<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/NCT02246491</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00038916</org_study_id>
    <secondary_id>J1491</secondary_id>
    <nct_id>NCT02246491</nct_id>
  </id_info>
  <brief_title>Cell-Based Approaches For Modeling and Treating Ataxia-Telangiectasia</brief_title>
  <official_title>Induced Pluripotent Stem (iPS) Cell-Based Approaches For Modeling and Treating Ataxia-Telangiectasia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johns Hopkins University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This research is being done to better understand the causes of the disease&#xD;
      Ataxia-Telangiectasia and, in the longer-term, develop new therapies for the disease using&#xD;
      stem cells.&#xD;
&#xD;
      Induced pluripotent stem cells (iPSC) are a type of cells that can be made in the laboratory&#xD;
      from cells in your body, such as blood cells or skin cells (fibroblasts). These stem cells&#xD;
      can then be used for research purposes. For example, stem cells can be used to investigate&#xD;
      how the mutation in ATM causes the actual symptoms of Ataxia-Telangiectasia. In addition, the&#xD;
      stem cells can be used to screen for drugs that could be helpful to treat the disease or to&#xD;
      develop new laboratory techniques to correct the mutation that causes Ataxia-Telangiectasia.&#xD;
      where the mutation that causes the disease is corrected by the investigators. The stem cells&#xD;
      generated in this study will not be used directly for patient therapy and therefore this&#xD;
      research does not have a direct benefit to you. However, it will help advance our&#xD;
      understanding of the disease and develop future therapies.&#xD;
&#xD;
      Patients who enroll in this study will get all of the standard therapy they would get for&#xD;
      their tumor whether or not they participate in this study. There is no extra or different&#xD;
      therapy given. The study involves a one-time procedure (either blood collection or skin&#xD;
      biopsy).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ataxia-Telangiectasia (A-T) is a devastating genetic syndrome of neurodegeneration,&#xD;
      immunodeficiency and cancer predisposition caused by mutations in the locus encoding ATM&#xD;
      (Ataxia-Telangiectasia Mutated). The current standard of care for A-T consists of aggressive&#xD;
      supportive measures, and the prognosis remains poor. There is therefore a pressing need to&#xD;
      develop novel experimental approaches and treatments for this disease. In this application,&#xD;
      we propose to address this need by developing for the first time human stem cell-based&#xD;
      technologies to: 1) generate novel experimental models for A-T that faithfully recapitulate&#xD;
      the features of the disease across its complex spectrum of clinical manifestations (Aim 1);&#xD;
      and 2) start to test the feasibility of regenerative therapies for A-T, via generation of&#xD;
      autologous stem cells that have been rendered disease-free by correction of the mutation (Aim&#xD;
      2). Mutations causing A-T are private, resulting in variable reduction in ATM activity and,&#xD;
      correspondingly, a wide spectrum of clinical manifestations. Although the most severe form of&#xD;
      the disease (&quot;classical&quot; A-T, with no detectable ATM) has been modeled in the mouse (ATM&#xD;
      &quot;knock out&quot;), this approach fails to recapitulate the neurological symptoms of the disease&#xD;
      and its characteristic tumor spectrum. Moreover, we are currently lacking experimental models&#xD;
      for those patients whose mutations result in reduced ATM activity (&quot;variant&quot; A-T). To address&#xD;
      these issues, experiments in Aim 1 will test the hypothesis that the genotype-phenotype&#xD;
      correlation in A-T is maintained in patient-derived induced pluripotent stem cells (iPSCs).&#xD;
      To test this hypothesis, we will reprogram fibroblasts from A-T patients with variable&#xD;
      reduction of ATM levels and determine whether: 1) ATM expression and activity in the iPSCs&#xD;
      correlate directly with those observed in the patient fibroblasts they are derived from; 2)&#xD;
      the iPSCs recapitulate the phenotypes observed in the fibroblasts, including impaired cell&#xD;
      cycle checkpoint activation, defective DNA double-strand break (DSB) repair, radiosensitivity&#xD;
      and genomic instability; and 3) these phenotypes in the iPSCs directly correlate with their&#xD;
      level of ATM expression/activity. If we find that the genotype-phenotype correlation is&#xD;
      maintained in A-T iPSCs, this work would validate a more general use of autologous iPSCs for&#xD;
      preclinical studies of A-T, including the evaluation of disease biomarkers, drug testing or&#xD;
      genetic screening. The clinical manifestations of A-T result from progressive cell loss and&#xD;
      tissue degeneration, making A-T a candidate disease for regenerative therapies. Experiments&#xD;
      in Aim 2 will test the hypothesis that correction of the ATM mutation in A-T somatic cells&#xD;
      will rescue their severe reprogramming defect and allow the generation of disease-free iPSCs.&#xD;
      To test this hypothesis, we propose a series of proof-of-principle experiments using a&#xD;
      well-characterized compound heterozygous A-T fibroblast cell line. First, we will &quot;repair&quot;&#xD;
      either one or the two ATM mutations in this line by recombination with an exogenous donor&#xD;
      plasmid carrying the intact sequence, to generate either &quot;carriers&quot; (one normal allele and&#xD;
      one mutated allele) or &quot;intact&quot; cells (two normal alleles). To increase the efficiency of&#xD;
      recombination, we will introduce a DSB in close proximity to the mutation using Transcription&#xD;
      Activator-Like Effector Nucleases (TALENS) that bind specifically to the mutated region. In&#xD;
      Preliminary Experiments, we find that we can successfully induce DSBs and site-specific&#xD;
      recombination at a human &quot;safe harbor&quot; locus as well as at the ATM locus itself. After&#xD;
      verifying that recombination restores ATM expression and function, we will reprogram the&#xD;
      corrected cells into iPSCs and characterize their level of ATM expression, activity and&#xD;
      function with passage. Because the &quot;null&quot;, &quot;carrier&quot; and &quot;intact&quot; lines are isogenic, the&#xD;
      effect of ATM gene dose on reprogramming and iPSC function can be evaluated in these&#xD;
      experiments. In this regard, approximately 1% of the US general population is an A-T&#xD;
      &quot;carrier&quot;, extending the significance of this work well beyond A-T patients. Overall,&#xD;
      completion of this Exploratory Project will provide the rationale, expertise and reagents for&#xD;
      longer-term studies aimed at modeling and treating A-T with autologous iPSCs and/or their&#xD;
      derived products and optimizing the use of regenerative therapies for the general population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Change in research objectives.&#xD;
  </why_stopped>
  <start_date type="Actual">February 3, 2015</start_date>
  <completion_date type="Actual">July 5, 2018</completion_date>
  <primary_completion_date type="Actual">July 5, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of samples of primary A-T fibroblast samples that can be successfully reprogrammed to iPSCs</measure>
    <time_frame>2 years</time_frame>
    <description>Fibroblasts from patients with A-T will be collected for eligible, consenting participants and processed for reprogramming and iPSC analysis in the laboratory</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of samples of patient A-T fibroblasts that can be reprogrammed to iPSCs with and without gene correction</measure>
    <time_frame>2 years</time_frame>
    <description>The ATM mutation in patient A-T fibroblasts will be corrected using guided nucleases and the reprogramming efficiency of isogenic corrected and uncorrected fibroblasts will be quantified using standard molecular assays.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantification of the cloning efficiency of primary cells haploinsufficient for ATM relative to healthy controls</measure>
    <time_frame>2 years</time_frame>
    <description>Fibroblasts from individuals heterozygous for an ATM null mutation will be reprogrammed according to standard protocols and the number of iPSC colonies will be compared to those of healthy controls reprogrammed in parallel.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Ataxia-Telangiectasia (A-T)</condition>
  <arm_group>
    <arm_group_label>iPSCs without gene correction</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This is not a clinical trial and there is no immediate benefit to the participants. At this time, iPSCs and their derived products are not suitable for administration to patients. However, they are useful for basic and preclinical studies of the disease, such as mechanistic studies of ATM function or screening for small molecules with therapeutic value. As regenerative medicine continues to advance, iPSCs and their products may ultimately be used for clinical studies aimed at replacing damaged tissues in A-T patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>iPSCs with gene correction</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This is not a clinical trial and there is no immediate benefit to the participants. At this time, iPSCs and their derived products are not suitable for administration to patients. However, they are useful for basic and preclinical studies of the disease, such as mechanistic studies of ATM function or screening for small molecules with therapeutic value. As regenerative medicine continues to advance, iPSCs and their products may ultimately be used for clinical studies aimed at replacing damaged tissues in A-T patients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>A-T iPS cell line</intervention_name>
    <description>Reprogramming A-T patients iPS cell line</description>
    <arm_group_label>iPSCs with gene correction</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Carrier patients iPS cell line</intervention_name>
    <description>Reprogramming iPS cell line from carrier patients</description>
    <arm_group_label>iPSCs without gene correction</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients that meet the classic diagnosis of A-T and for whom the underlying mutation(s) is&#xD;
        known. The diagnosis of A-T has been made by the clinician using the following criteria:&#xD;
&#xD;
          1. Characteristic neurological abnormalities, including but not limited to oculomotor&#xD;
             apraxia, bulbar dysfunction, postural instability, and ataxia.&#xD;
&#xD;
          2. Presence of telangiectasia on the conjunctivae and/or skin.&#xD;
&#xD;
          3. Laboratory abnormalities including but not limited to elevated serum alpha-feto-&#xD;
             protein, level, absence of ATM on western blot, increased x-ray induced chromosomal&#xD;
             breakage in comparison to a control population, mutations in both alleles of the ATM&#xD;
             gene. Parents of the patients above, who are haploinsufficient and whose mutation is&#xD;
             known.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients under 2 years of age No subjects will be excluded on the basis of age, sex, race,&#xD;
        or socio-economic status.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sonia Franco, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>SKCCC at Johns Hopkins</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>SKCCC at Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>September 18, 2014</study_first_submitted>
  <study_first_submitted_qc>September 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 22, 2014</study_first_posted>
  <last_update_submitted>March 15, 2019</last_update_submitted>
  <last_update_submitted_qc>March 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ataxia</mesh_term>
    <mesh_term>Cerebellar Ataxia</mesh_term>
    <mesh_term>Ataxia Telangiectasia</mesh_term>
    <mesh_term>Telangiectasis</mesh_term>
  </condition_browse>
  <!-- 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/NCT02246491
org study id: IRB00038916
secondary id: J1491
nct id: NCT02246491
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This research is being done to better understand the causes of the disease
      Ataxia-Telangiectasia and, in the longer-term, develop new therapies for the disease using
      stem cells.

      Induced pluripotent stem cells (iPSC) are a type of cells that can be made in the laboratory
      from cells in your body, such as blood cells or skin cells (fibroblasts). These stem cells
      can then be used for research purposes. For example, stem cells can be used to investigate
      how the mutation in ATM causes the actual symptoms of Ataxia-Telangiectasia. In addition, the
      stem cells can be used to screen for drugs that could be helpful to treat the disease or to
      develop new laboratory techniques to correct the mutation that causes Ataxia-Telangiectasia.
      where the mutation that causes the disease is corrected by the investigators. The stem cells
      generated in this study will not be used directly for patient therapy and therefore this
      research does not have a direct benefit to you. However, it will help advance our
      understanding of the disease and develop future therapies.

      Patients who enroll in this study will get all of the standard therapy they would get for
      their tumor whether or not they participate in this study. There is no extra or different
      therapy given. The study involves a one-time procedure (either blood collection or skin
      biopsy).
Ataxia-Telangiectasia (A-T) is a devastating genetic syndrome of neurodegeneration,
      immunodeficiency and cancer predisposition caused by mutations in the locus encoding ATM
      (Ataxia-Telangiectasia Mutated). The current standard of care for A-T consists of aggressive
      supportive measures, and the prognosis remains poor. There is therefore a pressing need to
      develop novel experimental approaches and treatments for this disease. In this application,
      we propose to address this need by developing for the first time human stem cell-based
      technologies to: 1) generate novel experimental models for A-T that faithfully recapitulate
      the features of the disease across its complex spectrum of clinical manifestations (Aim 1);
      and 2) start to test the feasibility of regenerative therapies for A-T, via generation of
      autologous stem cells that have been rendered disease-free by correction of the mutation (Aim
      2). Mutations causing A-T are private, resulting in variable reduction in ATM activity and,
      correspondingly, a wide spectrum of clinical manifestations. Although the most severe form of
      the disease ("classical" A-T, with no detectable ATM) has been modeled in the mouse (ATM
      "knock out"), this approach fails to recapitulate the neurological symptoms of the disease
      and its characteristic tumor spectrum. Moreover, we are currently lacking experimental models
      for those patients whose mutations result in reduced ATM activity ("variant" A-T). To address
      these issues, experiments in Aim 1 will test the hypothesis that the genotype-phenotype
      correlation in A-T is maintained in patient-derived induced pluripotent stem cells (iPSCs).
      To test this hypothesis, we will reprogram fibroblasts from A-T patients with variable
      reduction of ATM levels and determine whether: 1) ATM expression and activity in the iPSCs
      correlate directly with those observed in the patient fibroblasts they are derived from; 2)
      the iPSCs recapitulate the phenotypes observed in the fibroblasts, including impaired cell
      cycle checkpoint activation, defective DNA double-strand break (DSB) repair, radiosensitivity
      and genomic instability; and 3) these phenotypes in the iPSCs directly correlate with their
      level of ATM expression/activity. If we find that the genotype-phenotype correlation is
      maintained in A-T iPSCs, this work would validate a more general use of autologous iPSCs for
      preclinical studies of A-T, including the evaluation of disease biomarkers, drug testing or
      genetic screening. The clinical manifestations of A-T result from progressive cell loss and
      tissue degeneration, making A-T a candidate disease for regenerative therapies. Experiments
      in Aim 2 will test the hypothesis that correction of the ATM mutation in A-T somatic cells
      will rescue their severe reprogramming defect and allow the generation of disease-free iPSCs.
      To test this hypothesis, we propose a series of proof-of-principle experiments using a
      well-characterized compound heterozygous A-T fibroblast cell line. First, we will "repair"
      either one or the two ATM mutations in this line by recombination with an exogenous donor
      plasmid carrying the intact sequence, to generate either "carriers" (one normal allele and
      one mutated allele) or "intact" cells (two normal alleles). To increase the efficiency of
      recombination, we will introduce a DSB in close proximity to the mutation using Transcription
      Activator-Like Effector Nucleases (TALENS) that bind specifically to the mutated region. In
      Preliminary Experiments, we find that we can successfully induce DSBs and site-specific
      recombination at a human "safe harbor" locus as well as at the ATM locus itself. After
      verifying that recombination restores ATM expression and function, we will reprogram the
      corrected cells into iPSCs and characterize their level of ATM expression, activity and
      function with passage. Because the "null", "carrier" and "intact" lines are isogenic, the
      effect of ATM gene dose on reprogramming and iPSC function can be evaluated in these
      experiments. In this regard, approximately 1% of the US general population is an A-T
      "carrier", extending the significance of this work well beyond A-T patients. Overall,
      completion of this Exploratory Project will provide the rationale, expertise and reagents for
      longer-term studies aimed at modeling and treating A-T with autologous iPSCs and/or their
      derived products and optimizing the use of regenerative therapies for the general population.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Number of samples of primary A-T fibroblast samples that can be successfully reprogrammed to iPSCs
time frame: 2 years
description: Fibroblasts from patients with A-T will be collected for eligible, consenting participants and processed for reprogramming and iPSC analysis in the laboratory
measure: Number of samples of patient A-T fibroblasts that can be reprogrammed to iPSCs with and without gene correction
time frame: 2 years
description: The ATM mutation in patient A-T fibroblasts will be corrected using guided nucleases and the reprogramming efficiency of isogenic corrected and uncorrected fibroblasts will be quantified using standard molecular assays.
measure: Quantification of the cloning efficiency of primary cells haploinsufficient for ATM relative to healthy controls
time frame: 2 years
description: Fibroblasts from individuals heterozygous for an ATM null mutation will be reprogrammed according to standard protocols and the number of iPSC colonies will be compared to those of healthy controls reprogrammed in parallel.
arm group label: iPSCs without gene correction
arm group type: Other
description: This is not a clinical trial and there is no immediate benefit to the participants. At this time, iPSCs and their derived products are not suitable for administration to patients. However, they are useful for basic and preclinical studies of the disease, such as mechanistic studies of ATM function or screening for small molecules with therapeutic value. As regenerative medicine continues to advance, iPSCs and their products may ultimately be used for clinical studies aimed at replacing damaged tissues in A-T patients.
arm group label: iPSCs with gene correction
arm group type: Other
description: This is not a clinical trial and there is no immediate benefit to the participants. At this time, iPSCs and their derived products are not suitable for administration to patients. However, they are useful for basic and preclinical studies of the disease, such as mechanistic studies of ATM function or screening for small molecules with therapeutic value. As regenerative medicine continues to advance, iPSCs and their products may ultimately be used for clinical studies aimed at replacing damaged tissues in A-T patients.
intervention type: Other
intervention name: A-T iPS cell line
description: Reprogramming A-T patients iPS cell line
arm group label: iPSCs with gene correction
intervention type: Other
intervention name: Carrier patients iPS cell line
description: Reprogramming iPS cell line from carrier patients
arm group label: iPSCs without gene correction
criteria: 
gender: All
minimum age: 3 Years
maximum age: 100 Years
healthy volunteers: No
last name: Sonia Franco, M.D.
role: Principal Investigator
affiliation: SKCCC at Johns Hopkins
facility: 
country: United States
responsible party type: Sponsor
mesh term: Ataxia
mesh term: Cerebellar Ataxia
mesh term: Ataxia Telangiectasia
mesh term: Telangiectasis