Developing a Novel Genomic Biomarker for the Early Detection of Neurodegeneration

Summary

Developing a sequencing-based assay that can detect cfDNA originating from brain cell in human blood plasma samples to improve early diagnosis of neurodegenerative disease.

What are we doing?

Over 55 million people are affected by neurodegenerative diseases worldwide, which is projected to increase to 139 million by 2050. Diagnosis of neurodegenerative diseases is difficult, as the symptoms that are used to make a diagnosis do not appear until after irreversible damage to brain tissue has occurred. A diagnostic test that could detect neurodegeneration before clinical symptoms appear would lead to improvements in disease prognosis, symptom management, and testing of new disease treatments.

One promising target for a diagnostic test of neurodegeneration are cell-free DNAs (cfDNAs). cfDNAs are short fragments of DNA that are released from cells when they die, as occurs in neurodegeneration, and which are then found circulating in blood. We’ll leverage epigenetic profiling technologies to develop a sequencing-based assay that can detect cfDNA originating from degenerating neural tissue in human plasma samples as a biomarker for neurodegeneration. We then hope to use this to detect signs of neuronal loss using samples from neurodegenerative disease patients.

We hope to do this by:

• Developing a sequencing-based assay that can detect cfDNA originating from brain cells in human blood plasma samples
• Validating the ability of this assay to detect signs of neuronal loss using samples from neurodegenerative disease patients at the earliest stages of disease progression

How are we doing it?

We will collect blood samples from a range of neurodegenerative disease patients, including Huntington’s disease, Alzheimer’s disease, and motor neuron disease, at the earliest stages of disease progression and then at regular intervals. cfDNA will be isolated from these samples and will be prepared for enzymatic methyl sequencing using the Twist NGS methylation detection system. Libraries will be sequenced using Illumina short-read sequencing. Additionally, cfDNA will be directly sequenced using Oxford Nanopore Technologies sequencers for native detection of cfDNA DNA methylation and DNA hydroxymethylation.

We’ll use a novel cell type deconvolution method using neural cell type-specific epigenetic profiles generated by the Complex Disease Epigenetics Group for reference, to make inferences about cfDNA cell-type of origin in the plasma of neurodegenerative disease patients. Based on the results of cell type deconvolution we will assess the capability of this assay for detecting neurodegeneration using ROC curve analysis.

We’ll carry out further analysis of the rate of neural cell decline by collecting samples from the same patients as the disease progresses.

What happens next?

We are in the first stages of sample collection and laboratory method optimisation. When sufficient samples have been collected and laboratory methods, such as cfDNA isolation and sequencing library preparation are optimised, we’ll continue to the data collection stage.