Transplantation of genetically corrected iPSC-microglia for the treatment of Sanfilippo Syndrome (MPSIIIA)

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Grant Award Details

Grant Type:

Quest – Discovery Stage Research Projects

Grant Number:

DISC2-13077

Investigator(s):

Name:

Dr. Mathew Mark Blurton-Jones

Institution:

University of California, Irvine

Type:

Disease Focus:

Metabolic Disorders, Neurological Disorders, Sanfilippo Syndrome/MPS III

Human Stem Cell Use:

iPS Cell

Award Value:

$1,083,379

Status:

Closed

Progress Reports

Reporting Period:

Year 2

Sanfilippo syndrome, also known as MPSIIIA, is a pediatric neurodegenerative disease caused by mutations in the gene SGSH. SGSH is used by cells to degrade glycosaminoglycans (GAGs) and therefore patients with MPSIIIA accumulate GAGs which in turn leads to progressive neurodegeneration. Microglia, the primary immune cell of the brain, produce the highest amounts of SGSH, but this production is also disrupted in MPSIIIA. We therefore hypothesized that delivery of healthy stem cell-derived microglia could restore SGSH gene expression, promoting the degradation of GAGs, and slowing disease progression. This CIRM Discovery grant sought to test of this hypothesis.

We began by asking whether CRISPR gene editing could be used to ‘correct’ SGSH mutations within patient-derived induced pluripotent stem cells (iPSCs), allowing one to develop an ‘autologous’ cell therapy. We successfully developed three gene correction approaches and confirmed that corrected iPSCs could be differentiated into highly pure human microglia that express healthy levels of SGSH. We then pursued transplantation studies to deliver microglia into the brains of a specialized mouse model of MPSIIIA. Thus far, our studies have revealed several promising results. MPSIIIA mice that receive control saline injections continue to develop behavioral impairments and MPSIIIA-associated brain pathologies. In contrast, mice that received SGSH-producing iPSC-microglia exhibited a significant reduction in pathology including decreased GAG accumulation, reductions in enlarged lysosomes, decreased inflammation, and a partial restoration of disease-associated changes in gene expression. As these experiments continue, we will further determine the impact of microglial transplantation on behavior and determine the optimal gene-editing approach. Overall, we are greatly encouraged by our results and plan to apply for additional CIRM Translational Grant support to further develop this promising new therapeutic approach.

Grant Application Details

Application Title:

Transplantation of genetically corrected iPSC-microglia for the treatment of Sanfilippo Syndrome (MPSIIIA)

Public Abstract:

Research Objective

This research will discover whether transplantation of stem cell-derived microglia can be used to treat Sanfilippo syndrome, a devastating and currently untreatable childhood neurological disease.

Impact

If successful, this research will identify a promising new therapeutic approach for Sanfilippo Syndrome and provide the first evidence that stem cell derived microglia could be used therapeutically.

Major Proposed Activities

We will use CRISPR technology to correct disease-associated mutations in the SGSG gene in human stem cell lines that we have generated from patients with Sanfilippo Syndrome (MPSIIIA).
Patient-derived and CRISPR corrected stem cells will be differentiated into microglia, an immune cell type that is dysfunctional in MPSIIIA, and then transplanted into a mouse model of this disease.
Three months after transplantation we will examine MPSIIIA-associated neuropathologies to determine whether transplantation of genetically-corrected microglia has reduced disease pathology.
Microglia that are engineered to produce and secrete higher levels of the missing SGSH enzyme may provide additional long term benefits. We will therefore test the efficacy of this additional approach
6-months after transplantation we will examine neuropathologies to determine whether SGSH secreting microglia improve cognitive function and provide additional long-term benefits in MPSIIIA mice.
Analysis of biomarkers, neuropathology, cognitive function, and RNA sequencing of brain cells will be used to determine the optimal approach to reduce MPSIIIA cognitive deficits and neuropathology

Statement of Benefit to California:

Sanfilippo syndrome (MPSIIIA) is a devastating pediatric neurological disease that effects families of all ethnicities and race including many Californians. Sadly, currently approved therapies provide little benefit. Our research aims to develop a new stem cell-based therapy for MPSIIIA that uses microglia, the immune cell of the brain. If successful, this new approach could also potentially be developed to treat many other neurological diseases that are highly prevalent in California.