Novel Nanosensor Array for Detection of Volatile Biomarkers From Skin in Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      Multiple Sclerosis (MS) is the most common chronic neurological disease affecting young
      adults, with onset usually at the age 20-40 years. The disease is characterized by two main
      phenotypes: Relapse-Remitting MS (RR-MS) and Primary Progressive MS (PP-MS). RR-MS is the
      most common type of disease, for long-term management of the disease patients are treated
      with immunomodulatory drugs (IMD) which reduce disease activity. Response to therapy varies
      among patients. Presently there are no biomarkers available for diagnosis and routine
      follow-up of MS. Many MS patients suffer from unexpected relapsing episodes that influence
      dramatically their mental and physical conditions, with high stress levels, tremors, motoric
      disabilities, blindness and more. Therefore, early target treatment in relapse episodes is
      crucial, yet sufficient tools for predicting and identifying early symptoms of an upcoming
      relapse episode are not available. The investigators have most recently shown that breath
      VOCs can be used to classify among MS and non-MS patients. The major aims of the current
      proposal is to study the plausibility of skin based VOCs as biomarkers for MS diagnosis and
      To Identify and characterize skin-based VOCs as biomarkers of the clinical relapse and
      disease activity.
    

Detailed description: 
      BACKGROUND Multiple Sclerosis (MS) is the most common chronic neurological disease affecting
      young adults, with onset usually at the age 20-40 years. The disease is characterized by two
      main phenotypes: Relapse-Remitting MS (RR-MS) and Primary Progressive MS (PP-MS). RR-MS is
      the most common type of disease, for long-term management of the disease patients are treated
      with immunomodulatory drugs (IMD) which reduce disease activity. Response to therapy varies
      among patients. Presently there are no biomarkers available for diagnosis and routine
      follow-up of MS. Oligoclonal IgG in the CSF - which help confirm the diagnosis, require an
      invasive procedure and are not correlated with disease activity nor response to therapy and
      MRI, which allows monitoring of MS activity and its treatment, is too expensive to be
      routinely used. Moreover, RR-MS patients are under a significant stress as the relapse
      episode can appear instantly with no recognized warning sign. If relapse related biomarkers
      can be identified a potential prediction test could be developed, that eventually can allow a
      proper medical counter action provided before relapse escalates. Additionally, early
      diagnosis of MS and prediction of relapse would reduce the rate of accumulation of disability
      and save hospitalization days.

      Here, the investigators propose: further explore the ability of a simple and portable sensing
      technology to predict and monitor MS from volatile samples. The technology that has been
      developed in the lab of Prof. Hossam Haick has proved potential for diagnostics of a number
      of medical conditions such as malignancy, infectious, and neurological diseases, including
      two clinical studies on MS (Broza et al 2017; Broza et al 2015; Ionescu et al 2011; Nakhleh
      et al 2017 and Peng et al 2009). The approach relies on the fact that cell membrane consists
      primarily of amphipathic phospholipids, carbohydrates and many integral membrane proteins
      that are distinct for different cell types. In disease processes, cells undergo structural
      changes that may lead to oxidative stress,, i.e. a peroxidation of the cell membrane that
      causes volatile organic compounds (VOCs) to be emitted. Some of these VOCs appear in
      distinctively different mixture compositions, depending on whether a cell is healthy or not.
      Oxidative stress in MS is believed to contribute to tissue injury in focal inflammatory
      lesions and to be involved in diffuse axonal degeneration and demyelination (Gilgun-Sherki et
      al 2004). What is particularly significant about this approach is that each type of disease
      has its own unique pattern of VOCs, and, therefore, the presence of one disease would
      generally not screen other disease types. These VOCs can be detected directly from different
      bodily fluids as exhaled breath or skin. In certain instances, breath and skin analysis
      offers several potential advantages: (a) breath\skin samples are noninvasive and easy to
      obtain; (b) breath\skin contains less complicated mixtures than either serum or urine; and
      (c) breath\skin testing has the potential for real-time monitoring. The NA-NOSE performs odor
      detection using broadly cross-reactive sensors in conjunction with pattern recognition
      methods (Broza et al 2017; Peng et al 2009). In contrast to the "lock-and-key" approach, each
      sensor in the NA-NOSE is broadly responsive to a variety of odorants. This increases the
      variety of compounds to which the many different sensors are sensitive to, thus enabling
      analyses of biomarkers in complex multi-component media.

      REASERCH AIMS AND EXPECTED SIGNIFICANSE

      Early target treatment in relapse episodes is crucial, yet sufficient tools for predicting
      and identifying early symptoms of an upcoming relapse episode are not available. The
      investigators have most recently shown that breath VOCs can be used to classify among MS and
      non-MS patients ( Broza et al 2017). The major aim of the current proposal is to follow-up
      this recent achievement, and test the plausibility of skin-based VOC analysis for providing
      complementary information regarding potential biomarkers of disease type (RR-MS and PP-MS) as
      well as monitoring of disease activity and specifically prediction of relapse episode in MS
      patients. Project aims will be accomplished by the following specific objectives:

      Objective 1: To Study the plausibility of skin based VOCs as biomarkers for MS diagnosis. In
      this part, the investigators will 1) employ previously developed methodology for VOC skin
      sampling and adapt it for MS patients (RR-MS, SP-MS, PP-MS). 2) To determine the specificity
      of the findings the investigators will further test the difference in VOC profiles between MS
      and non-MS patients (healthy controls ) using sensor technology and\or Gas-Chromatography
      Mass-Spectrometry (GC-MS) (part of which will be planned for follow-up study). Where
      plausible, a sub-analysis will be performed to detect skin-based VOCs differences between
      RR-MS and SP-MS and PP-MS patients Based on the outcome of the first step that will identify
      volatile changes between MS and healthy controls from skin the investigators will evaluate
      the plausibility to include additional non-MS diseased population groups, such as patients
      with other autoimmune or other neurological diseases. If yes, than appropriate amendment will
      be submitted.

      Objective 2: To Identify and characterize skin-based VOCs as biomarkers of the clinical
      relapse and disease activity by measuring and analyzing VOCs profile during relapse and
      remission. Based on the outcome of the first step the investigators will test the ability of
      the skin-based VOC test to monitor subtle changes in the metabolites that might indicate on
      initiation, progression and termination of the relapse episode. It will be achieved by sensor
      and\or GC-MS analysis work for identifying potential change in biomarkers during the relapse.
      In a follow-up study, the investigators intend to assess Relapse vs "Pseudo-Relapse".

      Expected significance, the proposed study could have a major impact on the medical care and
      wellbeing of MS patients. Early diagnosis and prediction of disease activity will allow early
      and tailored therapeutic intervention, prevention of irreversible neurological damage and
      related accumulation of disability while reducing medical costs. Additionally, the project
      will be an important step in application of nanosensors for detection of biomarkers in
      medical research and practice of theranostics (therapy based on diagnosis) toward
      implementation of Precision Medicine.

      STUDY PLAN Sample collection Skin related VOCs would be collected using Polydimethylsiloxane
      (PDMS) patches from different body locations for sensors and\or GC-MS analysis. The absorbing
      materials will be attached to the skin at different locations (arm/hand or chest or
      forehead), after cleaning the skin with alcohol prep pad and clean water. The patches will be
      covered with aluminum foil and sealed with medical adhesive tape for up to an hour. A total
      of 2-4 silicon patches for each patient will be collected at each time. Collected samples on
      PDMS will be transferred to a glass vials and be stored up to 4 ˚C until sent to the Technion
      for the NA-NOSE and GC-MS analysis. All the samples collected will be coded. Signal response
      of the sensors will be evaluated in order to match the best sensors for the sample. GC-MS
      will provide initial information on the average skin profile of MS and control, and will
      assess the need for slight adjustment is sampling procedure (e.g., sample time).

      Statistics Specific patterns and predictive models for the studied MS conditions will be
      derived from the sensor array output, using advanced pattern recognition methods as
      discriminant function analysis (DFA), principal component analysis (PCA), neural networks
      (NN) or similar. Statistical significance of results will be determined by using parametric
      or a-parametric tests such as Student's T test, Man Whitney or paired analysis. Values p<0.05
      will be considered to be significant.
    

Intervention name(s): Diagnosis, skin volatile organic compounds (VOCs)
Intervention type(s): Diagnostic Test
Intervention description(s): The skin related VOCs will be collected by "off-line" method using Polydimethylsiloxane (PDMS) patches from different body locations for sensor system and\or GC-MS analysis
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Multiple Sclerosis; Skin volatile organic compounds (VOCs)