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

Sponsor
Roger Packer (Other)
Overall Status
Suspended
CT.gov ID
NCT03332030
Collaborator
(none)
20
1
115.1
0.2

Study Details

Study Description

Brief Summary

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

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

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

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

Condition or Disease Intervention/Treatment Phase
  • Diagnostic Test: Collection of Stem Cells

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 Design

Study Type:
Observational
Anticipated Enrollment :
20 participants
Observational Model:
Cohort
Time Perspective:
Other
Official Title:
Development of Stem Cell Lines in Children With Neurofibromatosis Type 1 and Tumors of the Central Nervous System
Actual Study Start Date :
Nov 27, 2015
Anticipated Primary Completion Date :
Jul 1, 2023
Anticipated Study Completion Date :
Jul 1, 2025

Outcome Measures

Primary Outcome Measures

  1. The identity of mutations in NF1 genes will be measured. [June 2019]

    The stem-cell characteristics of patient-derived induced pluripotent stem cell (iPSC) lines will be measured and reported.

Secondary Outcome Measures

  1. 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. [June 2019]

    The status of NF1 gene will be measured for the isogenic NF1 wild-type (NF1+/+), NF1 heterozygous (NF1+/-) and NF1 homozygous (NF1-/-) iPSC lines. The stem cell characteristics of isogenic NF1 iPSC lines will be measured.

  2. Measure neuronal characteristics of neurons derived from iPSC lines. [June 2019]

    Differentiate between and characterize the disease-relevant brain cells (excitatory and inhibitory interneurons, astrocytes, and oligodendrocytes) of the patient's iPSC (induced pluripotent stem cell) lines.

  3. Measure glial properties of glia derived from iPSC lines. [June 2019]

    After characterizing the disease-relevant brain cells (excitatory and inhibitory neurons, astrocytes, and oligodendrocytes) from patient-specific iPSC lines, screen and identify the drug(s) that can reverse or alleviate the specific disease phenotypes.

Eligibility Criteria

Criteria

Ages Eligible for Study:
N/A and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 Children's National Medical Center Washington District of Columbia United States 20010

Sponsors and Collaborators

  • Roger Packer

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Roger Packer, Senior Vice President, Center for Neuroscience & Behavioral Health, Children's National Research Institute
ClinicalTrials.gov Identifier:
NCT03332030
Other Study ID Numbers:
  • Pro00006360
First Posted:
Nov 6, 2017
Last Update Posted:
Mar 9, 2022
Last Verified:
Mar 1, 2022
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Mar 9, 2022