Combining Treatment and Clinical Research: Poised for Great Discovery and Change!!

Felicia B. Axelrod, MD

Professor, Department of Pediatrics, NYU School of Medicine

Co-Director, NYU Dysautonomia Center

This is our 24^th International Dysautonomia Day and we report that the Center is poised and ready to take on new challenges. To borrow a phrase from Star Trek fame in order to express our present position—we are ready to go where no man (or patient with FD) has ever gone before because we have made major progress, faced new challenges and are closer than ever before in achieving this goal.   

Our current population: Our worldwide registration has reached 643 patients. Of the 643 patients 355 (55%) reside in the United States and 221 (34%) reside in Israel. The remaining 67 (11 %) are dispersed throughout the world. Thus since almost 90% of FD patients are in the USA or Israel, it is appropriate that the two treatment Centers are also in these two countries.

            Since 2001 there has been a steady decline in new births per year from the previous average of 15/yr. We have been at 5/yr for past 2 years. For the first 6 months of 2009 there have been 3 births (all in USA). 

Our resources: Our greatest resource continues to be our patient population and the fact that there has been centralization of care. This has allowed us to give comprehensive treatment at the same time that we accumulate basic information on the disease. All of this has been put in a database, which provides an enormous repository of information. This database helps understand the natural history of FD, shows us the broad expression of disease, permits retrospective reviews and helps us determine which treatments are most efficacious and provides a basis for clinical trials and translational research.   

      Another important resource is our staff and our collaborators at NYU, Israel and at other institutions. Together we all work as a team to continue our evaluations and provide on-going care for the FD community. 

Current and Planned Projects:  A number of projects are being conducted.

1.      Those projects that focus on current major FD problems, i.e. those issues that impact strongly on health and well-being and can have long term consequences. Examples of these types of problems are crisis management, blood pressure control, anxiety and learning.

2.       Those projects that address the problems that are especially prevalent in the adult FD population. Examples of these types of problems are renal failure, worsening of balance, gait and vision and neoplasia.

3.      Finally there is translational research which are genetic studies. Here we are trying to understand the effect of the FD gene mutation in producing disease as well as to find drugs that modify expression.

The status of genetic research is discussed—after a brief review of the FD genetic mutation’s effect and an overview of the   special considerations needed planning a clinical trial in order to test a new drug for the FD population, the steps involved in kinetin research are presented.

1.      Kinetin was given mice--   it was safe and  it also altered splicing

2.      Kinetin was added  to FD neural cells--  it corrected splicing in this important cell population 

3.      Kinetin was given to parents (carriers of one copy of the splicing mutation) who were well but whose white blood cells had measurable decreases in IKAP.

a.       The drug was given for 8 days at escalating doses.

b.       Kinetin was considered safe in humans as side effects were generally transient and mild

c.       It was verified that there was a relationship between plasma kinetin level and the amount of wild type mRNA IKBKAP produced

d.      The optimal dose was determined, i.e. the dose that gave a blood level of kinetin equivalent to cell culture levels that had been shown to correct splicing.

 Based on these positive results   the first clinical trial of kinetin in FD subjects was started on February 5, 2009. This was a short term trial to confirm safety and study pharmacokinetics to see if FD patients processed the drug the same way as carriers. Only patients over 18 years could participate.

The preliminary results of this trial will be presented as well as plans for future trials

Mouse Models of FD – How will they help us?

Susan A. Slaugenhaupt

Associate Professor of Neurology (Genetics)

Center for Human Genetic Research, Massachusetts General Hospital/Harvard Medical School

            One of the major goals of my laboratory following our discovery of the FD gene has been to create a mouse model of FD in order to study what goes wrong during early development of the sensory and autonomic nervous system.  In addition, mouse models will enable us to test potential treatments that are developed for FD.  We have created a mouse knock-out of the Ikbkap gene, and this leads to death during early embryonic development.  Therefore, we learned that IKAP is crucial for fetal development.  We also created mice that carry the human IKBKAP gene and express human IKAP protein, which can completely compensate for the loss of mouse Ikbkap.  We have now crossed these lines with the knock-out mice and can show that increasing the amount of human IKBKAP can prolong embryonic life. 

            We have used these ‘transgenic’ mice (mice that carry the human gene) to test kinetin and have shown that feeding the mice a diet that includes kinetin can increase expression of normal IKBKAP.   In addition, we have created a system that should permit high-throughput screens for compounds by both myself and other groups.  I will briefly summarize all of the FD studies currently ongoing in my laboratory, and highlight some new collaborations and projects for the future.

Familial Dysautonomia: A disorder of interoception

Horacio Kaufmann, MD

Professor, Department of Neurology, NYU School of Medicine

Co-Director, NYU Dysautonomia Center

The autonomic phenotype of familial dysautonomia (FD) is different from other disorders of the autonomic nervous system. This is because in addition to a reduced number of efferent sympathetic neurons, a feature that FD shares with other autonomic disorders, new research shows that patients with FD also have profound abnormalities in the processing of vascular and visceral afferent signals to the brain.  Rather than a classic autonomic disorder, FD is a disorder of interoception. The interoceptive system guides autonomic motor control based on information (feelings) from the body that include pain, temperature, itch, sensual touch, muscular and visceral sensations, vasomotor activity, hunger, thirst and air hunger.   Abnormal interoception has devastating consequences. The lack of cardiovascular sensory feedback results in volatile blood pressure that is exquisitely sensitive to emotions.  Volatile arterial pressure accounts, at least partially, for renal failure and left ventricular hypertrophy, affecting over 70% of FD patients. Abnormal processing of chemoreceptor input with impaired responses to hypoxia and hypercapnia greatly contributes to chronic respiratory failure, present in almost every patient with FD. Aberrant central processing of visceral afferents may be a frequent trigger of disabling dysautonomic crises, suffered by many patients with FD. 

Our challenge is to devise the best medical approaches for these problems.

Kids of Courage- New Opportunities for FD Families

Stuart H. Ditchek, MD

Clinical Assistant Professor, Department of Pediatrics, NYU School of Medicine

Kids of Courage founded in January 2009 is composed of three primary programs. A travel program which had its inaugural trip to the west coast of the United States in March 2009. The organization is also organizing weekend gatherings where staff and participants spend three days together allowing new opportunities for socialization and building friendships. The third arm of the program being launched this August is the Kids of Courage Summer Camp which will host of children and young adults with FD as well as a variety of individuals with serious medical conditions in a fully medically supervised atmosphere. The program centers on utilizing humor and fun experiences as a primary coping mechanism for the affected individual and the staff.

The core medical team is comprised of Dr. Stuart Ditchek, chief paramedic Howard Kafka, and critical care nursing specialist Sara Miriam Kaplan and Dr. Robert Bocian. Travel and programming is done by Ari Adlerstein. Dr. Ditchek has been a pediatrician caring for a large population of high risk children and teens for over twenty years. He is the former Assistant Director of the NYU Familial Dysautonomia Treatment Center under the directorship of Dr. Felicia Axelrod and has coordinated care of FD patients since 1990. Having continued this relationship for almost 20 years allows Dr. Ditchek and his team a unique perspective of current management trends in the FD patient. Dr. Ditchek is also the current medical director of the Jewish Genetic Disease Consortium, a national umbrella organization which includes the Dysautonomia Foundation. The medical team coordinates all aspects of care with the FD Treatment center before, during and after their programs are completed. The medical team has worked together previously at Camp Simcha Special in past years establishing camp based care protocols for the FD patient. In August 2009, they are establishing a new Kids of Courage Camp in upstate New York which will put great emphasis on the needs of the FD population as well as other high risk individuals.    

The presentation will include details of planning air and ground travel specific to the FD population. It will also include details of care for the FD camper in a camp setting.  Specifics of planning and execution of those plans in a safe medically supervised setting is the center piece of the Kids of Courage program.

The presentation of the first ever trans-Atlantic Kids of Courage travel program will be disclosed. The first destination of this program will be Israel in the fall of 2009. Families will be given an option of participating as well.

Kids of Courage is a not for profit 501(c) 3 organization which is currently fully volunteer.