核磁共振技術協助帕金森病的基因治療

時間：2021-02-23  來自：盛諾一家 返回上頁

發表于2020年12月3日

麻省總醫院研究人員正在參加一項二期臨床試驗，測試一種有前景的帕金森病的基因療法。該團隊正在使用一種最先進的傳輸技術，可以讓他們看到輸入液進入大腦的過程，并根據需要實時調整。該方法代表了神經外科基因治療的一個進步，并將開啟直接給藥治療帕金森病和其它神經疾病的新時代。

麻省總醫院神經外科功能神經外科主任Dr. Mark Richardson說，探索基因療法治療神經系統疾病的研究已經進行了幾十年，但取得的成功有限。問題不一定是這些療法無效，而是它們沒有準確地擊中目標。

Dr. Richardson說：“基因治療領域之所以發展緩慢，其中一個原因是，要確定載體能到達你想要它到達的地方，真的不是那么簡單。但我們現在已經建立了一個黃金標準，在需要基因在特定位置表達的情況下，人們應該如何將基因治療傳遞到人腦?！?/p>

改變帕金森病的治療模式

帕金森病的病理非常復雜；這種情況起源于基底節區和黑質(SNc)，前者是大腦中調節運動的區域，后者產生神經遞質多巴胺。帕金森病患者黑質中的神經元死亡，導致基底神經節多巴胺水平下降，從而導致功能障礙。隨著病情進展，患者會出現特征性的震顫、僵直、遲鈍和其它運動癥狀。

目前治療帕金森病的黃金標準手術方法是腦深部刺激(DBS)，它使用電脈沖來對抗疾病癥狀。腦深部刺激的主要缺點是它作為植入設備的性質，需要持續編程和電池充電或更換電池。

自20世紀80年代以來，神經科學研究一直在尋求用細胞、酶或神經營養素替代等其它方法來解決帕金森病的運動和運動問題，以抵消或逆轉多巴胺的損失。

Dr. Richardson強調，到目前為止，這些試驗都是使用“盲注”輸液：研究人員沒有辦法監控載體，以確保它們被準確地輸送到大腦所需要的位置。

“輸入液在大腦中的作用取決于病人的解剖結構。脈管系統是不同的。每個人的基底神經節在血管的位置上都是不同的，”他說?！拜斎胍嚎裳匮軡B出，并沿血管周圍間隙排出灰質靶區。這意味著它不會有治療效果?！?/p>

術中MRI確保靶向治療

Dr. Richardson幫助開創了一種治療性輸液：芳香族L-氨基酸脫羧酶(AADC)，一種在帕金森病中減少的酶?！叭绻阕尨竽X恢復AADC，它就能在需要它的地方制造更多的多巴胺，”他說。

在過去的十年里，Dr. Richardson參與了一個把基因治療載體傳輸到正確位置的多機構研究。在《神經病學、神經外科和精神病學雜志》上發表的一篇論文中，他們描述了一種方法的演變，該方法允許神經外科團隊觀察載體傳輸，并根據需要進行實時更改:

病人被全身麻醉

該團隊在病人的頭骨上安裝一個臨時瞄準裝置

為此研制的特殊輸液套管被插入大腦，并由輸液泵輸送載體

術中磁共振成像(MRI)使研究小組能夠觀察輸入液在大腦中的分布情況

一個特殊的軟件系統可以幫助團隊調整手術軌跡，并在需要時做出調整

“觀察正在發生的事情很重要；在輸液過程中，你必須根據外科醫生通過觀察輸入液在大腦中的分布所解讀的視覺信息不斷調整套管，”Dr. Richardson說。

團隊可以進行實時調整的示例包括:

套管的軌跡和位置

套管的推進

控制輸入液的方向

體積和劑量

“在首次神經外科基因治療試驗中，手術方案在每一步都進行了調整，以優化最終結果，增加成功的機會，”Dr. Richardson說?！八@著提高了靶向覆蓋率，縮短了手術時間?！?/p>

臨床試驗招募開放

麻省總醫院將很快開始招募帕金森病患者進行二期臨床試驗，該試驗將使用這種新的給藥方法來管理AADC。

如果患者被診斷為帕金森病至少3年，并且有曾經通過藥物很好地控制但現在不能很好地控制的運動癥狀，神經學家和初級保健提供者可以建議他們考慮并登記。

神經退行性疾病研究的未來

全美各地的其它研究正在使用這項新技術治療其它神經退行性疾病和神經紊亂。該策略使研究人員能夠評估治療方案的真實程度，從而消除了僅僅因為錯過了治療方案而無法有效治療的可能性。

Dr. Richardson說:“麻省總醫院在功能性神經外科領域有著安全而又創新的發展歷史，我們很有資格成為腦基因治療的國際卓越中心。我們在神經學、精神病學和基礎科學等其它領域有很多合作者，未來我們可以與他們合作，擴大這項技術的應用?！?/p>

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."

本文編譯自麻省總醫院官網于2020年12月3日發表的《核磁共振技術協助帕金森病的基因治療》，USING MRI TO DELIVER GENE THERAPY FOR PARKINSON'S DISEASE，from: https://advances.massgeneral.org/neuro/article.aspx?id=1308