Nav: Home

Routing gene therapy directly into the brain

December 06, 2017

A therapeutic technique to transplant blood-forming (hematopoietic) stem cells directly into the brain could herald a revolution in our approach to treating central nervous system diseases and neurodegenerative disorders.

The technique, which could be used to transplant donor-matched hematopoietic stem cells (HSCs) or a patient's own genetically-engineered HSCs into the brain, was reported in Science Advances today by researchers from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the San Raffaele Telethon Institute for Gene Therapy.

In their study, the team tested the technique in a mouse model to treat lysosomal storage disorders, a group of severe metabolic disorders that affect the central nervous system.

The team's findings are groundbreaking because, until now, it was thought that HSCs -- from a healthy, matched donor or a patient's own genetically-corrected cells -- needed to be transplanted indirectly, through an intravenous line to the bloodstream.

Therapeutic success has then depended on those cells engrafting in a patient's bone marrow, maturing and naturally circulating into the brain, at a very slow and inefficient rate.

A race against time

But in children with lysosomal storage disorders, caused by enzyme imbalances that result in a dangerous build-up of lipids, carbohydrates or other materials in the body's cells, time is of the essence to stop the disease's progression.

"The main issue with the conventional HSC transplant strategy has been the length of time needed for the therapy to take effect in the brain," says Alessandra Biffi, MD, director of the gene therapy program at Dana-Farber/Boston Children's and the senior author of the new study.

"It can take up to a year for the genetically-engineered cell lineage to proliferate, spread and produce therapeutic effects in the brain -- oftentimes, patients don't have the luxury of time to wait," Biffi adds.

Biffi and her team wanted to find a faster -- and more direct -- way to transplant therapeutic HSCs into the brain.

In a mouse model of lysosomal storage disorders, Biffi's team transplanted HSCs -- which they had genetically engineered to correct the enzyme imbalance -- directly into the brain. They found the direct approach jumpstarted the therapeutic benefits much faster than intravenous infusion alone. They call their method, which infuses the cells into fluid-filled cavities in the brain called ventricles, "intracerebroventricular" delivery.

Creating a chimera

Once the genetically-engineered HSCs are transplanted into the brain's ventricles, the crucial enzyme they contain helps to metabolize the materials that were previously building up and causing tissue damage.

A new lineage of cells descended from the transplanted HSCs -- a type of cell called a myeloid -- begin to scavenge and consume the excess material that is responsible for neurodegeneration.

"There's a positive impact from the presence of the new, metabolically-functional myeloid cells because they release signaling cytokines that counteract neuroinflammation, which if unchecked can trigger neuronal damage," Biffi says.

Importantly, the transplanted HSCs engraft in the mouse brains without migrating to other areas of the central nervous system. This essentially could create a chimera -- a separate genetic profile within an organism -- within the brain.

The ability to engineer a chimeric population of brain cells could open powerful new avenues to preventing or reversing neurodegenerative diseases like Parkinson's, Alzheimer's, ALS and more.

From the lab to the human brain

Although transplanting HSCs directly into the human brain sounds invasive at first, Biffi explains that the procedure would not be overly complex in actuality.

"I envision this could be a one-time treatment accomplished via a catheter temporarily placed into the brain's ventricles, under standard anesthesia," Biffi says. "This would be in line with currently-used clinical procedures that enable access to the brain for treatment."

Based on the promising results of their mouse studies, Biffi and her colleagues are moving forward with plans to develop the procedure for the clinic.

She says there is great potential for intracerebroventricular delivery of genetically-modified HSCs, alone or in combination with intravenous gene therapies. This approach would be a new tool for clinicians to treat a range of conditions that affect the brain or the entire nervous system.
-end-
In addition to Biffi, other authors on the study were: Alessia Capotondo, Rita Milazzo, Jose M. Garcia-Manteiga, Eleonora Cavalca, Annita Montepeloso, Brian S. Garrison, Marco Peviani and Derrick J. Rossi.

This study was funded by the European Community (Consolidator European Research Council 617162), the Italian Ministry of Health (GR-2011-02347261), Telethon Foundation (TGT_B01) and Boston Children's Hospital.

Boston Children's Hospital

Related Gene Therapy Articles:

Mysterious gene transcripts after cancer therapy
Drugs that are used in cancer therapy to erase epigenetic alterations in cancer cells simultaneously promote the production of countless mysterious gene transcripts, scientists from the German Cancer Research Center now report in Nature Genetics.
Gene therapy could 'turn off' severe allergies
A single treatment giving life-long protection from severe allergies such as asthma could be made possible by immunology research at The University of Queensland.
Lipid nanoparticles for gene therapy
Twenty-five years have passed since the publication of the first work on solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as a system for delivering drugs.
New gene therapy for pseudarthrosis trialed at Kazan University
A team headed by Professor Albert Rizvanov, director of the Gene and Cell Technologies Open Lab, created a gene therapy drug that encodes growth factors for the stimulation of blood vessel and bone formation.
WSU researcher develops safer gene therapy
A Washington State University researcher has developed a way to reduce the development of cancer cells that are an infrequent but dangerous byproduct of gene therapy.
New gene therapy prevents muscle wasting associated with cancer
A new gene therapy could be used to prevent the loss of muscle mass and physical strength associated with advanced cancer
On the path to controlled gene therapy
The ability to switch disease-causing genes on and off remains a dream for many physicians, research scientists and patients.
Gene therapy against brain cancer
A team from the International School for Advanced Studies (SISSA) in Trieste has obtained very promising results by applying gene therapy to glioblastoma.
First gene therapy successful against human aging
Elizabeth Parrish, CEO of Bioviva USA Inc. has become the first human being to be successfully rejuvenated by gene therapy, after her own company's experimental therapies reversed 20 years of normal telomere shortening.
Designing gene therapy
Scientists in the Barabas group at EMBL have increased the efficiency of a genome-engineering tool called Sleeping Beauty, which is showing promise in clinical trials for leukemia and lymphoma immunotherapies.

Related Gene Therapy Reading:

The Forever Fix: Gene Therapy and the Boy Who Saved It
by Ricki Lewis (Author)

Fascinating narrative science that explores the next frontier in medicine and genetics through the very personal prism of the children and families gene therapy has touched.

Eight-year-old Corey Haas was nearly blind from a hereditary disorder when his sight was restored through a delicate procedure that made medical history. Like something from a science fiction novel, doctors carefully introduced viruses bearing healing genes into Corey's eyes―a few days later, Corey could see, his sight restored by gene therapy.
THE FOREVER FIX is the first book to tell the fascinating story... View Details


The Gene Therapy Plan: Taking Control of Your Genetic Destiny with Diet and Lifestyle
by Mitchell L. Gaynor MD (Author), Mehmet C. Oz M.D. (Foreword)

Your genes are not your destiny: learn to prevent disease, improve brain function, and reverse the course of obesity and premature aging through easy-to-adopt nutrition and lifestyle changes that target your DNA
 
While we cannot alter the genes we are born with, we can prevent and reverse disease with foods, supplements, and lifestyle choices that turn good genes on and bad genes off. In his pathbreaking plan, Dr. Mitchell Gaynor—a renowned oncologist and pioneer in integrative medicine—focuses on obesity, heart disease, diabetes, cancer, and aging to explain... View Details


Gene Therapy in Neurological Disorders
by Mingjie Li (Editor), B. Joy Snider (Editor)

Gene therapy has tremendous potential for the treatment of neurological disorders. There has been substantial progress in the development of gene therapy strategies for neurological disorders over the last two decades. Gene Therapy in Neurological Disorders thoroughly reviews currently available gene therapy tools and presents examples of their application in a variety of neurological diseases. The book begins with general reviews of gene therapy strategies with a focus on neurological disorders. The remainder of the chapters present approaches to specific neurological disorders.... View Details


The Gene: An Intimate History
by Siddhartha Mukherjee (Author)

THE #1 NEW YORK TIMES BESTSELLER
A New York Times Notable Book
A Washington Post and Seattle Times Best Book of the Year


From the Pulitzer Prize-winning author of The Emperor of All Maladies—a fascinating history of the gene and “a magisterial account of how human minds have laboriously, ingeniously picked apart what makes us tick” (Elle).

“Dr. Siddhartha Mukherjee dazzled readers with his Pulitzer Prize-winning The Emperor of All Maladies in 2010. That achievement was evidently just a warm-up for... View Details


Gene Therapy in Reconstructive and Regenerative Surgery
by Giorgio Giatsidis (Editor)

This book offers an updated overview of the most recent research advances in the field, a comparison of established techniques and methods, a discussion on current experimental and translational challenges, and a commentary on potential opportunities and future directions.

Dedicated chapters address and review the preclinical and clinical state-of-the-art of gene therapies for the reconstructive and regenerative surgery of skin and wounds, pathological scars, cartilage, tendons, skeletal muscles, and bio-engineered flaps. A brief guide to developing gene therapy clinical trials in the... View Details


Advanced Textbook on Gene Transfer, Gene Therapy and Genetic Pharmacology: Principles, Delivery and Pharmacological and Biomedical Applications of ... (Icp Textbooks in Biomolecular Sciences)
by Daniel Scherman (Author), Daniel Scherman (Editor)

This unique advanced textbook provides a clear and comprehensive description of the field of gene delivery, gene therapy and genetic pharmacology, with descriptions of the main gene transfer vectors and a set of selected therapeutic applications, along with safety considerations.

The use of gene transfer is exponential in the scientific and medical community, both for cell biology experiments and for gene therapy revolutionary strategies. The advanced textbook should thus be of invaluable utility to Master, PhD or MD students, post-doctoral scientists or medical doctors, and to any... View Details


Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Fourth Edition
by Nancy Smyth Templeton (Editor)

The Most Comprehensive, State-of-the-Art Book on Using Gene and Cell Therapy in Clinical Medicine

Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, Fourth Edition presents extensive background and basic information, state-of-the-art technologies, important achievements, and lingering challenges in the fields of gene and cell therapies. The fourth edition of this bestseller continues to provide the most comprehensive coverage of these fields in one volume. Some chapters have expanded introductions, making the book even more suitable for classroom... View Details


Adenoviral Vectors for Gene Therapy, Second Edition
by David T. Curiel (Editor)

Adenoviral Vectors for Gene Therapy, Second Edition provides detailed, comprehensive coverage of the gene delivery vehicles that are based on the adenovirus that is emerging as an important tool in gene therapy. These exciting new therapeutic agents have great potential for the treatment of disease, making gene therapy a fast-growing field for research.

This book presents topics ranging from the basic biology of adenoviruses, through the construction and purification of adenoviral vectors, cutting-edge vectorology, and the use of adenoviral vectors in preclinical animal... View Details


GUIDE TO HUMAN GENE THERAPY, A
by Roland W Herzog (Editor), Sergei Zolotukhin (Editor)

Ever since the birth of molecular biology, the tantalizing possibility of treating disease at its genetic roots has become increasingly feasible. Gene therapy — though still in its infancy — remains one of the hottest areas of research in medicine. Its approach utilizes a gene transfer vehicle ("vector") to deliver therapeutic DNA or RNA to cells of the body in order to rectify the defect that is causing the disease. Successful therapies have been reported in humans in recent years such as cures in boys with severe immune deficiencies. Moreover, gene therapy strategies are being... View Details


Gene Therapy
by Mary Colavito (Author), Michael A. Palladino (Author)

KEY MESSSAGE: Will gene therapy one day become the ultimate application of genetic technology?  Gene Therapy, the newest booklet in the Special Topics in Biology Series, addresses this question by exploring gene therapy as a complex technology for delivering therapeutic genes as a way to treat and cure human genetic diseases. Author Mary Colavito provides an overview of the basic science involved in gene therapy methods and chronicles the history of gene therapy by discussing successful and ongoing gene therapy treatments as well as adverse outcomes in... View Details

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

The Person You Become
Over the course of our lives, we shed parts of our old selves, embrace new ones, and redefine who we are. This hour, TED speakers explore ideas about the experiences that shape the person we become. Guests include aerobatics pilot and public speaker Janine Shepherd, writers Roxane Gay and Taiye Selasi, activist Jackson Bird, and fashion executive Kaustav Dey.
Now Playing: Science for the People

#479 Garden of Marvels (Rebroadcast)
This week we're learning about botany and the colorful science of gardening. Author Ruth Kassinger joins us to discuss her book "A Garden of Marvels: How We Discovered that Flowers Have Sex, Leaves Eat Air, and Other Secrets of the Way Plants Work." And we'll speak to NASA researcher Gioia Massa about her work to solve the technical challenges of gardening in space.