Seeking to unravel biological mysteries and to cure rare human diseases, the Jonathan Miner Laboratory studies rare diseases caused by single-gene mutations — including retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S).
What is Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL)?
Previously known as HERNS, RVCL is a small vessel vasculopathy characterized by brain, retina, kidney, and liver injury in all cases, as well as Raynaud's disease, osteonecrosis and thyroid disease in a subset of patients.
Frequently misdiagnosed as having systemic lupus erythematosus or multiple sclerosis, patients with RVCL develop autoantibodies. But the disease does not respond to immunosuppression.
A truly rare disease, there are approximately 200 patients in the world diagnosed with the disease, and there are undoubtedly many others who go undiagnosed.
Autosomal dominant mutations in the TREX1 gene cause RVCL. The impact of RVCL on families cannot be overstated, since 50% of family members become disabled and die prematurely.
Symptoms begin in the 4th or 5th decades of life — leading to blindness, brain lesions, chronic renal insufficiency, and abnormal liver function. Most patients lose the ability to walk. All patients with RVCL become disabled and die prematurely, often within 5 or 10 years of disease onset, and there is no effective treatment for the disease.
The Penn RVCL Research Center coordinates the care of these patients, which includes longitudinal monitoring, coordinated care with ophthalmology and neurology, genetic testing, and referrals for in vitro fertilization with pre-implantation genetic diagnosis.
Martyna Dziemian was recently hired as the RVCL Nurse Navigator. She, Rennie Rhee, MD, and Jonathan J. Miner, MD, PhD, are working together on longitudinal studies and a clinical trial of crizanlizumab. Crizanlizumab is a monoclonal antibody that blocks P-selectin, an adhesion molecule expressed on the activated vascular endothelium.
Researching RVCL
CRISPR allows scientists to locate a faulty gene
and cut the DNA strand where the error is located to remove, fix, or replace it.
Dr. Miner, an RVCL expert, began studying RVCL while he was training in a virology laboratory.
The TREX1 gene is important in regulating the response to viral infections. Dr. Miner became interested when he discovered that TREX1 regulated responses to West Nile virus infection, which was a major topic of his research at the time. When Dr. Miner discovered that there were rheumatic disease patients with mutations in genes that regulate antiviral immunity, he decided to generate animal models of these rare diseases.
The animal models are playing an important role in defining mechanisms using genetic and molecular approaches. The models also allow testing of therapies. This work has led to numerous international collaborations, including fruitful interactions with scientists at Niigata University in Japan as well as with geneticists and nephrologists in Australia.
In the last year, the Miner Laboratory identified molecular mechanism underlying RVCL in collaboration with colleagues in Japan. They also developed a CRISPR-based gene therapy for RVCL, which is currently being tested in animal models of the disease.
Additionally, they are working with a medicinal chemist at the University of Michigan to develop small molecular drugs that target the TREX1 protein.
Gene therapy trials involving the retina are underway using CRISPR prime editing delivered by Adeno-associated virus (AAV).
Newly established collaborations with the Institute for RNA Innovation at Penn are also underway.
The Weissman and Muzykantov Laboratories at Penn are generating RNA-nanoparticle complexes, which will be targeted to specific organs to correct the mutant TREX1 gene. There is also work underway to target specific organs using virus-based delivery of CRISPR-based gene therapies, including the retina. The other innovative approach under development includes monoclonal antibodies conjugated to small RNAs that block expression of the mutant TREX1 protein. These antibody-RNA hybrid biologics will hopefully provide new avenues for the treatment of other monogenic diseases.
New patients are identified every month, and many of the patients and families are crowd funding these efforts. Every year, a large RVCL fundraiser is held Chicago, called Illumination — a Halloween costume party. Thousands of people attend the event, where they raise more than 1 million dollars each year. The majority of those funds are donated to support our research center at the University of Pennsylvania.
Our hope is that the technologies and approaches being developed to treat RVCL will eventually become available for other rare diseases caused by single-gene mutations.
Dr. Miner has set an audacious goal to have multiple concurrent clinical trials running within the next five years that will test treatments in the retina, liver, brain, and kidney, where RVCL does the most organ and system damage.
View more information on the RVCL Research Center at the Perelman School of Medicine and Miner Laboratory websites.