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Summary

Since 2001, FD Hope has funded over $521,000 in medical research which has brought an understanding of how the mutation produces its effect and an approach to gene therapy, and research which has produced nutritional supplements which improve gene functioning. FD Hope has a proven track record of funding research with immediate practicality for those with FD.

With funding from FD Hope, researchers at several centers in Israel such as Hadassah Hospital and Tel Aviv University are fighting hard to find the answers that will bring treatments today, a cure tomorrow.

Four years ago the genetic mutation that causes FD was identified by Drs. Berish Rubin and Sylvia Anderson of Fordham University and Dr. Sue Slaugenhaupt of Mass General Hospital. The mutation, found in the IKAP gene, was inconsistent. Some cells made mostly normal IKAP protein; nerve cells made mostly abnormal IKAP protein. Within a year, Drs. Rubin and Anderson began testing compounds that would increase the amount of normal IKAP protein produced by cells. By May 2003, Dr. Rubin and Dr. Anderson's efforts had begun to pay off. The groundbreaking news that tocotrienol, a form of vitamin E, could increase the amount of normal IKAP made in cells astounded the FD community. Three months later, Drs. Rubin and Anderson published a second paper which showed that a component of green tea (EGCG) further increased normal protein by a different mechanis.

In July 2004, FD Hope began funding the lab of Dr. Gil Ast, of Tel Aviv University in Israel. Dr. Ast is an expert in the field of RNA research. He determined that the mutation affects the splicing (or cutting and pasting) of the RNA that produces the protein. Within a few short months, Dr. Ast had determined 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.

The next steps of identifying a gene cure, applying the techniques to in vivo (animal) models, and the eventual translation into a gene therapy for the children, are all possible in the foreseeable future, predicted at four to five years away.

Dr. Miguel Weil, a neurodevelopmental biologist and the parent of a child with FD, is developing such a model. FD Hope is funding the work of Dr Weil, also at Tel Aviv University, who is working with Dr Ast to grow FD cells in chick embryos that is essential to verifying new treatments. In addition, we are seeking funding to further the work being done by Dr Ron Goldstein at Bar-Ilan University in Tel Aviv whose work on FD is focused on stem cell therapies.

Because of the diligent and self-sacrificing work of the FD Hope-funded researchers, children with FD have the possibility of living normal, healthy life spans.

Dr Gil Ast, Associate Professor and Head, M.D./Ph.D. Program, Tel Aviv Medical Shool. Department of Human Genetics and Molecular Medicine

Dr Miguel Weil, Principle Investigator, Department of Cell Research and

  Immunology, Faculty of Life Sciences

Tel Aviv University, Israel

The aim of  Dr Gil Ast and the Tel Aviv University research team is to find out how the FD mutation affects develop-ment and why part of the peripheral nervous system does not develop normally, why cells are lost. 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 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.

Dr Berish Y. Rubin, Professor

Dr Sylvia L. Anderson, Laboratory Director

Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY

FD Hope provided funding for Dr. Rubin from 2001 through 2007. He has recently informed FD Hope that he no longer needs funding from us, though FD Hope is committed to resuming support to his lab upon his request. Dr Rubin's goal is to help children and adults who suffer from FD. Along with his colleagues at Fordham University, Rubin was one of the discovers of the gene for Familial Dysautonomia. This discovery allows potential carriers of the FD gene to be tested. This will help reduce the number of children born with the devastating complications of FD.

Dr Sylvia Anderson and her colleagues at the Laboratory were instrumental in the identification of two natural compounds, tocotrienols and a component of green tea, used to diminish the frequency and severity of crisis in FD.

Published Articles

Tocotrienols reverse IKAP and monoamine oxidase deficiencies in familial dysautonomia

[Abstract] [Full Text]

Sylvia L. Anderson and Berish Y. Rubin. Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY August 2005. Reprinted from Biochemical and Biophysical Research Communications Volume 336, Issue 1, with permission from Elsevier

The Alternative Genome [pdf]

Gil Ast. Scientific American. April 2005. Reprinted with permission. Copyright © 2005 by Scientific American, Inc. All rights reserved.

EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia [Abstract] [Full Text]

Sylvia L. Anderson, Jinsong Qiu and Berish Y. Rubin. Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY 31 July 2003. Reprinted from Biochemical and Biophysical Research Communications Volume 310, Issue 2, with permission from Elsevier

Gil Ast. Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. Nature Reviews. Genetics. October 2004. Reprinted with permission from Nature Publishing Group

Ido Carmel, Saar Tal, Ida Vig and Gil Ast. Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel RNA (2004)

Minimal Conditions for Exonization of Intronic Sequences: 5’ Splice Site Formation in Alu Exons

[Abstract] [Full Text]

Rotem Sorek, Galit Lev-Maor, Mika Reznik, Tal Dagan, Frida Belinky, Dan Graur, Gil Ast. Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel; Compugen, Tel Aviv, Israel; Department of Zoology, George S. Wise Faculty of Life Sciences, Tel Aviv Univer-sity, Ramat Aviv, Israel; Department of Biology and Biochemistry, University of Houston, Houston, TX. Molecular Cell, Vol. 14, 1–20, April 23, 2004. Reprinted with permission

Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia

[Abstract] [Full Text]

Sylvia L. Anderson, Jinsong Qiu and Berish Y. Rubin. Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY, 9 May 2003. Reprinted from Biochemical and Biophysical Research Communications Volume 306, Issue 1, with permission from Elsevier

Genomic organization and chromosomal localization of the mouse IKBKAP gene

[Abstract] [Full Text]

Rocco Coli, Sylvia L. Anderson, Sabrina A. Volpi and Berish Y. Rubin. Department of Biological Sciences, Laboratory for Familial Dysautonomia Research, Fordham University, Bronx, NY 24 September 2001. Reprinted from Gene Volume 279, Issue 1, with permission from Elsevier

Familial Dysautonomia Is Caused by Mutations of the IKAP Gene [Abstract] [Full Text]

Sylvia L. Anderson, Rocco Coli, Ira W. Daly, Elizabeth A. Kichula, Matthew J. Rork, Sabrina A. Volpi,  Josef Ekstein, Berish Y. Rubin. Department of Biological Sciences, Fordham University, Bronx, NY; and Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY/Jerusalem  January 10, 2001. Reprinted with permission from The American Society of Human Genetics