Clinical Trial: Cell-Based Approaches For Modeling and Treating Ataxia-Telangiectasia

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Induced Pluripotent Stem (iPS) Cell-Based Approaches For Modeling and Treating Ataxia-Telangiectasia

Brief Summary:

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).


Detailed Summary: 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 fibrobla
Sponsor: Sidney Kimmel Comprehensive Cancer Center

Current Primary Outcome: Number of samples of primary A-T fibroblast samples that can be successfully reprogrammed to iPSCs [ Time Frame: 2 years ]

Fibroblasts from patients with A-T will be collected for eligible, consenting participants and processed for reprogramming and iPSC analysis in the laboratory


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Number of samples of patient A-T fibroblasts that can be reprogrammed to iPSCs with and without gene correction [ Time Frame: 2 years ]
    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.
  • Quantification of the cloning efficiency of primary cells haploinsufficient for ATM relative to healthy controls [ Time Frame: 2 years ]
    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.


Original Secondary Outcome: Same as current

Information By: Sidney Kimmel Comprehensive Cancer Center

Dates:
Date Received: September 18, 2014
Date Started: September 2014
Date Completion: September 2018
Last Updated: March 23, 2016
Last Verified: March 2016