start date: February 25, 2020
estimated completion: February 2022
last updated: February 28, 2020
phase of development:
Not Applicable
size / enrollment: 10
study 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.
primary outcomes:
- Evaluation of muscle structure under therapy and change from baseline over time
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
- 3 time points (at 0,2, and 12 months)
secondary outcomes:
- Muscular lipid content
3 time points (at 0,2, and 12 months)
- Muscular collagen content
3 time points (at 0,2, and 12 months)
- Muscular hemo-/myoglobin content
3 time points (at 0,2, and 12 months)
- Muscular de-/oxygenated hemo-/myoglobin content
3 time points (at 0,2, and 12 months)
- Ratio of lipid to hemo/myoglobin signal or collagen to hemo/myoglobin signal
3 time points (at 0,2, and 12 months)
- T1 relaxation time
3 time points (at 0,2, and 12 months)
- T2 relaxation time
3 time points (at 0,2, and 12 months)
- Fat-water percentage
3 time points (at 0,2, and 12 months)
- Sodium concentration
3 time points (at 0,2, and 12 months)
- Correlation of MSOT data with therapy status
3 time points (at 0,2, and 12 months)
- Correlation of MSOT data with clinical data (age/disease duration)
3 time points (at 0,2, and 12 months)
- Correlation of MSOT data with physical assessment (HFMSE/RULM/6-MWT)
3 time points (at 0,2, and 12 months)
- Correlation of MRI data with therapy status
3 time points (at 0,2, and 12 months)
- Correlation of MRI data with clinical data (age/disease duration)
3 time points (at 0,2, and 12 months)
- Correlation of MRI data with physical assessment (HFMSE/RULM/6-MWT)
3 time points (at 0,2, and 12 months)
- Correlation of MSOT data and MRI data
3 time points (at 0,2, and 12 months)
- Side differences
3 time points (at 0,2, and 12 months)
inclusion criteria:
• Eligible Ages: 14 - 120
• Eligible Sexes: all
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: 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.
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