Research Progress Report 2012
Submitted by: Ellen Deater Burns, Medical Liaison
Shortly after the Deater Family Reunion in July, 2011, Larry Deater and Ellen Deater Burns traveled to Boston to meet with Dr. Eichler. We shared some concerns that the Deater Foundation had contributed $30,000 in January to the proposed research on Hereditary Sensory and Autonomic Neuropathy Type 1(HSAN1) and it seemed to us that the movement toward a study involving serine supplementation effects on people with HSAN1 was painfully slow.
Dr. Eichler had constructed a placebo controlled double blind study to meet the funding qualifications of large organizations such as the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Unfortunately, funding from those sources, which looked promising initially, has not materialized. The smaller trial of 5 persons affected with HSAN1 receiving serine supplementation was also off to a slow start. One of the criticisms that Dr. Eichler received from the FDA was the high cost of the L-serine. His team “shopped around” for a lower priced, high quality product. The L-serine had to be vetted by the pharmacists at Massachusetts General Hospital (MGH) to meet the same quality standards as the L-serine used in the first 10 week trial. Another hurdle to overcome was finding a suitable laboratory for the follow-up blood draws. In the end, the participants agreed to have their blood drawn and shipped to MGH via FedEx for analysis. There were continuing challenges with the MGH Institutional Review Board, which must review and approve all human research trials at MGH. Thanks in large part to the efforts of Jessica Pan, Clinical Research Coordinator in Dr. Eichler’s laboratory, the study was approved.
In December, 2011 an article was published in the Journal of Clinical Investigations: “Oral L-Serine Supplementation in Mice and Humans with Hereditary Sensory Autonomic Neuropathy Type 1.” The authors, in addition to Dr. Eichler, are: K. Garofalo, A. Penno, BP Schmidt, HJ Lee, MP Frosch, A. von Eckardstein, RH Brown, and T. Hornemann. The article reports on the mice study and the L-serine supplementation trial involving 14 Deater family members.
In the same publication, Steven S. Scherer, M.D., Ph.D., professor of neurology and researcher at the University of Pennsylvania, wrote an article titled, “The debut of a rational treatment for an inherited neuropathy?” He presents a succinct overview of the research to date in HSAN1 and concludes that “unraveling the cause of neuropathy in individuals with HSAN1 will require more study.”
In January, 2012, Dr. Eichler was informed that his large study was not likely to be funded in the spring. He plans to revise his application to make the proposal stronger and re-submit to the FDA in October of this year.
In a February analysis of the blood samples drawn some months previously, it was noted that the potassium levels were alarmingly high. Supplementation was stopped until it was determined that the elevated levels were due to an aberration of the shipping and storage of the blood samples, as they became overheated in the process of moving the samples about. Electrolytes had not been measured in the initial 10 week trial. The study continues with the participants in the study being followed quarterly through blood testing and analysis.
The studies with the mice also continue. “One important insight that is worth reporting,” Dr. Eichler says, “is the reaction of our HSAN1 mice to a high fat diet. Unlike wild type mice, the HSAN1 mice do not put on weight and start to have severe intestinal motility problems. These problems are related, but not exclusively, to pathology of the pancreas that is not seen in wild type mice or on other diets. All this happens very quickly, within a month, and tells us that beyond the amino acids there are other culprits to exacerbation in HSAN1. Now, the high fat diet (60% calories from lipids) is nothing a human would be exposed to but the fact that the HSAN1 mice react to it but not the wild type mice is significant. This lends more credence to a dormant autonomic dysfunction in HSAN1. I think the cumulative lipid content of the human diet could play a role in the lifelong disease.”
A young investigator at MGH is writing up the natural history of HSAN1 based on the surveys the family provided. Another family has also filled out the survey. The investigator has taken a special interest in the disease.
The abnormal lipids found by Thorsten Hornemann in HSAN1 are also found in diabetes patients but in lower amounts. The teams DFI DFI File Photos are exploring whether there is a common thread between the two diseases.
Further information, including graphs of the results of the 2009 Lserine supplementation study with Deater family members, can be found at the MGH Eichler Lab website, http:// eichler.mgh.harvard.edu/hsan1/.
Dr. Eichler continues to apply for funds to proceed with clinical trials. However, in the current economy it is hard to predict whether funding will be forthcoming. Deater Foundation funding remains an important support for the study of this disease. The Foundation sent a letter of support in June to Dr. Eichler for a modification to the second year of the proposed double blind randomized study that he has devised, and for which he continues to seek funding. The new grant proposal is going to the National Institute of Neurological Disorders and Stroke, a branch of the National Institutes of Health. If funded, the study would not start until the spring.
Dr. Eichler plans to resubmit the grant to the FDA this coming fall. He got an excellent score on the first try and funding seemed imminent but did not materialize, as resubmissions were considered in the same pool as new applications. We appreciate Dr. Eichler’s tenacity and persistence to get financial support for this important study. We pray that the current trial and next study will lead to a viable treatment of HSAN1.