Alexander disease (AxD) is a devastating childhood disease that affects neural development and causes mental retardation, seizures and spasticity. The most common form of AxD occurs during the first two years of life and AxD children show delayed mental and physical development, and die by the age of six. AxD occurs in diverse ethnic, racial, and geographic groups and there is no cure; the available treatment only temporally relieves symptoms, but not targets the cause of the disease. Previous studies have shown that specific nervous system cells called astrocytes are abnormal in AxD patients. Astrocytes support both nerve cell growth and function, so the defects in AxD astrocytes are thought to lead to the nervous system defects. We want to generate special cells, called induced pluripotent stem cells (iPSCs) from the skin or blood cells of AxD patients to create an unprecedented, new platform for the study and treatment of AxD. We can grow large quantities of iPSCs in the laboratory and then, using novel methods that we have already established, coax them to develop into AxD astrocytes. We will study these AxD astrocytes to find out how their defects cause the disease, and then use them to validate potential drug targets. In the future, these cells can also be used to screen for new drugs and to test novel treatments. In addition to benefiting AxD children, we expect that our approach and results will benefit the study of other, similar childhood nervous system diseases.
It is estimated that California has approximately 12% of all US cases of AxD, a devastating childhood neurological disorder that leads to mental retardation and early death. At present, there is no cure or standard treatment available for AxD. Current treatment is symptomatic only. In addition to the tremendous emotional and physical pain that this disease inflicts on Californian families, it adds a medical and fiscal burden larger than that of any other states. Therefore, there is a real need to understand the underlying mechanisms of this disease in order to develop an effective treatment strategy. Stem cells provide great hope for the treatment of a variety of human diseases. Our proposal to establish a stem cell-based cellular model for AxD could lead to the development of new therapies that will represent great potential not only for Californian health care patients, but also for the Californian pharmaceutical and biotechnology industries. In addition to benefiting the treatment of AxD patients, we expect that our approach and results will benefit the study of other related neurological diseases that occur in California and the US.
This proposal aims to generate a "disease in a dish" model of Alexander's disease (AxD), a very rare autosomal dominant leukodystrophy caused by mutations in glial fibrilary acidic protein (GFAP), the major structural protein found in adult astrocytes. The team will generate induced pluripotent stem cells (iPSCs) from 3 AxD patients, create genetically matched controls by correcting the mutant GFAP gene, and differentiate these iPS derived cells to astrocytes. Next, they will determine whether AxD iPSC-derived astrocytes will express the increased levels of GFAP and protein aggregates, hallmark features associated with this disease. If successful, they will explore potential molecular mechanisms and test whether compounds can improve the in vitro disease phenotype.
Significance and Innovation
- Reviewers noted that AxD disease is a very rare disorder; however, the potential disease mechanisms uncovered by this program may inform more common human neurodegenerative disorders involving protein aggregation and astrocyte dysfunction.
- While some reviewers did not find the proposed experiments highly innovative, others argued the proposalís focus on critical yet understudied astrocytes is innovative and of major importance.
- All reviewers agreed that if successful, the project could yield important results that would contribute to the field.
Feasibility and Experimental Design
- The panel did not find the preliminary data convincing that all techniques required to successfully execute the program were established in the PIs laboratory.
- Reviewers generally agreed that the proposal is well structured and follows a logical rationale; however, the interdependence of the specific aims could jeopardize the success of the program.
- The narrow pathway focus of the mechanistic studies was judged to be high risk; this risk could be mitigated by including additional signaling pathways.
- One reviewer suggested that examining the role of normal versus disease astrocytes in an intact nervous system following transplantation into a preclinical model would improve the proposal.
Principal Investigator (PI) and Research Team
- The PI has an established track record of studying neural stem cells in mammalian brain and has published in respected but not top tier journals. He/she has a more limited track record in the iPSC field.
- Although the PIís lack of experience in astrocytes derivation raised concern, reviewers agreed that the investigator has an established collaborator who is experienced in astrocyte differentiation.
- Some reviewers viewed the proposed budget as excessive.
Responsiveness to the RFA
- The proposed research was viewed as responsive to the RFA.
- This application scored below the initial scientific merit funding line, no programmatic reason to fund the application was proposed, and the GWG voted to place the application in Tier 3, Not Recommended for Funding.