Clinical trial NCT02285348: Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of A-T
Official title: Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of Patients With Ataxia Telangiectasia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Ataxia Telangiectasia
Keywords: Ataxia Telangiectasia
cerebrospinal fluid
inflammation
proteomic analysis
Lead sponsor: Johann Wolfgang Goethe University Hospital
Sponsor class: OTHER
First posted: 2014-11-07
Enrollment: 18
Sex: ALL
Minimum age (years): 2
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: Ataxia telangiectasia (A-T) is a rare devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. Laboratory diagnostic approaches to neurodegeneration in A-T are hampered by sampling issues. It is dangerous, impractical, and not ethically to directly sample brain tissue by surgical biopsy. In contrast cerebrospinal fluid (CSF), a fluid that is in direct contact with brain tissue, is relatively easy to sample in a safe procedure (lumbar puncture). The aim of the proposal is to investigate oxidative stress, low grade inflammation and tissue break down in the brain of A-T patients by analyzing CSF. In addition the alterations in protein expression related to A-T will be quantified by liquid chromatography/mass spectrometry (LC/MS)-based proteomic analysis of CSF from healthy individuals and A-T patients to determine candidate proteins (new biomarkers) which relative expression levels could be used as surrogate marker of disease progression.

Detailed description: Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. For clinicians and scientists the underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. In addition no surrogate marker of neurological degeneration and disease progression exist.

Three major factors may be responsible for progression of neurodegeneration:

1. A-T patients exhibit elevated levels of reactive oxygen species (ROS) and reduced anti-oxidative capacity. It has been proposed that ROS is responsible for destruction of the purkinje cells in the cerebellum.
2. Ongoing low grade inflammation due to immunodeficiency. Elevated serum interleukin-8 (IL-8) levels in patients with A-T are postulated that systemic inflammation may contribute to the disease phenotype. How inflammation and neurodegeneration interact is, however, a matter of ongoing debate.
3. Low levels of growth hormones (GH). Extracerebellar MRI - lesions in A-T go along with deficiency of the GH axis, high Ataxia scores and advanced age.

The aim of the proposal is to investigate oxidative stress, low grade inflammation, tissue breakdown and biomarkers in cerebrospinal fluid (CSF), a fluid that is in direct contact with central nervous system (CNS), of A-T patients.

* To analyse functional gene expression of oxidative stress and low grade inflammation by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array.
* To characterize the alterations in protein expression related to A-T, a LC/MS-based quantitative proteomic analysis of CSF from control and A-T patients
* To compare alterations in protein expression levels in CSF with MRI findings in different age groups of classical A-T.
* To determine candidate proteins whose relative expression levels could be used as surrogate marker of disease progression?
* To established an analysis system on a basis of multiplex ELISA-technique to evaluate potential candidates/surrogate markers for disease progression in a larger cohort of patients.

Eligibility criteria: Inclusion Criteria:

* Aim group: clinically and/or genetically diagnosed Ataxia telangiectasia; Control group: neurologic non-inflammatory disease with an indication for diagnostic or therapeutic lumbar puncture
* age between 2 and 40 years
* written informed consent

Exclusion Criteria:

* fever or clinical signs of an infection
* leucocyte count \>12´000/µl and C reactive protein (CrP) \>2mg/dl
* chronic diseases with need of immunomodulatory therapies (bronchial asthma, rheumatoid arthritis)
* medication with statins
* other diseases with influence in the immunosystem (i.e. diabetes mellitus, malignoma, renal failure requiring dialysis)

Primary outcomes:
measure: Concentration of IL-8 and oxidative stress in cerebrospinal fluid
timeFrame: 24 months
Secondary outcomes:
measure: Alterations in protein expression related to A-T
timeFrame: 24 months
measure: Number of Participants with Adverse Events
timeFrame: 24 months
measure: Alterations in protein expression levels in CSF compared with MRI findings in different age groups of classical A-T.
timeFrame: 24 months
measure: Alterations in protein expression levels in CSF with MRI findings in different age groups of classical A-T. Candidate proteins whose relative expression levels could be used as surrogate marker of disease progression.
timeFrame: 24 months
Other outcomes:
Locations:
city: Frankfurt
country: Germany
facility: Johann Wolfgang Goethe University Hospitals
state: Hessen
Study officials:
References:
citation: Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M. Neurodegeneration in ataxia telangiectasia: what is new? What is evident? Neuropediatrics. 2012 Jun;43(3):119-29. doi: 10.1055/s-0032-1313915. Epub 2012 May 21.
citation: Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia. Antioxid Redox Signal. 2002 Jun;4(3):465-9. doi: 10.1089/15230860260196254.
citation: McGrath-Morrow SA, Collaco JM, Crawford TO, Carson KA, Lefton-Greif MA, Zeitlin P, Lederman HM. Elevated serum IL-8 levels in ataxia telangiectasia. J Pediatr. 2010 Apr;156(4):682-4.e1. doi: 10.1016/j.jpeds.2009.12.007. Epub 2010 Feb 20.
citation: Zielen S, Schubert R. Workshop report: European workshop on ataxia-telangiectasia, Frankfurt, 2011. J Neurogenet. 2011 Oct;25(3):78-81. doi: 10.3109/01677063.2011.592553. Epub 2011 Jul 6.
citation: Dzieciatkowska M, Qi G, You J, Bemis KG, Sahm H, Lederman HM, Crawford TO, Gelbert LM, Rothblum-Oviatt C, Wang M. Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T) Patients Using a LC/MS-Based Label-Free Protein Quantification Technology. Int J Proteomics. 2011;2011:578903. doi: 10.1155/2011/578903. Epub 2011 Jun 23.