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University of Iowa scientists use blood-brain barrier as therapy delivery system
September 22, 2009Enzyme delivered through the bloodstream corrects deficiencies in the brain
The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.
Working with animal models of a group of fatal neurological disorders called lysosomal storage diseases, the UI team found that these diseases cause unique and disease-specific alterations to the blood vessels of the blood brain barrier. The scientists used these distinct alterations to target the brain with gene therapy, which reversed the neurological damage caused by the diseases.
The findings, which were published Sept. 13 in Nature Medicine's Advance Online Publication (AOP), could lead to a new non-invasive approach for treating neurological damage caused by lysosomal storage diseases.
"This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain," said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. "This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.
"In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons," she added.
Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.
Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.
"Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials," said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. "In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected."
To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.
The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.
The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.
The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.
University of Iowa
"This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain," said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. "This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.
"In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons," she added.
Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.
Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.
"Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials," said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. "In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected."
To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.
The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.
The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.
The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.
University of Iowa
Lysosomal Storage Current Events and Lysosomal Storage News RSSResearch reveals lipids' unexpected role in triggering death of brain cells
The lipid that accumulates in brain cells of individuals with an inherited enzyme disorder also drives the cell death that is a hallmark of the disease, according to new research led by St. Jude Children's Research Hospital investigators.
Scientists successfully reprogram blood cells
Researchers have transplanted genetically modified hematopoietic stem cells into mice so that their developing red blood cells produce a critical lysosomal enzyme -preventing or reducing organ and central nervous system damage from the often-fatal genetic disorder Hurler's syndrome.
Rare genetic disease successfully reversed using stem cell transplantation
A recent study by Scripps Research Institute scientists offers good news for families of children afflicted with the rare genetic disorder, cystinosis.
Gene therapy slows progression of fatal neurodegenerative disease in children
Gene therapy to replace the faulty CLN2 gene, which causes a neurodegenerative disease that is fatal by age 8-12 years, was able to slow significantly the rate of neurologic decline in treated children.
One shot of gene therapy spreads through brain in animal study
By targeting a site in a mouse brain well connected to other areas, researchers successfully delivered a beneficial gene to the entire brain-after one injection of gene therapy. If these results in animals can be realized in people, researchers may have a potential method for gene therapy to treat a host of rare but devastating congenital human neurological disorders, such as Tay-Sachs disease.
Stem cells act through multiple mechanisms to benefit mice with neurodegenerative disease
Human embryonic stem cells (hESCs) hold great promise for benefiting degenerative diseases, and do so by invoking multiple mechanisms. Such cells can be grown in a manner compatible with clinical use (i.e., without animal feeder layers) and even without the need for immunosuppression.
Previously approved drugs may be helpful in fatal pediatric disorder
A progressive neurodegenerative disorder that is often fatal within the first two decades of life may be treatable via a molecule already targeted by approved drugs.
Idursulfase is effective treatment for Hunter syndrome, clinical trial concludes
An article reporting results from a pivotal clinical trial that helped gain U.S. Food and Drug Administration approval for the first treatment for Hunter disease has been published online by the journal Genetics in Medicine.
Toward a less expensive, more convenient treatment of Gaucher's disease
Prospects for eventual development of a less costly and more convenient treatment for Gaucher's disease have brightened with new research findings reported in the May issue of ACS Chemical Biology.
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Lysosomal Storage Disorders: Principles and Practice by Gregory M., M.D. Pastores (Author) The book will present an overview of the lysosomal storage disorders, and will provide the reader with an understanding of clinical features, associated complications, diagnosis and management approaches. In addition, the book will also describe historical developments in the field and current thinking relating to pathophysiology and prospective therapeutic strategies. The book is written by an expert in the field who has been engaged in both basic and clinical research, in addition to having extensive practical experience patient care. The perspective is from someone who entered the field just as treatment was being introduced, and who has been engaged in the seminal clinical trials and the development of therapeutic guidelines. The book offers a broad perspective and should appeal to... |
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Enzyme therapy in lysosomal storage diseases: Proceedings of the Workshop Cell Biological and Enzymological Aspects of the Therapy of Lysosomal Storage ... Leiden, The Netherlands, April 4-5, 1974 by Elsevier (Publisher) | |
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Neurochemistry of Metabolic Diseases - Lysosomal Storage Diseases, Phenylketonuria and Canavan Disease by Edited by Sankar Surendran (Author), Sankar Surendran (Editor) This book provides critical, comprehensive overview of monogenic defects causing neurological abnormalities on lysosomal storage diseases, Phenylketonuria and Canavan disease and was compiled to understand how a single gene defect impedes normal metabolic activity to result in pathophysiological abnormalities. In addition, therapeutical approaches in treating monogenic traits have also been presented. The articles assembled in this book will bring the reader thoughtful appraisals of past accomplishments, fresh concepts on monogenic traits and an exciting glimpse of future developments in the field of metabolic disorder. It is hoped that the text will primarily interest advanced biomedical scientists, neuroscientists and pathologists interested in Lysosomal storage diseases,... |
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Bone marrow transplantation for treatment of lysosomal storage diseases: Proceedings of a colloquium held May 7, 1985, Washington, D.C (Birth defects, original article series) by William Krivit (Editor), Natalie W. Paul (Editor) | |
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Enzyme Therapy in Lysosomal Storage Diseases by Joseph M, etc. Tager (Author) | |
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Molecular Basis of Lysosomal Storage Disorders by John A. Barranger (Editor), Roscoe O. Brady (Editor) | |
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Lysosomal Storage Disease: Aspartylglycosaminuria (Medical Intelligence Unit) by Ilkka Mononen (Editor), Nathan N. Aronson Jr. (Editor) This volumes provides a comprehensive and up-to-date review of aspartylglycosaminuria (AGU), which is one of the most common lysosomal diseases worldwide. It gives an overview of the disease from its discovery and early history to the most recent developments. It also provides detailed reference material for clinical specialists and researchers working in the field of inborn errors of metabolism, in particular on lysosomal diseases. | |
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Lysosomal Storage Disorders by John A. Barranger (Author), John A. Barranger (Editor), Mario Cabrera (Editor) Lysosomal Biology and Storage Disorders John A. Barranger and Mario A. Cabrera-Salazar The knowledge of lysosomal biology and the consequences of its dysfunction have increased dramatically in the past 60 years. Research of these disorders has moved from diseases with unknown etiology to disorders with clear and defined pathophysiology and some of them have benefited from the development of disease specific therapeutics. Lysosomal Biology and Storage Disorders describes the nature of the diseases, the historical evolution of the field and future perspectives for the treatment of these clinical entities. Organized as a textbook, Lysosomal Biology and Storage Disorders describes the nature of lysosomal dysfunction, the synthesis and targeting of... |
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Lysosomal Disorders of the Brain: Recent Advances in Molecular and Cellular Pathogenesis and Treatment by Frances M. Platt (Author), Steven U. Walkley (Author) Univ. of Oxford, UK. Details recent advances in the molecular and cellular pathologies of a variety of lysosomal storage diseases. Also discusses the development of effective therapies. Provides an overview of each storage disease and describes the molecular mechanisms of storage. For clinicians. |
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Hematologic Cytology of Storage Diseases by H. G. Hansen (Author), Cooper-Schulter (Translator) |
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