Researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) are working towards the first human clinical trial of a novel treatment for Parkinson’s disease.
The new approach, published in Molecular Therapy in 2020, solves two pieces of the puzzle that have prevented previous treatments from working. The new treatment provides:
– A new way to perform stem cell transplantation without the toxicity that results from traditional protocols using irradiation or chemotherapy.
– A targeted method to deliver treatment naturally through the patient’s blood cells, across the blood-brain barrier, to reach the dysfunctional brain cells.
Parkinson’s is a chronic, neurodegenerative disease that causes a progressive loss of the ability to control muscle movements, as well as various non-muscle symptoms such as sleep disturbance, loss of smell and bowel problems. According to the Parkinson’s Foundation, more than 10 million people in the world are living with Parkinson’s, including well-known actor Michael J. Fox. Nearly 1 million individuals in the U.S. have the disease and approximately 60,000 are newly diagnosed each year.
Scientists have located the area deep within the brain where the damage occurs, the substantia nigra. Parkinson’s is characterized by a progressive loss of dopamine neurons in this area of the brain. Dopamine is a chemical messenger that sends signals between nerve cells. There is no cure for Parkinson’s.
UT Health San Antonio preclinical and animal research has shown that a protective agent called glial cell-line derived neurotrophic factor (GDNF) can help the neurons to survive and boost dopamine production to preserve and restore motor cell function. However, delivering GDNF into the brains of humans has been problematic for several reasons. It cannot be given systemically as it does not cross the blood-brain barrier, a protective layer of cells around the brain. If GDNF is injected into the human brain, it doesn’t disperse effectively to get to the damaged cells. And because of the large mass of the human brain compared with a mouse brain, used in the animal trials, it is even more difficult to inject GDNF where it is needed.
Researchers offer new approach
Although research into the injected delivery method continues, UT Health San Antonio scientists have taken a different approach to delivering GDNF through a genetically engineered stem cell transplantation method using the body’s own natural defense system.
Part of the body’s defense system involves macrophages — blood and tissue cells that are the body’s housekeeping staff. Generally, macrophages patrol the body looking for old or damaged cells and then ingesting them. Although macrophages do not ordinarily cross the blood-brain barrier, their cousins called microglia patrol the brain in search of dysfunctional cells. Because cleaning up damaged cells is their job, macrophages and microglial cells are naturally drawn to damaged cells, and this helps in harnessing them for treatment.
UT Health San Antonio researchers further have developed a system to transplant into the bone marrow the patient’s own genetically modified blood-generating stem cells carrying the GDNF gene. The researchers collect and separate the blood cells in the laboratory to isolate CD34-positive cells, a type of stem cell that can reproduce all types of blood cells. These stem/progenitor cells are genetically modified to carry the GDNF gene, which provides them with the ability to synthesize the neuroprotective agent GDNF. The genetically modified stem cells are infused into a vein in the patient’s arm, instead of needing to be injected into the brain.
In order to allow the use of stem cell transplantation in non-cancer settings, such as Parkinson’s patients, the researchers developed a non-toxic pre-conditioning approach involving the mobilization of stem cells from the bone marrow into blood circulation, leaving their specialized niches open and available to receive the incoming genetically modified stem cells. Once these therapeutic stem cells engraft in the bone marrow, they produce circulating blood cells, including monocytes, which convert to macrophages as they enter tissue sites. In Parkinson’s disease the blood-brain barrier is modified, allowing entry into the brain of therapeutic macrophages. These newly arrived cells form microglia, which home in on the areas damaged by Parkinson’s disease. The microglia produce and deliver GDNF, which protects and restores the damaged neurons, encouraging dopamine production.
“Once these genetically modified stem cells start to reproduce they do this indefinitely, essentially providing a lifelong source of therapy,” explained Senlin Li, MD, corresponding author of the Molecular Therapy publication. Dr. Li is a professor in the Division of Infectious Disease, part of the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.
“We are looking optimistically toward a Phase 1 human clinical trial,” added study co-author Robert Clark, MD, professor of medicine and of microbiology, immunology and molecular genetics. He also is co-director of the Perry & Ruby Stevens Parkinson’s Disease Center of Excellence.
Similar strategies using genetically modified stem cells/macrophages to deliver therapeutic proteins have already been successfully translated into treatments for two rare hereditary neurodegenerative disorders — metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD).
“If our preclinical and animal findings also prove translatable in human trials, it will be a major advance in treating Parkinson’s. It may also prove to be useful in treating Alzheimer’s disease and for countering some aspects of aging,” Dr. Clark added. Furthermore, the mobilization-based delivery system can be adopted to improve other stem cell-based therapies by reducing toxicity-related complications that plague current transplant conditioning strategies.
“This technology and treatment are awaiting Food and Drug Administration approval to launch a first-in-humans clinical trial,” added Andrea Giuffrida, PhD, vice president for strategic industry ventures at UT Health San Antonio.
Drs. Clark and Li are scientific founders of a UT Health San Antonio startup company called HemaCure, dedicated to this new technology and treatment. Other UT Health San Antonio co-inventers of the potential treatment are Cang Chen, now retired, and former graduate student Michael Guderyon. The invention is owned by The University of Texas System.