Muscular Diseases, Spinal Muscular Atrophy
Conditions
Keywords
Muscular Diseases, Spinal Muscular Atrophy (SMA), Multispectral Optoacoustic Tomography (MSOT), Magnetic Resonance Imaging (MRI)
Brief summary
This study aims to refine the capability of Multispectral Optoacoustic Tomography (MSOT) and Magnet Resonance Imaging (MRI) to characterise the molecular composition of muscle tissue non-invasively and to evaluate the therapeutic response in patients with spinal muscular atrophy (SMA) over time.
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 disease. However, most clinical trials lack primary outcomes other than clinical testing. Preliminary work shows that new methods such as multispectral optoacoustic tomography (MSOT) and magnetic resonance imaging (MRI) detect tissue changes very sensitively. Multispectral optoacoustic tomography (MSOT) is 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. In addition to this technology, MRI imaging has advanced in the field of muscle diseases, with 23Na-MRI being the first example. With both methods, the molecular composition of muscle tissue can be determined non-invasively and quantitatively at the same time. In this first pilot study on patients with SMA, the investigators will now assess whether the differences in the muscle composition of SMA patients with or without therapy can be quantified and whether they can be used simultaneously as markers during therapy with nusinersen (spinraza©) . Ideally, both techniques can complement or validate each other. In the future, this could generate a completely new, non-invasive method for evaluating endogenous biomarkers for therapy response.
Interventions
DEVICEMultispectral Optoacoustic Tomography (MSOT) and Magnetic Resonance Imaging (MRI)
Non-invasive transcutaneous imaging of molecular muscle components
Sponsors
University of Erlangen-Nürnberg Medical School
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Genetically confirmed SMA type III * From age 14 * Willingness and ability to participate, sufficient knowledge of the german language to understand the declaration of consent, or if not possible, information of the patient in his/her mother tongue or English * High probability that the patients will be able to fully participate in the study (defined by the ability to lie still for about 1 hour and follow any breathing commands) For therapy arm: • Medical indication for Spinraza® therapy; start of study before first administration Spinraza® administration For control arm: • No medical indication for Spinraza® therapy
Exclusion criteria
* Pregnancy * Tattoo on the skin area to be examined * General contraindications for MRT examinations * Electrical implants like pacemakers or perfusion pumps * Pronounced claustrophobia * Study participants with ferromagnetic or electrically conductive implants such as aneurysm clips, surgical clips, prostheses, artificial hearts, heart valves with metal parts, metal splinters, tattoos next to the eye, symmetrical tattoos on the extremities or steel implants must consult the study physician; they may not be able to be examined (relative contraindications for MRI). * Non-approved concomitant medication: strongly sedating medication must be excluded, as intensive monitoring of bodily functions during ongoing imaging cannot be guaranteed and the active participation of the test person might be necessary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of muscle structure under therapy and change from baseline over time | 3 time points (at 0,2, and 12 months) | Comparison of the molecular muscle structure determined by MSOT and MRI in patients with SMA with and without treatment and evaluation of changes from baseline over time |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscular collagen content | 3 time points (at 0,2, and 12 months) | Quantitative collagen signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA with and without therapy and change over time Units: arbitrary units (a.u.) |
| Muscular hemo-/myoglobin content | 3 time points (at 0,2, and 12 months) | Quantitative hemo/myoglobin signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA with and without therapy and change over time Units: arbitrary units (a.u.) |
| Muscular de-/oxygenated hemo-/myoglobin content | 3 time points (at 0,2, and 12 months) | Quantitative de-/oxygenated hemo-/myoglobin signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA with and without therapy and change over time Units: arbitrary units (a.u.) |
| Ratio of lipid to hemo/myoglobin signal or collagen to hemo/myoglobin signal | 3 time points (at 0,2, and 12 months) | Ratio of quantitative lipid signal to hemo/myoglobin signal or collagen signal to hemo/myoglobin signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA with and without therapy and change over time |
| T1 relaxation time | 3 time points (at 0,2, and 12 months) | T1 relaxation time determined by Magnetic Resonance Imaging (MRI) in patients with SMA with and without therapy and change over time |
| T2 relaxation time | 3 time points (at 0,2, and 12 months) | T2 relaxation time determined by Magnetic Resonance Imaging (MRI) in patients with SMA with and without therapy and change over time |
| Fat-water percentage | 3 time points (at 0,2, and 12 months) | Fat-water percentage determined by Magnetic Resonance Imaging (MRI) in patients with SMA with and without therapy and change over time |
| Sodium concentration | 3 time points (at 0,2, and 12 months) | Sodium concentration determined by Magnetic Resonance Imaging (MRI) in patients with SMA with and without therapy and change over time |
| Muscular lipid content | 3 time points (at 0,2, and 12 months) | Quantitative lipid signal derived by transcutaneous Multispectral Optoacoustic Tomography (MSOT) in patients with SMA with and without therapy and change over time Units: arbitrary units (a.u.) |
| Correlation of MSOT data with clinical data (age/disease duration) | 3 time points (at 0,2, and 12 months) | Correlation of lipid/collagen/haemo/myoglobin and de-/oxygenated hemo-/myoglobin content determined by MSOT with disease duration/patient age and evaluation of change over time |
| Correlation of MSOT data with physical assessment (HFMSE/RULM/6-MWT) | 3 time points (at 0,2, and 12 months) | Correlation of lipid/collagen/haemo/myoglobin and de-/oxygenated hemo-/myoglobin content determined by MSOT with HFMSE/Revised Upper Limb Module/6-MWT and evaluation of change over time |
| Correlation of MRI data with therapy status | 3 time points (at 0,2, and 12 months) | Correlation of T1 relaxation time/T2 relaxation time/fat water portion/sodium concentration in patients with and without therapy and evaluation of change over time |
| Correlation of MRI data with clinical data (age/disease duration) | 3 time points (at 0,2, and 12 months) | Correlation of T1 relaxation time/T2 relaxation time/fat water portion/sodium concentration with disease duration and patient age and evaluation of change over time |
| Correlation of MRI data with physical assessment (HFMSE/RULM/6-MWT) | 3 time points (at 0,2, and 12 months) | Correlation of T1 relaxation time/T2 relaxation time/fat water portion/sodium concentration with HFMSE/Revised Upper Limb Module/6-MWT and evaluation of change over time |
| Correlation of MSOT data and MRI data | 3 time points (at 0,2, and 12 months) | Correlation of MSOT determined lipid/collagen/haemo/myoglobin and de-/oxygenated hemo-/myoglobin content and MRI derived T1 relaxation time/T2 relaxation time/fat water portion/sodium concentration and evaluation of change over time |
| Side differences | 3 time points (at 0,2, and 12 months) | Measurement of the signal differences in right / left comparison derived by Multispectral Optoacoustic Tomography (MSOT) and Magnetic Resonance Imaging (MRI) and evaluation of change over time |
| Correlation of MSOT data with therapy status | 3 time points (at 0,2, and 12 months) | Correlation of the quantitative lipid/collagen/hemo/myoglobin and de-/oxygenated hemo-/myoglobin content determined by MSOT in patients with and without therapy and evaluation of change over time |
Countries
Germany
Contacts
Primary ContactAlexandra Wagner, MD
Backup ContactFerdinand Knieling, MD
Outcome results
None listed