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Accessing the Blood Brain Barrier for Chemotherapy

Posted in Cancer and Current Therapeutics, Clinical & Translational, Curation, Innovations in Neurophysiology & Neuropsychology, Neurodegenerative Diseases, tagged , , on November 9, 2015| Leave a Comment »

Accessing the Blood Brain Barrier for Chemotherapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Blood-Brain Barrier Opened Noninvasively with Focused Ultrasound for the First Time

Mon, 11/09/2015 – 9:26amby Focused Ultrasound Foundation
http://www.mdtmag.com/news/2015/11/blood-brain-barrier-opened-noninvasively-focused-ultrasound-first-time

The blood-brain barrier has been non-invasively opened in a patient for the first time. A team at Sunnybrook Health Sciences Centre in Toronto used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB), allowing the more effective delivery of chemotherapy into a patient’s malignant brain tumor.

The team, led by neurosurgeon Todd Mainprize, MD, and physicist Kullervo Hynynen, PhD, infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.

“The blood-brain barrier has been a persistent impediment to delivering valuable therapies to treat tumors,” said Dr. Mainprize. “We are encouraged that we were able to open this barrier to deliver chemotherapy directly into the brain, and we look forward to more opportunities to apply this revolutionary approach.”

This patient treatment is part of a pilot study of up to 10 patients to establish the feasibility, safety and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. The Focused Ultrasound Foundation is currently funding this trial through their Cornelia Flagg Keller Memorial Fund for Brain Research.

“Breaching this barrier opens up a new frontier in treating brain disorders,” said Neal Kassell, MD, Chairman of the Focused Ultrasound Foundation. “We are encouraged by the momentum building for the use of focused ultrasound to non-invasively deliver therapies for a number of brain disorders.”

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.

The procedure was conducted using Insightec’s ExAblate Neuro system. “This first patient treatment is a technological breakthrough that may lead to many clinical applications,” said Eyal Zadicario, Vice President for R&D and Director of Neuro Programs, Insightec.

While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.

A recent study by Gerhard Leinenga and Jürgen Götz from the Queensland Brain Institute in Australia further corroborated Hynynen’s research, demonstrating opening the blood-brain barrier with focused ultrasound reduced brain plaques and improved memory in a mouse model of Alzheimer’s disease.

Based on these two pre-clinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s is being organized.

Blood-brain Barrier Opened Non-invasively for the First Time

http://www.biosciencetechnology.com/news/2015/11/blood-brain-barrier-opened-non-invasively-first-time

Scientists, for the first time, have non-invasively opened the blood-brain barrier (BBB) in a patient.

A team at Sunnybrook Health Sciences Centre in Toronto, led by neurosurgeon Todd Mainprize, M.D., used focused ultrasound technology to more effectively introduce chemotherapy drugs into a patient’s malignant brain tumor.  The results were verified with a post procedure MRI scan, Mainprize said at a press conference Tuesday.

The blood-brain barrier is a protective layer that keeps harmful substances such as toxins from entering from the blood vessels into the brain.  Unfortunately, it also prevents many drugs from reaching the brain in adequate doses.

At the press conference, Mainprize stressed that this is a phase one safety and concept study to show that they could pass through the BBB. He noted the operation went smoothly and the patient, a 56-year-old women, who is the first of 10 to undergo the procedure for the study, is doing well.

To breach the BBB, doctors infused a chemotherapy drug, along with tiny gas-filled bubbles, into the blood stream. Then focused ultrasound was applied to the tumor and surrounding brain, causing the bubbles to vibrate, and open the BBB so high concentrations of the chemotherapy could enter targeted tissues.

The team is actively analyzing brain tissue samples to see how much of the drug was able to enter.  The findings have not been published yet, but were presented at the Focused Ultrasound Surgery Foundation meeting, according to Mainprize.

Mainprize described the device: It has 1,024 transducers that are arranged in a helmet shape that goes around the head and the forehead, and corrects for aberrations in the skull.

While the BBB has been non-invasively opened in animals, this was the first instance in humans.

“There have been hundreds and hundreds of animal models opening the blood-brain barrier, in mice, dogs, pigs, and primates, all of which have shown a very good safety profile with no changes in function behavior or hemorrhage,” Mainprize said at the press conference.

He noted that this is a reversible procedure, and the barrier is restored back to its normal function in 24 hours.

Nathan McDannold, Ph.D., associate professor of radiology at Brigham and Women’s Hospital said, “If you compare this to alternative methods, whatever risks there are, there much less than if you were invasively injecting drugs.”

The scientists believe the technology has applications beyond brain tumors, such as in Alzheimer’s and Parkinson’s diseases.

McDannold said that groups are in the process of planning a protocol that would deliver antibodies to clear amyloid proteins, associated with Alzheimer’s, and for Parkinson’s they are looking at neuroprotectives and potential gene therapies.

The trial is being funded by the Focused Ultrasound Foundation.

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Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Innovations in Neurophysiology & Neuropsychology, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, tagged , , , , , , on December 3, 2012| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

With $15.5M Grant, EU Consortium to Sequence 1,100 Exomes to Develop Diagnostics for Neurologic Diseases

November 28, 2012

A consortium of 18 European and Australian institutions and industry partners will spend five years sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases to create diagnostic panels and uncover novel therapeutic targets.

The group, known as the Neuromics Consortium, is funded with €12 million ($15.5 million) under the European Union’s seventh framework program.

Headed by the University of Tübingen, the project will involve collaboration between 12 academic centers. Iceland’s Decode Genetics will do the sequencing and will support analysis and return of results to participants. The group also plans to work with Agilent Technologies to develop and validate targeted sequencing-based diagnostic panels for specific neurologic diseases, including ataxia/paraplegias, spinal muscular atrophies and lower motor neuron diseases, and neuromuscular diseases, according to Tübingen’s Holm Graessner, the manager of the consortium.

Graessner told Clinical Sequencing News in an email that the Neuromics Consortium hopes its work will yield better diagnostic panels that can increase the diagnosis rate for ten main neurodegenerative and neuromuscular disease types — including ataxia, spastic paraplegia, Huntington’s disease, muscular dystrophy and spinal muscular atrophy — as well as provide information on genes and pathways that could inform new treatments.

According to the consortium, 30 percent to 80 percent of patients with these diseases are still undiagnosed by current single-gene tests or gene panels, and cohorts for each individual disorder are small. By combining patient groups and data from many centers and looking for commonality between some of these diseases, the consortium hopes to create diagnostics that cover a greater range of causative mutations.

While each specific disorder the group will study is relatively rare, many have overlapping manifestations, which suggest similarities in disease pathways pointing to common therapeutic strategies, according to the group.

Graessner said that the project’s whole-exome sequencing component will take place mostly in the first two years. According to the consortium’s plan, Decode Genetics — which expanded last year from array-based SNP genotyping research to a next-gen sequencing approach (CSN 11/9/2011) — will use its Illumina HiSeqs to sequence at least 1,100 subjects. The group expects this to increase the percentage of disease genes known for some of the more heterogeneous diseases in the set from about 50 percent to 80 percent.

According to Graessner, RNA sequencing is also part of the plan, as well as proteomic and other ‘omic analyses, especially as the researchers move from sequencing toward diagnostic panel development and therapeutic target research.

“We plan to [do whole-exome sequencing for] 1,100 subjects for gene identification … equally distributed over 10 disease areas,” Graessner wrote. “[This] will be done mainly in the first two years. However, for some of the diseases, such as ataxia/paraplegias, we have diagnostic panels already and in that case we [will] do the panels first and send the still unclear families for WES or WGS,” he wrote.

Graessner said that the group is just now shipping its first sample package to Decode. When this is finished the group will hold a workshop to discuss and train all the participating academic centers in the use of the Decode database for analysis of the results.

He said the team plans to work with the Halo Genomics division of Agilent, to validate diagnostic panels for ataxia, spinal muscular atrophies, lower motor neuron disease, and neuromuscular diseases. Halo was acquired by Agilent last year, and had developed an enrichment technology dubbed HaloPlex that it said was especially suited for targeted gene panels less than one megabase in size (IS 12/6/2011).

The group’s bioinformatics partner, Ariadne Genomics, will also analyze data to support the diagnostics research, as well as research on potential novel therapeutic targets, according to Graessner.

In a document describing the project, the consortium wrote that at the end of the funding period, it expects “to have elucidated the genetic basis for [more than] 80 [percent] of investigated patient groups.”

According to the group, the new genes will be added to existing databases and used to develop the first overlapping gene panel that can be used to diagnose several of these individual diseases, “overcoming time consuming and costly single gene analysis.”

Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here.

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Two Centuries of Neurology and Psychiatry in the Journal NEJM

Posted in Innovations in Neurophysiology & Neuropsychology, tagged , , , , , , , on July 5, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

http://www.nejm.org/doi/full/10.1056/NEJMra1104781?query=TOC

Fifty years ago, when the curator of the Boston Medical Library, Henry Viets, collated a score of the most important articles that had been published in the first century and a half of the New England Journal of Medicine, 10 of the 20 related to neurologic conditions. Viets HR. A score of significant papers published in the Journal during the last hundred and fifty years. N Engl J Med 1962;266:23-28

On the occasion of its 200th anniversary, one might ask why so many articles on neurologic and psychiatric diseases have been published in the Journal and what impact these pieces have had on their respective fields. Although the Journal is replete with reports of neurologic conditions that have entered the canon of medicine, it has been the large number and the breadth of clinical trials that have redefined neurology and psychiatry as active, therapeutic specialties. This article reviews the evolution of our understanding of neurologic and psychiatric conditions during the past two centuries.

Modern scientific neurology, based on neuropathology and neurophysiology, began after World War II. By 1952, patients with tabes dorsalis and general paresis had practically disappeared from hospital wards. Antimicrobial agents had changed the course of bacterial and tuberculous meningitis, but poliomyelitis was still a nemesis. Denny-Brown‘s Shattuck Lecture on the state of neurology that year in the Journal pronounced that, freed from its preoccupation with syphilology and now separating itself from internal medicine and psychiatry, neurology had “entered on an extremely productive and virile phase.” Denny-Brown DE. The changing pattern of neurologic medicine. N Engl J Med1952;246:839-846

Denny-Brown emphasized recent contributions on the neurologic aspects of liver failure, the recognition that transient ischemic attacks were due to occlusion of the carotid artery, and the emerging understanding of increased intracranial pressure. There was little question at the time that neurologic and psychiatric diseases both acted on the same brain, but Denny-Brown’s position in his Shattuck Lecture marked the emergence of American neurology, pointedly disengaging it from the popular practice of neuropsychiatry and aligning it with internal medicine. He provided a modern manifesto for neurology, which nonetheless remained largely an elegant diagnostic specialty.

TWO INFLUENTIAL ARTICLES

A seemingly mundane clinical neurology article in the pages of the Journal had a highly felicitous effect on the relief of human suffering by addressing the problem of sciatica. That 1934 report by Mixter and Barr

Mixter WJ, Barr JS. Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 1934;211:210-215 established intervertebral disk rupture with nerve-root compression as the mechanism and also provided a remarkably sophisticated analysis of cervical-disk herniation and cord compression. It presented detailed instructions for the cure — in both instances, laminectomy. Twelve terse pages provided meticulous clinical descriptions and drawings of the corrective operation (Figure 1FIGURE 1Mixter and Barr’s Descriptions and Operation for Disk Rupture.). The enduring impact of that article, as well as the continuity of attention to this topic in the Journal, was affirmed by a 2007 report on a clinical trial that showed the superiority of surgery over conservative management. Peul WC, van Houwelingen HC, van den Hout WB, et al. Surgery versus prolonged conservative treatment for sciatica. N Engl J Med 2007;356:2245-2256

The excess of ill-advised laminectomies for back pain that followed Mixter and Barr’s article was not their doing; in a less frequently cited but more detailed contribution published in the Journal 6 years after their first report, they state, “We wish to emphasize at this point that a large proportion of the cases of sciatica resolve spontaneously or under conservative orthopedic treatment.” Mixter WJ, Barr JS. Protrusion of the lower lumbar intervertebral disks. N Engl J Med1940;223:523-529

Second article, An influential article in psychiatry from the New England Journal of Medicine with vast secular influence was “Neurasthenia, or Nervous Exhaustion” by George Beard, published in 1869. Beard G. Neurasthenia, or nervous exhaustion. Boston Med Surg J 1869;80:217-221

He spoke of “a condition of the system that is, perhaps, more frequently than any other in our time at least, the cause and effect of disease. . . . Both anemia and neurasthenia are most frequently met with in civilized intellectual communities. They are part of the compensation for our progress and refinement.” Beard G. Neurasthenia, or nervous exhaustion. Boston Med Surg J 1869;80:217-221

The use of the label “neurasthenia,” and probably its reported incidence, expanded greatly after Beard’s article appeared. It was called the “American disease” by the illustrious French neurologist, J.-M. Charcot, who took it up for study as a strictly neurologic condition. By medicalizing the misfortunes of life, for which care is still so frequently sought, physicians became comfortable invoking a patient’s constitutional makeup, as if it were a physical entity, as the substrate for exhaustion, melancholia, depression, discouragement, weakness, and headache.

THE RISE OF BIOLOGIC PSYCHIATRY

Some topics in every field turn out to be fraught with specious ideas, and neurology and psychiatry have grappled with many of them. We cannot know whether the absence of articles on phrenology in BMSJ was an implicit message or whether it was a reflection of Boston’s medical orthodoxy. Many positive reports of magnetism applied to nervous conditions and endorsements of autointoxication as the cause of mental diseases were, however, published in the Journal. Briggs LV. A consideration of auto-intoxication and auto-infection as cause of various mental disorders. Boston Med Surg J 1905;152:1-5, 36

Most of these quaint notions simply reflected the medical ideologies of the time. For an example of early continuity of subject matter regarding the nerves that has appeared in the Journal one has only to look at Brown-Séquard’s work on electrical activity of the nervous system and J.C. Warren’s derisive article “Animal Magnetism,” stating that the concept, “which some thirty years ago excited great attention . . . has since been viewed as one of the remarkable impositions on the credulity of mankind.” Warren JC. Animal magnetism. Boston Med Surg J 1814;3:40-46

But the use of electricity for brain disorders is now again invoked through the technology of deep-brain stimulation. Escaping from the stigma of psychosurgery, articles in the Journal have expanded the application of deep-brain stimulation well beyond its usual use in Parkinson’s disease and found substantiation for its use in intractable obsessive–compulsive disorder. Mallet L, Polosan M, Jaafari N, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 2008;359:2121-2134[Erratum, N Engl J Med 2009;361:1027.] and in dystonia. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:1978-1990 and Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005;352:459-467

When psychodynamic systems that attributed mental diseases to unconscious conflicts were popularized in the mid-20th century, there was a conspicuous absence of articles about them in theJournal. The exception was psychosomatic medicine. In a 1948 article in the Journal, A.O. Ludwig wrote that “emotional influences acting over longer or shorter periods result at first in disturbed physiology and eventually in structural change. Peptic ulcer is the simplest example . . . [u]lcerative colitis . . . asthma, hay fever and urticaria, certain skin diseases, such as eczema and neurodermatitis, migraine, possibly certain cases of epilepsy; hypertension and rheumatoid arthritis.” Ludwig AO. The practical importance of modern concepts of psychosomatic relations. N Engl J Med 1948;238:175-178. Concerning much of 20th-century psychiatry, including psychoanalysis, however, the Journal spoke through its silence. With the ascent of biologic psychiatry in the first decade of the 21st century, large pragmatic “efficacy” trials identified by their acronyms have appeared in the pages of the Journal — for depression (STAR*D), Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252 psychosis (CATIE), Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223[Erratum, N Engl J Med 2010;363:1092-3.] and dementia (CATIE-AD). Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-1538

These studies affirm the value but expose the shortcomings and risks of medical treatment for mental conditions and suggest that the field may have moved a bit too far, as in a quip by the late Leon Eisenberg, from “brainlessness to mindlessness.” Eisenberg L. Mindlessness and brainlessness in psychiatry. Br J Psychiatry 1986;148:497-508

These articles about psychiatry published in the Journal are influencing that field, as other articles have in neurology and neurosurgery, bringing the study of mental life and its diseases back into contemporary medicine and thereby rejoining the specialties of the brain.

For 200 years, the Journal has seen neurology and psychiatry evolve from a European to an international scope, from an emphasis on diagnosis to an emphasis on treatment, and has published many of the fundamental descriptions of nervous and mental diseases while cultivating a new and potent therapeutic course. One would expect the next 100 years to bring a new outlook on diseases of the nervous system that is based on fundamental biology, but the need for keen observation of the individual patient is not likely to be supplanted.

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