Project Details
Description
PROJECT SUMMARY/ABSTRACT
In this P01 proposal entitled “Pathophysiology of genetically defined dementia and
neurodegeneration: Defining therapeutic targets and pathways,” we seek to push forward the
development of precise medicines to treat debilitating diseases associated with C9ORF72 G4C2 repeat
expansions, the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral
sclerosis (ALS). Success in developing a treatment for c9FTD/ALS will require a well-orchestrated effort that
addresses multiple aspects of the drug discovery process. To improve the prognosis for patients suffering from
c9FTD/ALS, we thus propose to investigate pathomechanisms by which C9ORF72 G4C2 repeat expansions
cause disease, as well as develop bioactive small molecules and biomarkers. We have assembled a world-
class team combining expertise in chemistry, neurology, cell biology, disease modeling, and biomarker
development that has worked closely together and has all resources in place. Our significant progress to
elucidate how expanded G4C2 repeat RNA transcripts drive toxicity and how to abrogate aberrant features
associated with c9FTD/ALS has led to the discovery of: (i) novel pathomechanisms caused by the
accumulation of G4C2 repeat RNA or “c9RAN proteins” unconventionally translated from G4C2 repeat
RNA; (ii) the first small molecule known to influence c9FTD/ALS disease biology; and (iii) a first-in-
class biomarker to investigate new therapeutic strategies.
We now bring forward novel and innovative chemical approaches to develop and optimize chemical probes
to study and mitigate c9FTD/ALS disease mechanisms. We also present evidence that nucleocytoplasmic
transport defects may be a fundamental pathway of c9FTD/ALS pathogenesis amenable to therapy. Indeed,
we reported that disruption of the nuclear pore complex and nucleocytoplasmic transport is a primary cause of
neurodegeneration in Drosophila and patient-derived cell models of c9FTD/ALS. In addition, we have
established that poly(GP) c9RAN proteins are not only detectable in cerebrospinal fluid (CSF) from c9FTD/ALS
patients but also in peripheral blood lymphocytes. What is more, preliminary data suggest that CSF poly(GP)
levels associate with clinical features of disease. As such, poly(GP) proteins may prove useful in monitoring
disease severity and rate of progression. Building upon these exciting findings, our multi-disciplinary studies
will improve understanding of C9ORF72-related neurodegeneration, identify therapeutic targets and potential
clinical and pharmacodynamic biomarkers, and lead to the design of bioactive small molecules with therapeutic
potential. Combined, our efforts are anticipated to accelerate the discovery of an effective therapy for
c9FTD/ALS.
Status | Finished |
---|---|
Effective start/end date | 6/15/17 → 4/30/23 |
Funding
- National Institute of Neurological Disorders and Stroke: $1,435,400.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.