<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03811496</url>
  </required_header>
  <id_info>
    <org_study_id>18-LDRTC-01</org_study_id>
    <nct_id>NCT03811496</nct_id>
  </id_info>
  <brief_title>Biomarker Analysis for GBA Associated Parkinson's Disease</brief_title>
  <official_title>Biomarker Analysis for Parkinson's Disease in Subjects With Glucocerebrosidase Mutations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lysosomal and Rare Disorders Research and Treatment Center, Inc.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lysosomal and Rare Disorders Research and Treatment Center, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary aim of the study is to conclusively demonstrate the possibility of using the&#xD;
      following molecules, α-Synuclein, LRRK2 and Parkin individually or in combination as&#xD;
      biomarkers for Parkinson's disease (PD) progression in patients/ carriers of Gaucher disease&#xD;
      (GD). All the assays will be performed only using peripheral blood, thus the identification&#xD;
      of a peripheral marker that can be used in both diagnosis and prognosis of the disease and&#xD;
      symptom severity would lead to a fast, efficient and reliable assay that can be performed on&#xD;
      an easily accessible tissue type outside of the brain. It is now known that patients with GD,&#xD;
      even carriers with one mutated GBA gene (OMIM 606463) are at a higher risk for developing PD,&#xD;
      and at an earlier age. In an attempt to assess whether GBA alterations would also impact&#xD;
      α-Synuclein and Parkin metabolism in humans, the expression at both molecular and protein&#xD;
      level in the peripheral blood mononuclear cells (PBMCs) will be investigated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The GBA (OMIM 606463) gene codes for beta-glucocerebrosidase, a lysosomal enzyme. Disease&#xD;
      causing mutations in both alleles of GBA gene cause Gaucher disease (GD) while mutations in&#xD;
      one allele lead to Gaucher carrier status. It has been shown recently that patients with GD,&#xD;
      even carriers with one mutated GBA gene are at a higher risk for developing Parkinson disease&#xD;
      (PD), and at an earlier age, and that the GBA mutations comprise the primary genetic risk&#xD;
      factor in the development of PD and other forms of parkinsonism. However, there are no&#xD;
      biomarkers to determine the diagnosis of PD, especially in the early and minimally&#xD;
      symptomatic or asymptomatic stage. The progression of PD in subjects with a mutation in the&#xD;
      GBA gene can currently not be determined. In some cellular and animal models,&#xD;
      glucocerebrosidase alterations were shown to impact the metabolism of other proteins&#xD;
      implicated in PD pathology. α-Synuclein and Parkin, encoded by SNCA and PARK2 respectively,&#xD;
      are implicated in rare genetic forms of parkinsonism. α-Synuclein aggregates are seen in&#xD;
      cells of the central and peripheral nervous system and is considered to be the pathological&#xD;
      culprit in PD. Mutated glucocerebrosidase has been shown to be present in α-Synuclein&#xD;
      aggregates in postmortem brain samples from individuals with GBA mutations and PD.&#xD;
      α-Synuclein in addition, is shown to affect the solubility of Parkin in the cells. As an&#xD;
      attempt to assess whether GBA alterations would also impact α-Synuclein and Parkin metabolism&#xD;
      in humans in easily accessible cell types outside the brain, the expression at both molecular&#xD;
      and protein level will be investigated in the peripheral blood mononuclear cells (PBMCs). The&#xD;
      study includes three cohorts: 1) Patients and carriers of Gaucher disease with confirmed&#xD;
      disease causing mutations in GBA gene who have developed Parkinson's disease symptoms&#xD;
      (GD-PD), 2) Patients and carriers of Gaucher disease with no known Parkinson's symptoms&#xD;
      (GD-nonPD) and 3) Non-Gaucher disease/healthy controls (HC). PBMCs extracted from 3-5 ml&#xD;
      peripheral blood will be used for intracellular staining for α-Synuclein, LRRK2 and Parkin&#xD;
      and then acquired on Flow cytometer (BD accuri). Lymphocytes and monocytes will be analyzed&#xD;
      for α-Synuclein, LRRK2 and Parkin expression. PBMCs will also be used for RNA extraction and&#xD;
      subsequent molecular analysis using qPCR. Since the assay utilizes an easily accessible&#xD;
      tissue type i.e., peripheral blood and requires a very small amount (2-3 ml), this assay&#xD;
      could be developed as a potential biomarker for diagnosis and a disease progression indicator&#xD;
      for Parkinson disease in subjects with GBA gene mutations.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Anticipated">July 2020</completion_date>
  <primary_completion_date type="Anticipated">February 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Gene expression levels of SNCA</measure>
    <time_frame>18 months</time_frame>
    <description>Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of SNCA.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Gene expression levels of LRRK2</measure>
    <time_frame>18 months</time_frame>
    <description>Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of LRRK2.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Gene expression levels of Parkin</measure>
    <time_frame>18 months</time_frame>
    <description>Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of Parkin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Protein expression levels of alpha-synuclein</measure>
    <time_frame>18 months</time_frame>
    <description>Protein expression levels of alpha-synuclein will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Protein expression levels of LRRK2</measure>
    <time_frame>18 months</time_frame>
    <description>Protein expression levels of LRRK2 will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Protein expression levels of Parkin</measure>
    <time_frame>18 months</time_frame>
    <description>Protein expression levels of Parkin will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Parkinson Disease</condition>
  <condition>Gaucher Disease</condition>
  <arm_group>
    <arm_group_label>GD-PD</arm_group_label>
    <description>Patients and carriers of Gaucher disease with confirmed mutations in GBA gene who have developed Parkinson's disease symptoms</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GD-nonPD</arm_group_label>
    <description>Patients with Gaucher disease but no known Parkinson's symptoms</description>
  </arm_group>
  <arm_group>
    <arm_group_label>nonGD-nonPD</arm_group_label>
    <description>Non-Gaucher disease/healthy controls</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Study will include three cohorts:&#xD;
&#xD;
          1. Patients and carriers of Gaucher disease with confirmed mutations in GBA gene who have&#xD;
             developed Parkinson's disease symptoms (GD-PD),&#xD;
&#xD;
          2. Patients with Gaucher disease but no known Parkinson's symptoms (GD-nonPD) and&#xD;
&#xD;
          3. Non-Gaucher disease/healthy controls (nonGD-nonPD). All participants will be recruited&#xD;
             after obtaining informed consent using IRB (Independent Review Board) approved&#xD;
             informed consent form.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        The study will include&#xD;
&#xD;
          1. adult subjects age 21 or older with Gaucher disease with and without parkinsonism and&#xD;
             individuals from families with a Gaucher proband and a history of parkinsonism.&#xD;
&#xD;
          2. Controls will include unaffected siblings of patients with Gaucher disease and&#xD;
             subjects with sporadic PD, without glucocerebrosidase mutations, and healthy&#xD;
             volunteers who do not have a family history of parkinsonism or Gaucher disease.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects excluded from the study include those who:&#xD;
&#xD;
          1. present with severe cognitive deficits impairing decision making&#xD;
&#xD;
          2. are unable to or for whom it is medically unsafe to withdraw from their current&#xD;
             medications, such as subjects on SSRI s and other psychoactive drugs. The subjects on&#xD;
             SSRIs may be included in the study only with an approval from the prescribing&#xD;
             physician to discontinue their medications temporarily for the study.&#xD;
&#xD;
          3. are pregnant or nursing. All women of child bearing potential will undergo a pregnancy&#xD;
             test.&#xD;
&#xD;
          4. have a history of neurologic conditions such as stroke or any focal brain lesion that&#xD;
             may result in parkinonian manifestations. Individuals with such MRI findings will be&#xD;
             excluded from the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ozlem Goker-Alpan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>LDRTC</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Renuka Limgala, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>LDRTC</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Renuka Limgala, PhD</last_name>
    <phone>2407155382</phone>
    <email>rlimgala@ldrtc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ozlem Goker-Alpan, MD</last_name>
    <phone>7032616220</phone>
    <email>ogoker-alpan@ldrtc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>LDRTC</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Renuka Limgala, PhD</last_name>
      <phone>240-715-5382</phone>
      <email>rlimgala@ldrtc.org</email>
    </contact>
    <investigator>
      <last_name>Ozlem Goker-Alpan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Renuka Limgala, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.ldrtc.org</url>
    <description>Institute website for more details</description>
  </link>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>January 18, 2019</last_update_submitted>
  <last_update_submitted_qc>January 18, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 23, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Parkinson disease</keyword>
  <keyword>Gaucher disease</keyword>
  <keyword>GBA gene</keyword>
  <keyword>alpha-synuclein</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
    <mesh_term>Gaucher Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03811496
org study id: 18-LDRTC-01
nct id: NCT03811496
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The primary aim of the study is to conclusively demonstrate the possibility of using the
      following molecules, α-Synuclein, LRRK2 and Parkin individually or in combination as
      biomarkers for Parkinson's disease (PD) progression in patients/ carriers of Gaucher disease
      (GD). All the assays will be performed only using peripheral blood, thus the identification
      of a peripheral marker that can be used in both diagnosis and prognosis of the disease and
      symptom severity would lead to a fast, efficient and reliable assay that can be performed on
      an easily accessible tissue type outside of the brain. It is now known that patients with GD,
      even carriers with one mutated GBA gene (OMIM 606463) are at a higher risk for developing PD,
      and at an earlier age. In an attempt to assess whether GBA alterations would also impact
      α-Synuclein and Parkin metabolism in humans, the expression at both molecular and protein
      level in the peripheral blood mononuclear cells (PBMCs) will be investigated.
The GBA (OMIM 606463) gene codes for beta-glucocerebrosidase, a lysosomal enzyme. Disease
      causing mutations in both alleles of GBA gene cause Gaucher disease (GD) while mutations in
      one allele lead to Gaucher carrier status. It has been shown recently that patients with GD,
      even carriers with one mutated GBA gene are at a higher risk for developing Parkinson disease
      (PD), and at an earlier age, and that the GBA mutations comprise the primary genetic risk
      factor in the development of PD and other forms of parkinsonism. However, there are no
      biomarkers to determine the diagnosis of PD, especially in the early and minimally
      symptomatic or asymptomatic stage. The progression of PD in subjects with a mutation in the
      GBA gene can currently not be determined. In some cellular and animal models,
      glucocerebrosidase alterations were shown to impact the metabolism of other proteins
      implicated in PD pathology. α-Synuclein and Parkin, encoded by SNCA and PARK2 respectively,
      are implicated in rare genetic forms of parkinsonism. α-Synuclein aggregates are seen in
      cells of the central and peripheral nervous system and is considered to be the pathological
      culprit in PD. Mutated glucocerebrosidase has been shown to be present in α-Synuclein
      aggregates in postmortem brain samples from individuals with GBA mutations and PD.
      α-Synuclein in addition, is shown to affect the solubility of Parkin in the cells. As an
      attempt to assess whether GBA alterations would also impact α-Synuclein and Parkin metabolism
      in humans in easily accessible cell types outside the brain, the expression at both molecular
      and protein level will be investigated in the peripheral blood mononuclear cells (PBMCs). The
      study includes three cohorts: 1) Patients and carriers of Gaucher disease with confirmed
      disease causing mutations in GBA gene who have developed Parkinson's disease symptoms
      (GD-PD), 2) Patients and carriers of Gaucher disease with no known Parkinson's symptoms
      (GD-nonPD) and 3) Non-Gaucher disease/healthy controls (HC). PBMCs extracted from 3-5 ml
      peripheral blood will be used for intracellular staining for α-Synuclein, LRRK2 and Parkin
      and then acquired on Flow cytometer (BD accuri). Lymphocytes and monocytes will be analyzed
      for α-Synuclein, LRRK2 and Parkin expression. PBMCs will also be used for RNA extraction and
      subsequent molecular analysis using qPCR. Since the assay utilizes an easily accessible
      tissue type i.e., peripheral blood and requires a very small amount (2-3 ml), this assay
      could be developed as a potential biomarker for diagnosis and a disease progression indicator
      for Parkinson disease in subjects with GBA gene mutations.
observational model: Cohort
time perspective: Prospective
measure: Gene expression levels of SNCA
time frame: 18 months
description: Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of SNCA.
measure: Gene expression levels of LRRK2
time frame: 18 months
description: Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of LRRK2.
measure: Gene expression levels of Parkin
time frame: 18 months
description: Gene expression levels relative to internal reference genes will be compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression of Parkin.
measure: Protein expression levels of alpha-synuclein
time frame: 18 months
description: Protein expression levels of alpha-synuclein will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.
measure: Protein expression levels of LRRK2
time frame: 18 months
description: Protein expression levels of LRRK2 will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.
measure: Protein expression levels of Parkin
time frame: 18 months
description: Protein expression levels of Parkin will be analyzed using flow cytometry and compared between the individual subjects as well as grouped analysis to identify a specific pattern in alterations in level of expression.
arm group label: GD-PD
description: Patients and carriers of Gaucher disease with confirmed mutations in GBA gene who have developed Parkinson's disease symptoms
arm group label: GD-nonPD
description: Patients with Gaucher disease but no known Parkinson's symptoms
arm group label: nonGD-nonPD
description: Non-Gaucher disease/healthy controls
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ozlem Goker-Alpan, MD
role: Principal Investigator
affiliation: LDRTC
last name: Renuka Limgala, PhD
role: Principal Investigator
affiliation: LDRTC
last name: Renuka Limgala, PhD
phone: 2407155382
email: rlimgala@ldrtc.org
last name: Ozlem Goker-Alpan, MD
phone: 7032616220
email: ogoker-alpan@ldrtc.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
url: http://www.ldrtc.org
description: Institute website for more details
responsible party type: Sponsor
mesh term: Parkinson Disease
mesh term: Gaucher Disease
sharing ipd: Undecided