MANHASSET, NY – A decade ago, Betty Diamond, MD, a lupus investigator at The Feinstein Institute for Medical Research, identified auto-antibodies in the brains of patients with Systemic Lupus Erythematous (SLE) and realized at the time that these auto-antibodies could be a potentially important target for drug development. Now, working with chemists at the Feinstein Institute, Dr. Diamond may realize her dream to block lupus auto-antibody activity.
The team of investigators has developed and tested a unique small molecule that sits at the door of the auto-antibody and stops it from cross-reacting with a major excitatory neuron in the brain. The hope is that it can protect neurons and kidney cells that are most vulnerable to the anti-DNA antibodies.
In a paper published this week in the Proceedings of the National Academy of Sciences, Ona Bloom, PhD, and others at the Feinstein, led by Dr. Diamond and Yousef Al-Abed, PhD, head of the Feinstein’s Laboratory of Medicinal Chemistry, tested the molecule to see whether it blocks the disease-causing activity of anti-DNA antibodies. After they tested it in a laboratory model of lupus, they studied its activity in serum taken from lupus patients.
“This is very exciting,” said Dr. Diamond. “There are no therapies that are based on blocking this antibody from damaging target organs.”
What does it take to build a molecule from the ground up? Dr. Al-Abed said that the antibody detected in lupus patients was known to recognize a 5-amino acid peptide that is part of the NMDA glutamate receptor. NMDA is a major excitatory neurotransmitter in the body. Dr. Al-Abed and his team studied the structure of the peptide and began building a drug piece by molecular piece until they came up with a promising candidate they called FISLE-412.
“The surprise was that we were able to create a small molecule that binds to the site on the antibody that prevents it from becoming active,” said Dr. Al-Abed. “This is very early in the development of this compound but right now it is showing us that as a proof of concept, it works. We can block the auto-antibody and maybe someday we will be able to develop and test it as a treatment for lupus patients. It is an attractive approach.”
Dr. Diamond said the next step is to test it in a larger number of laboratory models and then to design clinical studies with patients. The Feinstein Institute has a large lupus research initiative with scientists from all fields homing in on this autoimmune disease. The Feinstein also supports four clinics for lupus patients on Long Island, Queens and Manhattan.
About The Feinstein Institute for Medical Research Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson’s disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. For more information: www.FeinsteinInstitute.org.