麻省总医院神经外科功能神经外科主任Dr. Mark Richardson说，探索基因疗法治疗神经系统疾病的研究已经进行了几十年，但取得的成功有限。问题不一定是这些疗法无效，而是它们没有准确地击中目标。
USING MRI TO DELIVER GENE THERAPY FOR PARKINSON'S DISEASE
PUBLISHED ON DECEMBER 3, 2020
Massachusetts General Hospital researchers are joining a phase II clinical trial to test a promising gene therapy for Parkinson's disease. The team is using a state-of-the-art delivery technique that allows them to view an infusion as it enters the brain and adjust as needed in real time. The approach represents an evolution in neurosurgical gene therapy and will begin a new era of direct drug delivery in Parkinson's disease and other neurologic disorders.
Studies exploring gene therapy to treat neurological diseases have been ongoing for decades, but with limited success, says Mark Richardson, MD, PhD, director of Functional Neurosurgery in the Department of Neurosurgery at Mass General. The problem is not necessarily that the therapies are ineffective, but rather that they were not accurately hitting their targets.
"One of the reasons that the gene therapy field has been evolving slowly up to this point is that it's really not that simple to make sure that the vector goes where you want it to go," Dr. Richardson says. "But we've now established a gold standard for how one should deliver gene therapy to the human brain in instances where it is required to have the gene expressed in a certain location."
Changing the Parkinson's Treatment Paradigm
Parkinson's pathology is very complex; the condition originates in the basal ganglia, an area of the brain that regulates movement, and the substantia nigra pars compacta (SNc), which produces the neurotransmitter dopamine. Neurons within the SNc die in those with Parkinson's disease, decreasing levels of dopamine in the basal ganglia and resulting in dysfunction. As the disease progresses, patients experience characteristic tremor, rigidity, slowness and other motor symptoms.
The current gold-standard surgical treatment for Parkinson's is deep brain stimulation (DBS), which uses electrical impulses to counter disease symptoms. The main drawback to DBS is its nature as an implanted device, which requires ongoing programming and battery recharging or replacement.
Since the 1980s, neuroscience studies have sought to address Parkinson's motor and movement issues with other methods, such as cell, enzyme or neurotrophin replacement, to counteract or reverse the loss of dopamine.
Until now, Dr. Richardson emphasizes, those trials have used "blind" infusions: The researchers had no way to monitor the vectors to make sure they were accurately delivered where they are needed in the brain.
"How infusions behave in the brain is very dependent on the patient's anatomy. The vasculature is different. Everyone's basal ganglia are different in terms of where blood vessels are," he says. "Infusate can leak out along the blood vessels and exit the gray matter target along perivascular spaces. That means it's not going to have its therapeutic effect."
Intraoperative MRI Ensures Targeted Therapy
Dr. Richardson has helped pioneer one such therapeutic infusion: aromatic L-amino acid decarboxylase (AADC), an enzyme reduced in Parkinson's disease. "If you give the brain back AADC, it can make more dopamine in the place where it's needed," he says.
For the past ten years, Dr. Richardson has been involved in a multi-institutional effort to deliver gene therapy vectors to the right location. In a paper published in the Journal of Neurology, Neurosurgery and Psychiatry, they describe the evolution of an approach that allows the neurosurgical team to watch vector delivery and make real-time changes as needed:
The patient is put under general anesthesia
The team mounts a temporary aiming device on the patient's skull
A special infusion cannula developed for this purpose is inserted into the brain, and an infusion pump delivers the vector
Intraoperative magnetic resonance imaging (MRI) allows the team to watch the infusate as it is distributed in the brain
A special software system helps the team align the surgical trajectory and make adjustments if needed
"It's critical to watch what's happening; you have to adjust the cannula continuously during the infusion based on visual information that the surgeon interprets while watching the infusion distribute in the brain," Dr. Richardson says.
Examples of adjustments the team can make in real-time include:
Trajectory and placement of the cannula
Advancement of the cannula
Control over where the infusate is going
Volume and dosing
"This is the first time in a neurosurgical gene therapy trial that the surgical protocol has been adjusted at each step, in a way to optimize the eventual outcomes and increase the chance for success," Dr. Richardson says. "It has significantly improved target coverage and reduced surgical time."
Enrollment Opening for Clinical Trial
Mass General will soon start to enroll patients with Parkinson's disease in a phase II clinical trial, which will administer AADC using the novel delivery method.
Neurologists and primary care providers can refer patients for possible consideration and enrollment if they have had a diagnosis of Parkinson's disease for at least three years and have motor symptoms that were once well-controlled with medication but are no longer well-controlled.
The Future of Research in Neurodegenerative Disease
Additional studies across the country are now using this new technique for other neurodegenerative diseases and neurologic disorders. The strategy allows researchers to evaluate the true extent of therapeutic delivery, eliminating the possibility that an effective therapy won't work simply because it missed its mark.
"Mass General has a history of making safe but innovative advances in functional neurosurgery, and we're well-positioned to be an international center of excellence for gene therapy in the brain," Dr. Richardson says. "We have a lot of collaborators in other areas of neurology, psychiatry and the basic sciences with whom we can partner in the future to expand the application of this technique."
本文编译自麻省总医院官网于2020年12月3日发表的《核磁共振技术协助帕金森病的基因治疗》，USING MRI TO DELIVER GENE THERAPY FOR PARKINSON'S DISEASE，from: https://advances.massgeneral.org/neuro/article.aspx?id=1308出国看病，寻求更好的医疗救治！官方合作转诊通道7个工作日预约美、英、德、日排名前十医院400-875-6700 咨询在线顾问