Developing new therapies for neurodegenerative diseases

Current projects in our lab center on the following 4 areas:

  1. iPSC modeling of neurodegenerative diseases and biomarker development: We used human iPSC from patients and healthy controls and differentiate them into neurons, microglia and other cell types relevant to CNS disease. We aim to build better models of human disease (including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)) that replicate the pathobiology of human patients and better predict patient response to the therapies we are developing. We build biomarker assays in human cells and tissues that will facilitate future clinical trials.

  2. CRISPR gene editing of mutations that cause neurodegenerative diseases. Our group is currently focused on correcting single gene mutations that cause AD, FTD, ALS and PD using novel CRISPR approaches. We are building the tools necessary to advance these discoveries to clinical trials.

  3. Delivery of CRISPR technology to human CNS cell types: One of the major barriers to utilizing CRISPR as a therapy for neurologic disease is delivery of CRISPR technology to targeted cells and tissues. This challenge is amplified by biological sequestration of the CNS (such as through the blood brain barrier) – the brain actively defends against bacterial invaders! Combining clinical expertise and basic biology, we have developed screening platforms to test CRISPR delivery technologies in relevant human cell types, animal models and human tissue
  4. Bioinformatic tools to faciliate gene therapy and future clinical trials.

Reversal of C9orf72 mutation-induced transcriptional dysregulation and pathology in cultured human neurons by allele-specific excision.


Novel avenues of tau research.

Check out a look at novel research avenues from the Tau2022 conference. 

Validated assays for the quantification of C9orf72 human pathology.

We aim to improve reproducibility in the C9 field and for future clinical trials using well-validated tools. He we validate human-specific tools to measure the C9orf72 repeat expansion and its products across DNA, RNA and C9 and DPR proteins. 

Building CRISPR gene therapies for the central nervous system: A review.

Our perspective on where CNS CRISPR field is currently and what is required to move novel therapies to clinic. 

Functional characterization of Alzheimer's disease genetic variants in microglia.

Congrats to Xiaoyu and The Shen lab for this fresh and insightful look at AD GWAS hits in human microglia. 

Two therapeutic CRISPR/Cas9 gene editing approaches revert FTD/ALS cellular pathology caused by a C9orf72 repeat expansion mutation in patient derived cells

We compared three editing approaches in a C9-patient iPSC line and found that we must remove the repeat expansion to revert pathology. Preprint now available on BioRxiv.