The Deater Foundation, the Deater Family, and Human Trials
Submitted by: Ellen Deater Burns, Medical Liaison
The Deater Family has been involved in human research for Hereditary Sensory and Autonomic Neuropathy type 1 (HSAN1) since Harvey and Russell Deater presented themselves for study at the Thomas Jefferson Hospital in Philadelphia in 1937. The research has gone down many paths and some dark alleys since then.
In 2000 there was a major breakthrough in determining the basis of the disease when a specific gene mutation was identified as the cause of HSAN1. The gene was known to encode an enzyme, serine palmitoyl transferase; that is the first step in synthesizing a fatty substance known as ceramide that then is involved in the synthesis of another fatty substance known as sphingolipids. Dr. Garth Nicholson and his team from Australia, and Dr. Robert Brown, Jr. and Dr. Khemissa Bejaoui in Boston published the results of this discovery in 2001. The Deater Foundation supported the work of Drs. Brown and Bejaoui.
In subsequent years, much more has been learned about the cellular pathology of HSAN1. At a Deater Foundation sponsored international conference in 2008, Dr. Thorsten Hornemann proposed that a toxic property, resulting from defective cell receptors, was causing elevations of atypical sphingolipoids and the symptoms of HSAN1. Dr. Eichler devised a mouse study that tested this theory. The results were so striking that a human trial followed in 2009, conducted exclusively on members of the Deater family. The results of this trial were also promising.
The researchers then sought to create a study that would prove conclusively, one way or another, the theory that the serine receptors in the cells of persons with HSAN1 are able to bind with amino acids (building blocks of protein) other than serine, with toxic results. A threepronged approach was devised: a second international conference with participants who can move the research along— especially researchers working with other HSAN1 families; compiling a “natural history of the disease” with anecdotal reporting and definitive objective testing; and funding to continue and expand the research.
In February 2010 another conference was convened. Dr. Hornemann advocated for action to test the hypothesis. Dr. Brown and Dr. Eichler determined that the prudent approach was to methodically examine volunteer members of the family at specified intervals with a barrage of objective tests. Deater family members began testing in late spring and early summer at both Massachusetts General Hospital (MGH) and at the University of Massachusetts (UMass).
In August, Dr. Eichler met with Dr. Mary Reilly, who works with about 40 HSAN1 patients in England, to enlist her partnership in studies. Collaboration such as this would help overcome the criticism and funding barriers of the National Institutes of Health (NIH), that the current studies involve a small number of patients from only one (Deater) family. Dr. Eichler attended the Clinical Trials Methods Course where he developed a randomized, double-blind, placebo controlled clinical trial protocol. The protocol was well conceived and well written. Drs. Brown and Eichler were eager to move forward. Dr. Eichler submitted a request to the Deater Foundation for $30,000 “seed money” for the L-serine supplement and a part time assistant to “jump start” the study and to “enroll first patients without delays.”
The $30,000 request closely matched the resources of the Deater Foundation. The officers discussed the pros and cons of putting all the financial eggs in one basket and concluded that this proposal was the bold trial we were hoping for. In January, 2011 the Deater Foundation sent a check for the requested amount which Dr. Eichler “labeled for the serine study” at MGH.
Concurrently, a research group in Belgium published the discovery of another gene mutation seeming to cause a severe, early onset form of HSAN1. Elevations in atypical sphingolipids were found in these patients, consistent with the work of the Boston research team.
In 2011 there has been additional progress:
- The research team submitted and received an IND (investigational new drug) designation for L-serine from the Federal Drug Administration (FDA)
- The team also submitted a grant request to the FDA for the clinical study (expecting a response in July or August).
- Dr. Eichler did get an RO1 (NIH Research Project Grant Program) funding to continue the animal work on HSAN1.
- The human RO1 got a good score but did not get funded. Drs. Brown and Eichler may resubmit in the fall.
- Dr. Eichler presented study data on L-serine in HSAN1 at the American Academy of Neurology in Honolulu; it was chosen for the Scientific Highlights Plenary Session.
- Dr. Eichler continues to work on the natural history of HSAN1 based on the Deater surveys and in collaboration with Dr. Mary Reilly and her group in the UK to better understand the progression of the disease.
- Dr. Eichler will be presenting some of his findings at the Peripheral Neuropathy Society Meeting this summer.
- At this writing, one year follow up studies have been done on some of the participants in the MGH/ UMass study. They will be completed in June.
Dr. Eichler’s clinical study protocol was based to some extent on NIH funding guidelines. Re-application will need DFI and let me know when you are ready! I’ll do my best to capture your family and will be happy to send you the file(s) via email. Just be sure that I have your email address. This year’s event is the 69th Deater Family Reunion. We’ll be meeting at the Butler property again on July 16, 2011. I plan to be there, the Lord willing. How about you? DFI File Photos to be made for that funding and it is not guaranteed. NIH guidelines call for randomization and a placebo (nontreated) group. One member of the 6 person group tested so far has been receiving supplementation. Others are eager to begin. Good baseline data has been established. The original randomized, double-blind, placebo controlled study remains the ideal, but an interim pilot study of the 6 people can be done at a lower cost, with minor modification of the study proposal before the Institutional Review Boards at both MGH and UMass, until the larger, more extensive study can be conducted.
At a meeting on May 29, 2011, Dr. Brown and Dr. Eichler both reaffirmed their commitment to the Deater Family. They believe serine supplementation is at least part of the answer to the HSAN1 symptoms, although it may not be the whole answer. They believe that the time has come to move forward. We are confident that there are answers at the end of this road.