C C O C C O CONTENTS (click to jump to):
FD RESEARCH: INTRODUCTION
Since 2001, FD Hope has funded over $620,000 in medical research with immediate benefit to individuals with Familial Dysautonomia (FD) and which has advanced the scientific and medical understanding of the FD mutation’s effect in the body. By supporting both clinically relevant and scientific research FD Hope has worked to help the lives of individuals with FD in the short term as well as working towards a cure to halt the progression of this devastating disease. as carriers and since they are unaffected, often are not aware they have the mutation until they have a child with FD. FD has a carrier rate of 1 in 27 Ashkenazi Jews (Jews of Eastern European
THE FD MOUSE: IMPLICATIONS (RETURN TO TOP)
In June, 2010, FD Hope funded researcher, Dr. Gil Ast, announced to the FD community the birth and development of the first mouse pups with the FD mutation. FD is primarily a neurologic disease and nervous tissue (brain and peripheral nerves) is difficult to biopsy and maintain in culture. It is therefore difficult to study how therapeutic agents (drugs and supplements) affect FD in living tissue. The mouse model will allow researchers to test possible therapies without putting children with FD at risk. About the FD mice: This mouse model was based on their scientific achievements in the understanding of the molecular mechanism of FD and is the first transgenic mouse that recapitulates a human alternative splicing disease. The mice were created by generating embryonic mice cells that contain the human gene with or without the mutation causing FD. These cells were inserted into mice that were mated to produce heterozygous mice, carriers of the FD mutation, and finally homozygous mice, which have the mutated FD gene. The FD mice will be used to further study the etiology the FD disease and for testing agents they identified in cell culture and other therapeutic approaches for treatment of this devastating disease.
ALTERING THE EFFECTS OF THE FD MUTATION: (RETURN TO TOP)
One of the exciting areas of FD research is the search for products (drugs, nutritional products, etc) that will increase the amount of normal protein produced by FD cells. FD Hope funded research has identified several substances that improve normal IKAP production:
• Dr. Gil Ast of Tel Aviv University, in FD Hope funded research, found that phosphatidylserine, (an over the counter supplement often used for memory, cognition, and attention-deficit hyperactivity disorder) improves normal IKBKAP gene expression as well as normal IKAP protein production. To read the Research Report, click here.
• Drs. Rubin and Anderson of Fordham University, in FD Hope funded research, found that EGCG (a constituent of green tea used in various cancers and auto-immune disorders) can increase IKBKAP gene expression in the cell. In related research, they also found that tocotrienols, a variant of Vitamin E, increase IKBKAP gene expression, producing increased amounts of normal protein.
• Dr. Sue Slaugenhaupt of Massachusetts General Hospital (not funded by FD Hope) determined that kinetin can also increase IKAP production.
• Dr. Gil Ast’s FD Hope funded research independently confirmed the positive effect of kinetin on IKAP production, but failed to find any effect due to tocotrienol.
THE RESEARCH CONSORTIUM: (RETURN TO TOP)
FD Hope is proud to be a part of the FD Research Consortium, a collaboration between three FD funding organizations whose purpose is to work together to fund important FD research (see timeline below for more information on FDRC). Current funding projects include:
••• Dr Gil Ast, Associate Professor and Head, M.D./Ph.D. Program, Tel Aviv Medical Shool. Department of Human Genetics and Molecular Medicine. Dr. Ast is working on multiple levels to improve the futures of individuals with FD.
Because the brain and nervous system cells affected in FD cannot be readily biopsied and used for the evaluation of treatments, a vital step in this research is the development of animal models to test substances. In May, 2010, Dr. Ast’s lab announced the birth of the first documented FD mice. His lab now has sufficient FD mice to be able to perform evaluations of pathology and testing of treatment modalities. The aim of Dr Gil Ast and the Tel Aviv University research team is to find out how the FD mutation affects development and why part of the peripheral nervous system does not develop normally, why cells are lost. His goal is to identify ways to improve normal IKAP expression.
The most common FD mutation causes a defect in the production of the FD protein IKAP. In more than 99% of FD individuals the mutation is inherited from both parents and thus appears on both copies of the gene. More specifically, the mutation results in a smaller than normal gene product (a mutant IKAP protein). This mutation is tissue specific, which means it affects some tissues more than others. Brain tissue and presumably neurons of the autonomic and sensory nervous system are most susceptible to the mutation.
••• Dr Miguel Weil, Principle Investigator, Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University, Israel.
Dr Weil's goal is to understand the meaning of the FD mutation in IKAP and its effect in the development and maintenance of the specific neurons that are reduced or missing in FD individuals. In the near future, this approach could lead to ways that will be feasible to rescue the FD mutation in neurons derived from stem cells obtained from FD patients. By studying the effects of the FD mutation and why cells are lost in development, and by understanding the mechanisms of cell loss, the effect of the mutation can be better understood and methods for a cure can be tested.
FD RESEARCH: A TIMELINE(RETURN TO TOP)
••• April, 2001
FD Hope initiates the first ever survey of GI symptoms in FD. The survey results along with FD Hope’s book, The GI Tract in Familial Dysautonomia, are presented to gastroenterologists and GI researchers at the international gastroenterology conference, DDWC, held in Atlanta, GA. To receive a copy of "The GI Tract in Familial Dysautonomia", please contact us by email or phone.
••• June, 2001
FD Hope begins funding Drs. Berish Rubin and Sylvia Anderson at Fordham University. To read the abstract of their article "Genomic Organization and Chromosomal Localization of the Mouse IKBKAP Gene" click here.
••• June, 2003
With FD Hope funding, Drs. Rubin and Anderson identify tocotrienol (a form of vitamin E) as a nutrient which raises normal IKAP expression in cells. To read the abstract of the resultant article, click here.
••• July, 2003
FD Hope provides the initial funds for FD research at the Tel Aviv University lab of Dr. Gil Ast. Dr. Ast, an expert in the field of RNA research, determines that the FD mutation affects the splicing (cutting and pasting) of the RNA that produces the IKAP protein affected in FD. Within a few short months, Dr. Ast identifies the molecular basis of the disease -- what the mutation does and how it produces an abnormal protein, how the mutation causes its effect, and how to reverse that effect.
••• October, 2003
With continued FD Hope funding, Drs. Rubin and Anderson identify a second nutrient supplement, EGCG (a component of green tea), which also increases normal IKAP expression. To read the abstract of the resultant article, click here.
Drs. Ast and Miguel Weil form a consortium of researchers in Israel, working in collaboration to advance research to improve the lives of those with FD. Research funding in Israel is substantially cheaper in Israel than in the USA. The consortium works hard to maximize the value for FD funding, using developments from other research for FD projects.
••• May, 2004
Dr. Gil Ast publishes "Comparative Analysis Detects Dependencies Among the 5' Splice-site Positions." To read the abstract of this article, click here
••• April, 2004
Dr. Gil Ast publishes "Minimal Conditions for Exonization of Intronic Sequences: 5' Splice-site Formation in Alu Exons" To read the abstract of the this article, click here.
••• October, 2005
FD Hope funded researchers, Drs. Rubin and Anderson, determine that individuals with FD exhibit deficiencies in MAO-A, an enzyme responsible for the metabolism of noradrenaline, and suggest that this is a mechanism for autonomic crisis. To read the abstract of the resultant article, click here.
FD Hope begins funding Dr. Miguel Weil’s lab at Tel Aviv University in Israel. Dr. Weil, himself the father of a child with FD, adapts a method he developed to study ALS (Lou Gehrig’s disease) for the study of FD. Dr. Weil’s technique of grafting human bone marrow stem cells onto chick embryoes leads to the creation of living peripheral nervous system cells with the FD mutation.
••• September 2007
Drs. Ast and Maayan publish an article on cerebrum deficiencies. To read abstract click here.
Creation of the FD Research Consortium. FD Hope collaborates with the Dysautonomia Foundation and the Israel Familial Dysautonomia Foundation to form the FDRC, whose purpose is to provide joint funding for FD research projects, increasing funding for the Israeli FD consortium and ensuring that this important work continues.
••• Jan-March 2008
Article by Dr. Gil Ast (FD Hope funded research) "Alternative Splicing and Disease". To read the abstract for this article click here.
••• September 2009
Article by Dr. L Studer, Sloan –Kettering Institute "Modelling Pathogenesis and Treatment of Familial Dysautonomia Using Patient-specific iPSCs." To read the abstract for this article, click here.
••• February 2010
Article by Dr. Miguel Weil, et al. (FD Hope funded research) "Enriched Population of PNS Neurons Derived From Human Embryonic Stem Cells as a Platform for Studying Peripheral Neuropathies". To read the abstract for this article, click here.
••• October 2010
Article by Dr. Miguel Weil, et al. (FD Hope funded research) "IKAP/hELP1 Downregulation in Neuroblastoma Cells Causes Enhanced Dell Adhesion Mediated by Contactin Overexpression.". To read the abstract for this article, click here.