Epigenetic Liquid Biopsy for Duchenne and Becker Muscular Dystrophy
Abstract
Background: There is a pressing need for developing novel biomarkers for Duchene and Becker Muscular Dystrophy (DMD and BMD), particularly given the emergence of advanced therapies requiring tools for early and accurate determination of drug activity and toxicity. Dying cells shed fragments of cell-free DNA (cfDNA) to the blood. Liquid biopsies, based on analysis of such fragments, are revolutionizing prenatal and cancer diagnostic medicine. We have pioneered the use of a novel version of liquid biopsies, based on DNA methylation patterns – chemical marks on DNA that can be used to determine the tissue origins of cfDNA and consequently to infer the rate of cell death in specific tissues via a blood sample. However, the potential of liquid biopsies has not been explored so far in muscle pathologies. The present proposal represents a collaborative effort of Duchenne clinical specialists and experts in methylation-based liquid biopsy, aiming at developing a novel type of blood test to assess the response of patients with DMD/BMD to therapy. Objective/Hypothesis: We hypothesize that liquid biopsies can provide critical and missing information on the response of patients with DMD and BMD to therapy, including inflammation and fibrosis, skeletal and cardiac muscle damage, and potential cardiac and liver toxicity. Specific Aims: 1. To establish and validate a liquid biopsy assay kit tailored for DMD/BMD. 2. To prepare a longitudinal cohort of blood samples from patients with DMD/BMD during the course of treatment with standard and novel molecular therapies, as well as controls from children with no muscle disease and children with other muscle pathologies. 3. To test the performance of the cfDNA assay in comparison to standard biomarkers and clinical assessment. Study Design: We will collect blood plasma samples from 30 children with DMD/BMD over the course of 2 years to be able to assess disease progression and response to therapy. We will also collect blood from children with other muscle pathologies and age-matched controls. In parallel, we will establish and validate the liquid biopsy assay for assessment of damage to specific relevant tissues in patients. We will then use the new assay to study blood samples from patients with DMD/BMD and to seek correlations of liquid biopsy findings to clinical status and trajectory, particularly in response to therapy. This is a first exploratory study that will pave the way for larger studies designed and powered to formally assess the performance of cfDNA technology. Innovation and Impact: This will be the first assessment of the utility of cfDNA methylation, a novel emerging diagnostic technology, for muscle pathologies. If epigenetic liquid biopsies are proven to be useful in these diseases, they are expected to profoundly impact clinical management and the conductance of clinical trials via early detection of both treatment response and drug toxicity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311065
Entities
People
- Yuval Dor
Organizations
- Hebrew University of Jerusalem
- United States Army