New Imaging Biomarkers for Muscular Diseases – Multispectral Optoacoustic Imaging in Spinal Muscular Atrophy

Overview

This study aims to refine the capability of MSOT to characterise muscle tissue and to determine non-invasive, quantitative biomarkers for the disease assessment in patients with spinal muscular atrophy (SMA) using Multispectral Optoacoustic Tomography (MSOT).

Full Title of Study: “New Imaging Biomarkers for Muscular Diseases – Multispectral Optoacoustic Imaging in Spinal Muscular Atrophy”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Diagnostic
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 30, 2020

Detailed Description

SMA is an autosomal-recessive disorder, characterized by progressive muscle weakness and atrophy with an incidence of 1/10,000. The condition is caused by a homozygous deletion or mutation in the survival motor neuron 1 (SMN1), resulting in reduced expression of the survival motor neuron (SMN) protein. This leads to the degeneration of motor neurons in the spinal cord and brain stem. A nearby related gene, survival motor neuron 2 (SMN2), could partially compensate the loss of SMN1. Individuals with a higher copy number of SMN2 do in general have a milder phenotype. New therapeutic approaches, e.g. nusinersen (spinraza©), an antisense oligonucleotide medication that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene, are promising to help the formerly incurable children. However, most clinical trials lack primary outcomes other than clinical testing. At the moment there are no prospective, quantitative biomarkers available to detect muscle atrophy at an early age, and to follow up disease progression. As a new imaging modality, optoacoustic imaging (OAI) combines benefits of optical (high contrast) and acoustic (high resolution) imaging. Multispectral optoacoustic tomography (MSOT) is therefore capable of visualizing the distribution of endogenous absorbers by initiating laser-induced thermoelastic expansion and detection of resulting pressure waves. This imaging technique enables the label-free detection and quantification of different endogenous chromophores, such as melanin, hemoglobin, deoxyhemoglobin and lipids. Previously, it was demonstrated that MSOT is capable to monitor disease severity in Crohn's disease by detecting different signal levels of hemoglobin as markers of intestinal inflammatory activity. In this study we want to refine the capability of MSOT to characterize muscle tissue and to determine a non-invasive, quantitative biomarker for the disease assessment in SMA patients from birth using MSOT.

Interventions

  • Device: Multispectral Optoacoustic Tomography (MSOT)
    • Non-invasive transcutaneous imaging of subcellular muscle components

Arms, Groups and Cohorts

  • Active Comparator: Healthy Volunteers (HV)
    • Multispectral Optoacoustic Tomography (MSOT) and B-Mode Ultrasound of muscles (left and right, total 8 sites) leg proximal: Musculus quadriceps, distal: Musculus triceps surae arm proximal: Musculus biceps, distal: forearm flexors; physical assessment/milestones: Hammersmith Infant Neurological Examination (HINE)/ expanded Hammersmith functional motor scale (HFMSE)/ The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP Intend)/ Upper Limb Module (ULM)
  • Experimental: Spinal Muscular Atrophy (SMA) patients
    • Multispectral Optoacoustic Tomography (MSOT) and B-Mode Ultrasound of muscles (left and right, total 8 sites) leg proximal: Musculus quadriceps, distal: Musculus triceps surae arm proximal: Musculus biceps, distal: forearm flexors; physical assessment/milestones: Hammersmith Infant Neurological Examination (HINE)/ expanded Hammersmith functional motor scale (HFMSE)/ The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP Intend)/ Upper Limb Module (ULM)

Clinical Trial Outcome Measures

Primary Measures

  • Spectral profile of muscle tissue
    • Time Frame: Single time point (1 day)
    • Spectral profile of muscle tissue determined by multispectral optoacoustic tomography (MSOT) of patients with spinal muscular atrophy compared to healthy volunteers units: arbitrary units (a.u.)

Secondary Measures

  • Muscular lipid content
    • Time Frame: Single time point (1 day)
    • Quantitative lipid signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA compared to healthy control Units: arbitrary units (a.u.)
  • Muscular collagen content
    • Time Frame: Single time point (1 day)
    • Quantitative collagen signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA compared to healthy control Units: arbitrary units (a.u.)
  • Muscular myo-/hemoglobin content
    • Time Frame: Single time point (1 day)
    • Quantitative myo-/hemoglobin signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA compared to healthy control Units: arbitrary units (a.u.)
  • Muscular de-/oxygenated myo-/hemoglobin content
    • Time Frame: Single time point (1 day)
    • Quantitative de-/oxygenated myo-/hemoglobin signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA compared to healthy control Units: arbitrary units (a.u.)
  • Correlation of lipid signal with clinical data (age/disease duration)
    • Time Frame: Single time point (1 day)
    • Quantitative lipid signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual clinical data (disease duration/age (in month))
  • Correlation of collagen signal with clinical data (age/disease duration)
    • Time Frame: Single time point (1 day)
    • Quantitative collagen signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual clinical data (disease duration/age (in month))
  • Correlation of myo-/hemoglobin signal with clinical data (age/disease duration)
    • Time Frame: Single time point (1 day)
    • Quantitative myo-/hemoglobin signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual clinical data (disease duration/age (in month))
  • Correlation of de-/oxygenated myo-/hemoglobin signal with clinical data (age/disease duration)
    • Time Frame: Single time point (1 day)
    • Quantitative de-/oxygenated myo-/hemoglobin signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual clinical data (disease duration/age (in month))
  • Correlation of lipid signal with physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
    • Time Frame: Single time point (1 day)
    • Quantitative lipid signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
  • Correlation of collagen signal with physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
    • Time Frame: Single time point (1 day)
    • Quantitative collagen signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
  • Correlation of myo-/hemoglobin signal with physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
    • Time Frame: Single time point (1 day)
    • Quantitative myo-/hemoglobin signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
  • Correlation of de-/oxygenated myo-/hemoglobin signal with physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
    • Time Frame: Single time point (1 day)
    • Quantitative de-/oxygenated myo-/hemoglobin signal (Units: arbitrary units (a.u.)) derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA correlated with individual physical assessment (HINE/HFMSE/CHOP INTEND/ULM)
  • Side differences of MSOT signals
    • Time Frame: Single time point (1 day)
    • Quantitative collagen signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA compared between sides Units: arbitrary units (a.u.)
  • Correlation of RUCT and B-Mode Ultrasound
    • Time Frame: Single time point (1 day)
    • Quantitative grey scale signal derived by reflection mode ultrasound computed tomography (RUCT) correlated with grey scale B-Mode Ultrasound

Participating in This Clinical Trial

Inclusion Criteria

  • genetically proven SMA

Exclusion Criteria

  • Pregnancy
  • Tattoo on skin to be examined
  • For healthy volunteers only: suspected muscular disease/myopathia

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Erlangen-Nürnberg Medical School
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ferdinand Knieling, MD, Principal Investigator, University Hospital Erlangen, Department of Pediatric and Adolescent Medicine
    • Regina Trollmann, MD, Principal Investigator, University Hospital Erlangen, Department of Pediatric and Adolescent Medicine

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