Research
Though RVCL is a rare genetic disorder, we strive to promote education, identification, and research generation.
We are determined to find a cure…
for Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL) and maintain long-term ongoing research grants with the University of Pennsylvania, The University of Michigan, and Washington University. The space between scientific potential and human application can broadly be categorized as “academic research.” Without this important bridge, new advancements would cease to exist, hope would wane, and RVCL would continue unchecked. Fortunately, scientific progress exists, and we are excited to be a part of such a revolution. Favor fortunes the brave, and we love to support researchers who have innovative ideas and projects that may one day clinically benefit RVCL patients.
Currently, we are supporting several active research projects which have the potential for great knowledge to be gained and clinical advancements achieved.
Institutional Partners
Institutional Partner: University of Pennsylvania
The RVCL Research Center at the University of Pennsylvania (“UPenn”) is directed by Dr. Jonathan Miner, a rheumatologist with an extensive publication record in studies of rare rheumatic diseases. Dr. Miner currently directs a research laboratory that is supported by the National Institutes of Health and by The Clayco Foundation. Dr. Miner initiated a clinical trial of Crizanlizumab for RVCL, which is currently being conducted at Penn and WashU. Additionally, Dr. Miner leads a multidisciplinary team that cares for RVCL patients from around the world. The Miner laboratory collaborates with investigators from around the world to develop personalized medicines for RVCL.
Institutional Partner: Washington University in St. Louis
RVCL was discovered at Washington University in St. Louis (“WashU”) in the late 1980s, and the disease-causing mutation was reported in 2007 by the laboratory of Dr. John Atkinson. Until recently, RVCL was referred to by other names including CRV, HERNS, and CHARIOT. WashU stroke neurologist Dr. Andria Ford currently cares for RVCL patients from around the United States and directs clinical research efforts at WashU. Dr. Ford also collaborates with physicians in multiple other subspecialties in the care of RVCL patients. In the laboratory, WashU researcher Dennis Hourcade collaborates with Dr. Miner at Penn in an NIH-funded study of the TREX1 gene.
International Partner: The Netherlands – RVCL-S studie, LUMC
The Clayco Foundation RVCL Venture is teaming up with a highly qualified and RVCL-experienced group of researchers in the Netherlands to increase the scope of research and of patient identification and aid. This kind of global connection is one of the exact reasons this venture was created and an example of where effort is being focused. With this trans-Atlantic relationship, research will be able to be expedited and we just may get to treatment options sooner.
Active Research Awards
Research Award: Washington University in St. Louis
Dr. Rajendra Apte M.D, Ph.D
Determining the extent to which retinal changes can be used as an RVCL diagnostic biomarker, and explore how new therapies may benefit overall eye health in RVCL patients.
It has been well established that RVCL patients suffer from retinal lesions and associated problems, though the extent and measurability of these retinal changes are still not fully understood. If further studied, it is possible that a more conclusive ‘retinal signature’ could be discovered that may help diagnose future RVCL patients in a quicker, more beneficial manner. In addition to diagnosability, better detailed understanding of RVCL associated eye problems may help guide treatment options and responses.
Research Award: The University of Edinburgh
Dr. David Hunt M.D, Ph.D
Developing a better model which mimics physiological human RVCL so that future therapeutic studies can be expedited.
In a sense, RVCL is a disease largely due to collapse of the microvascular system all over the body, which then causes a variety of observed symptoms. However, an RVCL model which mimics this collapse does not adequately exist, making it difficult to truly measure disease progression traits and how various treatments may benefit this underlying issue.The development of this ‘microfluidic, vascular’ RVCL model system would provide a significant tool for future study and help progress the best treatment options to the clinic for subsequent human study.
Research Award: The Institut Curie
Dr. Nicolas Manel Ph.D
Determining if RVCL is caused or exacerbated by unique DNA damage
It is a mutation in the TREX1 code and the accidental “free floating” nature of the TREX1 protein that leads to RVCL, versus the membrane-tethered Trex-1 protein in healthy individuals. To date, it is still not known why this free nature of Trex-1 causes such problems, such as vascular collapse and RVCL-associated demise. A portion of the Trex-1 protein is a DNase, a section capable of degrading DNA. In the RVCL condition, it is possible that it is this dysregulated DNAse that is inappropriately degrading important signals and causing or exacerbating the condition. The research here will investigate this possibility, which would represent an important finding as it would help to point future studies towards this functional area for therapeutic intervention.
Research Award: Washington University in St. Louis
Dr. Chao Zhou Ph.D
Developing a quicker RVCL drug-screening platform
As of today, there exist a nearly incalculable number of drugs with more constantly being created. It is possible that one of these existing drugs or a soon-to-exist drug will be beneficial in treating RVCL, however the ability to test such drugs is drastically limited by number of patients, insufficient models, and lack of time. By using the popular genetic screening system of the fruit fly, a system that can allow for genetic condition and drug testing at rapid pace, these efforts can be greatly expanded. The research here will begin with creation of the genetic system, and then subsequent vast analysis of potential therapeutic targets.
RVCL Research & Publications
Our mission is to serve as a resource for patients and clinical partners in providing education on RVCL.
RVCL Research Center at the University of Pennsylvania (Penn)
The RVCL Research Center at Penn is directed by Dr. Jonathan Miner, a rheumatologist with an extensive publication record in studies of rare rheumatic diseases. Dr. Miner currently directs a research laboratory that is supported by the National Institutes of Health and by The Clayco Foundation. Dr. Miner initiated a clinical trial of Crizanlizumab for RVCL, which is currently being conducted at Penn and WashU. Additionally, Dr. Miner leads a multidisciplinary team that cares for RVCL patients from around the world. The Miner laboratory collaborates with investigators from around the world to develop personalized medicines for RVCL.
RVCL Research Center at Washington University (WashU)
RVCL was discovered at WashU in the late 1980s, and the disease-causing mutation was reported in 2007 by the laboratory of Dr. John Atkinson. Until recently, RVCL was referred to by other names including CRV, HERNS, and CHARIOT. WashU stroke neurologist Dr. Andria Ford currently cares for RVCL patients from around the United States and directs clinical research efforts at WashU. Dr. Ford also collaborates with physicians in multiple other subspecialties in the care of RVCL patients. In the laboratory, WashU researcher Dennis Hourcade collaborates with Dr. Miner at Penn in an NIH-funded study of the TREX1 gene.
RVCL Research at the University of Michigan
Dr. Nouri Neamati is a medicinal chemist at the University of Michigan. With the support of The Clayco Foundation, the Neamati laboratory is collaborating with Miner laboratory at Penn to develop small molecule therapies that target the TREX1 protein.
Finding a Cure for RVCL
The Clayco Foundation partners with physicians and scientists from around the world to find a cure for RVCL.
Therapies currently in development
CRISPR/Cas9 is a gene editing technology that can delete a gene entirely in patients or, in some cases, to correct mutations in specific cell types. We partner with the University of Pennsylvania who is using a specialized form of CRISPR and collaborating with experts on delivery systems so that we can use CRISPR to treat RVCL by correcting the mutated TREX1 gene in patients with RVCL. This is an exciting potential treatment option, but using CRISPR to treat RVCL is no small task. Nevertheless, CRISPR is one of the key personalized medicine pathways to finding a cure for RVCL.
University of Pennsylvania laboratories are developing CRISPR-based editing technologies that will fully correct disease-causing mutations in the TREX1 gene, and we are hopeful that CRISPR-based therapies will eventually become available for the treatment RVCL.
Scientists and doctors have been talking about gene therapy for decades. Now, gene therapy is becoming a reality for rare diseases, but this type of therapy must be conducted carefully, ethically, and with rigorous testing. One major challenge for RVCL will be delivering gene therapies to the correct cell types, but Penn Medicine has experience developing and testing delivery systems for genetic diseases. You can learn more about the vital role that Penn Medicine played in the development of gene therapy in this video from the Howard Hughes Medical Institute. Note the major contributions of Penn Medicine physician-scientists Jean Bennett and Albert Maguire, a key member of our RVCL Research Center at Penn.
Small molecular inhibitors are less precise than antibody drugs and gene therapies, but they still have several major advantages. One major advantage of small molecular inhibitors is that they are easier to produce, and they can target many cell types throughout the body very easily. The University of Pennsylvania is working with collaborators to develop inhibitors and PROTACs, which are molecules that can stick to a target protein and cause it to be degraded or destroyed. The goal is to generate a PROTAC drug that will preferentially destroy the mutant form of TREX1. Dr. Nouri Neamati at the University of Michigan is sending compounds to Dr. Miner’s laboratory at the University of Pennsylvania for validation and additional testing. The Miner laboratory has generated multiple model systems for the testing of therapies for RVCL.
PROTACs are small molecule drugs that are designed to interact with a target protein and cause it to be destroyed by the cell’s own machinery. In this case, Dr. Nouri Neamati at the University of Michigan is collaborating with the Miner laboratory at Penn on the development and testing of inhibitors and PROTACs that target TREX1 for the treatment of RVCL.
Clinical Trial Status
Prevention of RVCL
