The Giorgio Foundation is proud to join with Dr Sameer Agnihotri of the University of Pittsburgh to fund an exciting proof of principle project. While the Giorgio Foundation works to fund research into treatments and a cure for disfiguring dermal tumors, we are also interested in other new exciting areas of research.
Neurofibromatosis Type 1 is caused by a mutation in the NF1 or tumor suppressor gene. A loss of the NF1 protein promotes over active cell growth and causes tumors as well as other problems. Dr Agnihotri will test the concept of adding NF1 back into the gene using a method called transplicing.
As research into gene therapy advances, the Giorgio Foundation is proud to fund this proof of concept in the hopes that one day, instead of treating the symptoms, we can fix the NF1 gene.
More NF research from UT-Southwestern was published in this 2020 edition of Neuro-Oncology Advances. There are new insights into the origin cells for NF-related tumors. Pinpointing this cell is very important in developing targeted therapy. See the full article.
“Although research is underway to find an effective medical treatment for cNF, there is an urgent need to develop a surgical approach that is accessible to all NF1 patients worldwide with the skill set and equipment found in most general medical office settings. Here, we present a robust surgical approach to remove cNFs that does not require a sterile surgical field, uses accessible clinical equipment, and can be performed by any health care provider, including family practitioners and physician assistants.”
Research funded by the Giorgio Foundation was just published in JCI insight medical journal.
Dr. Anastasaki is a geneticist and the senior staff scientist in Dr. Gutmann’s laboratory. While she was a postdoctoral research fellow, she spearheaded the development of the NF1 patient induced pluripotent stem cell (iPSC) repository at Washington University. For the Giorgio Foundation NF1 Dermal Neurofibroma Consortium project, Dr. Anastasaki has generated human iPSC lines from NF1 patients that don’t develop cutaneous neurofibromas (cNFs), specifically those individuals who harbor the Arg1809Cys NF1 gene mutation. As a complementary approach, she also engineered normal iPSCs with different NF1 gene mutations found in NF1 patients with and without cNFs. Over the past three years, Dr. Anastasaki has provided these novel NF1-iPCs to Dr. Le and Dr. Kesterson for collaborative studies, as well as generated a genetically engineered mouse with the Arg1809Cys Nf1 gene mutation.
Dr. Gutmann’s lab has generated a collection of human induced pluripotent stem cells (iPSCs) harboring different NF1 gene mutations found in NF1 patients with or without cutaneous neurofibromas (cNFs). The availability of these iPSCs has been transformative, allowing researchers to study the effects of NF1gene mutations on human cells, as well as to develop novel human models of cutaneous neurofibromas.
Dr. Le is a Dermatologist with a scientific and clinical focus in Neurofibromatosis. He received his M.D. and Ph.D. from the Medical Scientist Training Program at UCLA, completed his residency and cancer biology postdoctoral research fellowship at University of Texas Southwestern Medical Center, where he is currently an associate professor. As a principal investigator in this Giorgio Foundation funded project, Dr. Le works with other scientists in his laboratory that includes Dr. Juan Mo, Ph.D (postdoctoral fellow); Dr. Andy Chen, M.D., Ph.D. (postdoctoral fellow); and Tracey Shipman (Senior Research Associate) to understand the biology that give rise to cutaneous neurofibroma as well as to develop novel therapeutic targets for these disfiguring tumors.
A lay person’s description of Giorgio Foundation funded project:
Cutaneous neurofibroma is the most common tumor in Neurofibromatosis Type 1. They usually arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for cutaneous neurofibroma aside from elective surgery. The major barriers that impede progress in this field are the lack of accurate models of these common tumors for drug identification and evaluation of factors that are required for their development. In this Giorgio Foundation collaborative project between different laboratories, Dr. Le and his research team leverage on their clinical and laboratory research expertise in neurofibromatosis to generate novel, physiologically relevant mouse and human derived cutaneous neurofibroma models to study what cause these tumors to develop and for therapeutic testing. The next step for Dr. Le and his team is to utilize these reagents to pinpoint the biological steps that are critical for neurofibroma development so that they can be therapeutically targeted to prevent or delay tumor development.
David H. Gutmann, MD, PhD received his undergraduate, graduate (PhD) and medical (MD) degrees from the University of Michigan, where he trained in immunogenetics in the laboratory of Dr. John Niederhuber. During his residency in Neurology at the University of Pennsylvania, he worked with Dr. Kenneth Fischbeck who sparked his interest in neurogenetics. He then returned to the University of Michigan for research fellowship training in Human Genetics with Dr. Francis Collins. During this time, he identified the neurofibromatosis type 1 (NF1) protein and began to elucidate its function as a RAS regulator. In late 1993, he was recruited to Washington University, becoming a full professor in 2001 and the Donald O. Schnuck Family Professor in 2002. He established the St. Louis Children’s Hospital Neurofibromatosis Clinical Program in 1994 and the Washington University Neurofibromatosis Center in 2004.
Dr. Gutmann serves as the Program Director for the Giorgio Foundation NF1 Dermal Neurofibroma Consortium, and works closely with Drs. Kesterson and Le to employ a combination of human induced pluripotent stem cells, genetically engineered mouse strains, and molecular approaches to understand why dermal neurofibromas form and grow.
In addition, his laboratory is focused on understanding the genomic, molecular and cellular basis for nervous system problems affecting children and adults with NF1 using both human biospecimens and novel genetically-engineered mouse strains. Over the past 25 years, his team has developed numerous mouse models of NF1-associated optic glioma, somatic growth defects, attention deficit, autism, plexiform neurofibroma, and spatial learning impairments as well as NF2-associated meningioma. They have used these preclinical models to define the cellular origins of tumors, the contribution of the tumor microenvironment, and the major growth control pathways that dictate brain development in NF.
Dr. Gutmann has published over 430 peer-reviewed manuscripts, and has been internationally recognized for his achievements with numerous awards, including the 2012 Children’s Tumor Foundation Frederich von Recklinghausen Lifetime Achievement Award, the 2013 Washington University Distinguished Faculty Research Award, the 2014 Riley Church Lectureship and the 2017 Alexander von Humboldt Award. He also serves as a member of the National Institute of Neurological Disorders and Stroke Advisory Council. Dr. Gutmann is an elected fellow of the American Academy of Neurology and the American Neurological Association.