Experimental molecular therapy crosses blood-brain barrier to treat neurological disease
Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.
Posted online in PNAS Early Edition on Feb. 4, the study was led by scientists at Cincinnati Children's Hospital Medical Center.
"This study provides a non-invasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders," said Dao Pan, PhD, principal investigator on the study and researcher in the Cancer and Blood Diseases Institute at Cincinnati Children's. "Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson's and Alzheimer's."
The scientists assembled the large molecular agents by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a-L-idurondase (IDUA). Naming the agents IDUAe1 and IDUAe2, researchers used them initially to treat laboratory cultured human cells of the disease mucopolysaccharidosis type I (MPS I). They also tested the agents on mouse models of MPS I.
MPS I is one of the most common lysosomal storage diseases to affect the central nervous system, which in severe form can become Hurler syndrome. In humans, patients can suffer from hydrocephalus, learning delays and other cognitive deficits. If not treated, many patients die by age 10.
Lysosomes are part of a cell's internal machinery, serving as a waste disposal system that helps rid cells of debris to retain normal function. In lysosomal storage diseases like MPS I, enzymes needed to dissolve debris are missing, allowing debris to build up in cells until they malfunction.
In MPS I, cells lack the IDUA enzyme, allowing abnormal accumulation of a group of large molecules called glycosaminoglycans in the brain and other organs. Researchers in the current study used the new therapeutic procedure to deliver IDUA to brain cells. But first they had to successfully engineer the therapy to carry IDUA through the blood-brain barrier to diseased brain cells.
The blood-brain barrier is a physiological blockade that alters the permeability of tiny blood vessels called capillaries in the brain. Its purpose is to protect the brain by preventing certain drugs, pathogens and other foreign substances from entering brain tissues. The barrier has also been a persistent roadblock to treating brain disease with drugs.
The scientists experimented with a set of derivative components of the fatty protein apoE, which binds to fat receptors on endothelial cells that form the inside surface of capillaries in the blood-brain barrier. They discovered that tagging some of the apoE components to the IDUA enzyme allowed the modified protein to attach to endothelial cells and cross through the cells to reach brain tissues.
Researchers injected experimental IDUAe1 into the tail veins of MPS I mouse models. The tests showed that – unlike currently available un-modified enzyme treatments – the modified enzyme penetrated the blood-brain barrier and entered brain neurons and astrocytes in a dose-dependent manner.
The researchers also reported that brain cells in the treated mice exhibited normalized levels of the glycosaminoglycans and the lysosomal enzyme beta-hexosaminidase. With continued treatment through hematopoietic stem cell gene therapy, normalized levels persisted until the end of a five-month observation period, researchers said.
The scientists are continuing their preclinical studies to further verify the use of the experimental IDUA-based agents for treating MPS I, cautioning that results in laboratory mice may face additional challenges when translating to clinical application in humans.
Researchers are also testing whether the large-molecule therapeutic procedure used in the current study can be leveraged to develop other neurotherapeutic agents that cross the blood-brain barrier.
Also collaborating on the study was Roscoe O. Brady, MD, a researcher and scientist emeritus at the National Institute of Neurological Disorders and Stroke.
Journal reference: Proceedings of the National Academy of Sciences
Provided by Cincinnati Children's Hospital Medical Center
- Scientists successfully reprogram blood cells Nov 09, 2009 | not rated yet | 0
- Scientists use blood-brain barrier as therapy delivery system Sep 21, 2009 | not rated yet | 0
- One shot of gene therapy spreads through brain in animal study Oct 09, 2007 | not rated yet | 0
- Calcium aids protein folding as therapy for enzymes in types of lysosomal storage diseases Feb 05, 2008 | not rated yet | 0
- NIH grant for the move toward clinical trials targeting the lysosomal storage disease MPSIIIB May 25, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
14 hours ago Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
By discovering the new mechanism by which estrogen suppresses lipid synthesis in the liver, UC Irvine endocrinologists have revealed a potential new approach toward treating certain liver diseases.
Medical research 2 hours ago | not rated yet | 0 |
Aortic arch pulse wave velocity, a measure of arterial stiffness, is a strong independent predictor of disease of the vessels that supply blood to the brain, according to a new study published in the June issue the journal ...
Medical research 2 hours ago | not rated yet | 0
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological ...
Medical research 4 hours ago | not rated yet | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as the sensation of ...
Medical research 4 hours ago | 5 / 5 (1) | 0 |
Spanish researchers have discovered that the daily clearance of neutrophils from the body stimulates the release of hematopoietic stem cells from the bone marrow into the bloodstream, according to a report published today ...
Medical research 5 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
25 minutes ago | not rated yet | 0 |
Two out of five medical students have an unconscious bias against obese people, according to a new study by researchers at Wake Forest Baptist Medical Center. The study is published online ahead of print in the Journal of ...
53 seconds ago | not rated yet | 0
International efforts to combat a new pneumonia-like virus that has now killed 22 people are being slowed by unclear rules and competition for the potentially profitable rights to disease samples, the head ...
52 seconds ago | not rated yet | 0
Breast cancer characterized as "triple negative" carries a poor prognosis, with limited treatment options. In some cases, chemotherapy doesn't kill the cancer cells the way it's supposed to. New research from Western University ...
36 minutes ago | not rated yet | 0
Mayo Clinic researchers have used next generation genomic analysis to determine that some of the more aggressive prostate cancer tumors have similar genetic origins, which may help in predicting cancer progression. The findings ...
40 minutes ago | not rated yet | 0
(HealthDay)—A shortage of a critical tuberculosis drug has hampered the efforts of health departments across the United States to contain the spread of the highly infectious lung disease, federal officials ...
40 minutes ago | not rated yet | 0