Genetic Modifiers of Treatment Response in DMD
Abstract
Duchenne muscular dystrophy is among the most common genetic disorders. In healthy individuals dystrophin is expressed in skeletal muscle and heart at high levels in fetal life and does not change with age. In DMD patients dystrophin is lost from fetal life onwards. We have shown that DMD skeletal muscle shows little cellular pathology in fetal life but soon after birth there is broad activation of NFkB inflammation followed by failure of myofiber metabolic differentiation then progressive fibrofatty replacement of muscle and an early death. The presentation and progression of DMD is variable in part due to genetic modifiers. We and others have identified a response to anti-inflammatory drugs is also variable corticosteroids like vamorolone. The goal of the proposed research is to develop computational models drawing on multivariate data that are able to explain disease variation onset progression and drug response in DMD. The hypothesis to be tested is that integration of robust longitudinal clinical biomarker and pharmacological data in clinical trial settings will lead to validated multiscale models of DMD disease onset progression and response to therapy. The patient resources to carry out this study are in hand and are from 168 DMD boys recruited into vamorolone clinical trials. Longitudinal clinical outcomes, biomarker assessments, mutation genetic modifiers, serum proteins, and pharmacokinetics will be used to develop the proposed models. Aim 1 is to complete the full data set through generation of serum biomarker data somaSCAN 5,000 biomarkers. Aim 2 is to model drug response and validate models for both prednisone and vamorolone using an independent clinical trial. Aim 3 is to model disease onset and progression similarly validating the models for both prednisone and vamorolone using an independent data.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1226975
Entities
People
- Eric Hoffman
Organizations
- Binghamton University