Stem Cells in NF1 Patients With Tumors of the Central Nervous System

Learn more about:
Related Clinical Trial
Phase I Study to Assess the Effect of Food on the PK and Gastrointestinal Toxicity of Selumetinib in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas NFX-179 Topical Gel Treatment for Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF) Mechanism of Action of Transcranial Direct Current Stimulation in Neurofibromatosis Type 1 Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1 Evaluating Genetic Modifiers of Cutaneous Neurofibromas in Adults With Neurofibromatosis Type 1 Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas Systematically Assessing Changes in Plexiform Neurofibroma Related Disfigurement From Photographs of Subjects With Neurofibromatosis Type 1 on a Phase 2 Clinical Trial Pilot Randomized Control Trial of Telehealth Group for Improving Peer Relationships (PEERS) in NF1 Open Trial of Telehealth Group for Improving Peer Relationships (PEERS) in NF1 Identification of Pre-Malignant Lesions In Pediatric Patients With Neurofibromatosis Type 1 Using Novel Magnetic Resonance Imaging Techniques Paired With Artificial Intelligence A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN) Innovation in the Treatment of Persistent Pain in Adults With NF1: Implementation of the iCanCope Mobile Application- Clinical Trial Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1 Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1 A Long-term Study of NPC-12G Gel in Neurofibromatosis Type I NFX-179 Topical Gel Treatment in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF) Analysis of Data Collected From Individuals Administered Neurobehavioral Assessments Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia Comparison of Gastrointestinal Motility in Healthy Children and Children With Constipation AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors Photodynamic Therapy for Benign Dermal Neurofibromas- Phase II Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NCS 716051) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas Medical Treatment of “High-Risk” Neurofibromas Fludeoxyglucose F 18 Positron Emission Tomography and Magnetic Resonance Perfusion Imaging in Patients With Neurofibromatosis 1 and Plexiform Neurofibroma Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1 Use of Topical Liquid Diclofenac Following Laser Microporation of Cutaneous Neurofibromas in Patients With NF1 Development and Validation of Patient Reported Outcome (PRO) Measures for Individuals With Neurofibromatosis 1 (NF1) and Plexiform Neurofibromas (PNs) Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas Treatment of NF1-related Plexiform Neurofibroma With Trametinib Subtle Myocardial Deformation Abnormalities in Asymptomatic Nf-1 Patients R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas Ranibizumab for Neurofibromas Associated With Neurofibromatosis 1 AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas Neurofibromatosis Type 1 Brain Tumor Genetic Risk Acceptance and Commitment Therapy for Adolescents and Young Adults With Neurofibromatosis and Chronic Pain Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas Adaptation and Quality of Life Among Adults With Neurofibromatosis Type I Reliability of Functional Outcome Measures in Neurofibromatosis 1 Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults Medication Adherence in Children, Adolescents and Adults With Neurofibromatosis Type 1 (NF1) on Clinical Treatment Trials Targeting the Mechanisms Underlying Cutaneous Neurofibroma Formation in NF1: A Clinical Translational Approach. Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST) Quality of Friendships in Children With Neurofibromatosis Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1) MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas Interventions for Reading Disabilities in NF1 Everolimus for Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis1 CRAD001CUS232T Clinical Trial of Pirfenidone in Adult Patients With Neurofibromatosis 1 Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain Neurobiology and Treatment of Reading Disability in NF-1 From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1 Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1) Efficacy of Computerized Cognitive Training and Stimulant Medication in Neurofibromatosis Type 1 Analysis of Plasma for Diagnosis and Follow-up of Neurofibromatosis Type 1 Study About Annoucement of the Diagnosis of Neurofibromatosis 1 in de Novo Forms MicroRNAs in Patients With Neurofibromatosis Type 1 Pirfenidone in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas Stem Cells in NF1 Patients With Tumors of the Central Nervous System Function of the Pigment Epithelium in Patients With Type 1 Neurofibromatosis NF1-Attention: Study of Children With Neurofibromatosis Type 1 Treated by Methylphenidate Trial to Evaluate the Safety of Lovastatin in Individuals With Neurofibromatosis Type I (NF1) Internet Support Group for Parents of a Child With Neurofibromatosis Type 1 Reading Disability in Children With NF1 Multi-center Project: Spinal Abnormalities in Neurofibromatosis Type1 (NF1) Patients Functional Imaging and Reading Deficit in Children With NF1 Effects of Physical Training on Bone and Muscle Quality, Muscle Strength, and Motor Coordination in Children With NF1 Effect of Lamotrigine on Cognition in NF1 A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1 Neurofibromatosis Type 1 (NF1) and Tibial Dysplasia Non-invasive Stimulation in Neurofibromatosis Type 1 Modifying Genes in Neurofibromatosis 1 Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1 Vision, Attention and Reading in Neurofibromatosis Type 1 (NF1) Children Neuropsychological Impairment and Quality of Life in Neurofibromatosis Type 1 Spinal Abnormalities in Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 1 Patient Registry Frameshift Peptides of Children With NF1 Prevalence of Constitutional Mismatch-repair Deficiency Among Suspected Neurofibromatosis Type 1/Legius Syndrome Children Without a Malignancy and Without a NF1 or SPRED1 Mutation How Neurofibromatosis Type 1 (NF1) Affects Schoolwork and Self-Esteem

Brief Title

Stem Cells in NF1 Patients With Tumors of the Central Nervous System

Official Title

Development of Stem Cell Lines in Children With Neurofibromatosis Type 1 and Tumors of the Central Nervous System

Brief Summary

      Objectives 1. Establish an induced pluripotent stem cell (iPSC) bank for phenotypically
      well-characterized patients with NF1.

      2. Develop isogenic NF1 wild-type (NF1+/+), NF1 heterozygous (NF1+/-) and NF1 homozygous
      (NF1-/-) iPSC lines from individual patients using CRISPR/CAS9 technology.

      3. Differentiate and characterize disease-relevant brain cells such as excitatory and
      inhibitory neurons, astrocytes and oligodendrocytes from patient-specific iPSC lines.

      4. Screen and identify the drug(s) that can reverse or alleviate the disease phenotypes.
    

Detailed Description

      Hypothesis: Subjects with NF1 and central nervous system tumors who have aggressive lesions
      (including, but not limited to optic pathway gliomas) and/or those with tumors causing
      neurologic (including visual) morbidity will manifest unique differences in their stem cells
      and stem cell-derived differentiated cells compared to patients with NF1 and central nervous
      system tumors who have less aggressive disease and/or those with tumors causing minimal to no
      morbidity.

      Background and Significance: Optic pathway gliomas (OPGs) are low-grade astrocytic tumors
      primarily involving the optic nerve, chiasm and tracts that occur mainly in children. Nearly
      20% of children with Neurofibromatosis type 1 (NF1) will develop OPGs, although less than
      half will develop vision loss from their tumor.1 These tumors have excellent survival
      outcomes, making vision loss the primary morbidity in these patients. Furthermore, OPGs are
      inherent to the visual pathway, therefore they are rarely, if ever biopsied. This paucity of
      OPG tissue limits our ability to clarify the biologic differences between OPGs that cause
      vision loss and those that do not. Low-grade astrocytic gliomas in the other regions of the
      brain including the hypothalamus, brainstem and cerebellum can also be found in a subset of
      children associated with NF1. These NF1-associated brain tumors can progress and also grow at
      variable rates and may cause neurologic dysfunction ranging from severe compromise to little
      or no symptomality.

      This study seeks to develop stem cells lines in children with NF1-related tumors in the
      central nervous system (the optic nerve and those from other brain sites). Stem cells from
      these subjects will provide a critical insight into the mechanisms responsible for tumor
      progression and symptoms associated with the central nervous system, accelerating the
      identification of therapeutic targets.

      Preliminary Studies: Three recent research developments make it possible to develop a
      patient-specific disease model in a dish (so-called "human disease model in dish") and to
      study induced pluripotent stem cell (iPSC)-derived disease relevant cells in an isogenic
      background. First, embryonic stem cell (ESC)-like cells, also known as induced pluripotent
      stem cell or iPSC, can be generated from skin or blood cells in adult patients. Second,
      recent research efforts have started to develop culture protocols that differentiate iPSCs
      into a variety of cell types in the central and peripheral nervous system (CNS and PNS),
      which are affected in NF1 patients. Third, the CRISPR/CAS9 technology allows to genetically
      edit the specific disease genes either by repairing the existing mutant genes or creating new
      mutations. In order to position at the forefront of NF1 research, it will be important for
      the Gilbert Family Neurofibromatosis Institute (GFNI) at the Children's National Medical
      Center to explore these recent exciting research developments, to systematically develop
      patient-specific human NF1 disease models, and to provide a tool for drug screening and
      evaluation on the individual NF patients.

      Design and Methods:

      3.1 Study Design Cross-sectional collection of NF1 subjects with tumors in the central
      nervous system as documented by MRI.

      3.2 Study Visits Subjects will have only one visit to collect the blood sample.

      3.3 Study Procedures 3.31 Blood Draw Subjects have 20 ml of whole blood drawn during either
      1)their sedation for their clinically indicated MRI (IV already being placed for clinical
      purpose) or through the outpatient laboratory.

      3.32 Stem Cell Processing Blood collected will be immediately transferred to the stem cell
      facility at the National Institutes of Health for processing of the specimens in order to
      develop stem cell lines.

      3.33 Demographics We will collect the subject's age, gender, race, ethnicity, location of
      tumors in the central nervous system on MRI, history of vision loss and other neurological
      deficits.

      3.34 Statistical Analysis As a first step to establish a stem cell library from a specific
      population of NF1 children with nervous system tumors, we will not need statistical analysis
      at this stage.
    


Study Type

Observational


Primary Outcome

The identity of mutations in NF1 genes will be measured.

Secondary Outcome

 The iPS cell lines with NF1 mutations will be engineered to inactivate the remaining NF1 wild-type or fix the mutant allele using CRISPR/CAS9 technology.

Condition

Neurofibromatosis Type 1

Intervention

Collection of Stem Cells


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

20

Start Date

November 27, 2015

Completion Date

July 1, 2025

Primary Completion Date

July 1, 2023

Eligibility Criteria

        Inclusion Criteria:

          -  Males or females of any age

          -  Confirmed diagnosis of NF1

          -  Willingness to submit blood sample and collect clinical history

          -  MRI documentation confirming tumor location in the central nervous system.

          -  For study group d, "Non-NF1 full sibling for control purposes" subject must be a full
             sibling of a patient with confirmed diagnosis of NF1 and willing to submit blood
             sample and collect clinical history.

        Exclusion Criteria:

          -  Does not have diagnosis of NF1 and CNS Tumor

          -  Does not have full-sibling with NF1 and CNS Tumor diagnosis (for unaffected sibling
             cohort)
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Roger Packer, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03332030

Organization ID

Pro00006360


Responsible Party

Sponsor-Investigator

Study Sponsor

Roger Packer


Study Sponsor

Roger Packer, MD, Principal Investigator, Children's National Research Institute


Verification Date

January 2021