the vision and neuro-behavior of mice born to immunized mothers.
Statement of Benefit to California: 

In the past year, millions of people have been infected with Zika virus globally. Currently, the California Department of Public Health has reported 490 travel-associated ZIKV infections including 6 cases of sexual transmission and 82 infected pregnant women (4 live births with microcephaly and eye disease). Mosquitos carrying ZIKV have been reported in California, which increases the risk of local transmission. A ZIKV vaccine can greatly benefit the people in California and beyond.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10182
Investigator: 
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.

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