對話 | 重塑腦部疾病的治療，哪些策略更具潛力？如何將疾病出現推遲5到10年？

編者按：在充滿挑戰且快速發展的神經科學領域，鮮有領導者能像Stacie Weninger博士這般在塑造行業格局方面發揮關鍵作用。作為F-Prime生物醫學研究倡議（FBRI）主席兼F-Prime風險合伙人，她活躍于基礎科學與企業創建的交匯點：發掘顛覆性研究成果，并組建頂尖團隊將其轉化為創新藥物。憑借聯合創立Denali Therapeutics和Neumora等行業中堅企業的經歷，以及近期聯合主導Tenvie Therapeutics完成2億美元融資的成果，Weninger博士逐步形成了清晰的成功法則：降低創新靶點研發風險，深耕小分子藥物的持久潛力，并將臨床試驗重心重新聚焦于生物標志物與真實世界數據。近日，我們與Weninger博士展開對話，深入探討她構建新一代神經科學企業的策略，以及開創腦部重大疾病治療新紀元的愿景。

Stacie Weninger博士現任F-Prime生物醫學研究倡議主席及F-Prime風險合伙人。她擁有深厚的神經科學背景，職業生涯橫跨學術研究、風險投資與科研管理等多個領域。作為神經退行性疾病與精神疾病領域創新療法研發的重要推動者，她還擔任Target ALS等疾病基金會的董事會成員，持續支持生物醫學界的研究協作。

感謝您接受我們的采訪。我們想首先從您近期的工作談起，特別是您共同主導Tenvie Therapeutics完成的2億美元融資。在您看來，這個項目最突出的亮點是什么？它又體現了您在評估神經科學領域企業時關注的哪些關鍵特質？

Stacie Weninger博士：對我而言，成功始終來源于科學基礎與團隊能力的有機結合。此前我曾共同領導創立Denali公司，其中令人振奮之處在于其廣闊的發展前景：新技術不斷涌現，我們對疾病生物學機制的理解也在持續加深。當Denali決定重點發展其突破性的血腦屏障穿越技術平臺時，公司還擁有極具潛力的小分子藥物研發項目。我們認為這些項目更適合通過私募融資獨立發展，于是我們組建了一支頂尖團隊將其獨立孵化出來，使它們獲得足夠的資源與專注度。這樣就形成了理想的組合：卓越的團隊搭配極具前景的基礎研發項目。

當前神經科學領域正迎來蓬勃發展的階段，創新治療模式不斷涌現。然而從長遠來看，小分子藥物仍將是理想治療方案之一。一旦我們能夠成功降低靶點風險，并證實調控靶點能改變疾病進程，那么最終目標便是研發出具有同等療效的口服藥物。

您清晰闡述了重新聚焦小分子藥物的重要性，但同時您也提及了對新型治療模式的高度關注。在腦衰老治療領域，您認為還有哪些治療策略最具潛力？

Stacie Weninger博士：穿越血腦屏障的遞送技術正展現出強大潛力。最初我們主要考慮如何遞送那些無法輕易穿越血腦屏障的抗體藥物，但現在我們意識到其應用遠不止于此，比如寡核苷酸和酶等大分子都能通過該技術遞送。Denali公司通過遞送患者缺失的蛋白酶來治療亨特綜合征（Hunter syndrome）的數據就十分令人振奮。此外，通過RNAi等技術來調控基因表達也展現出巨大前景。隨著這些技術在中樞神經系統直接給藥模式下不斷獲得概念驗證，若未來能與其他遞送技術結合，實現外周給藥即可作用于大腦，將會是極具突破性的進展。

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如果我們聚焦于阿爾茨海默病這一富有挑戰性的領域，您認為過去十年中最具影響力的進展是什么？未來投資的重大機遇又在哪里？

Stacie Weninger博士：首先，如果靶點本身不正確，就無法開發有效的藥物。因此，推進我們對這類復雜、多因素疾病的生物學理解至關重要。同時，我認為研究影響疾病進展速度的基因將帶來變革性影響。迄今為止，大多數遺傳學研究都聚焦于疾病風險因素，但對于已出現癥狀的患者而言，影響疾病進展速度的生物通路和基因或許才是更可行的治療靶點。這方面我們才剛剛開始。

生物標志物同樣正在重塑藥物研發，其重要性怎么強調都不為過。基于在醫生診所進行的認知測試來評估藥效的策略面對噪音大，難度高的挑戰。諸多因素都會影響測試結果，比如睡眠質量、通勤壓力等等。我們需要建立針對疾病亞型和進展程度的客觀、量化生物標志物體系。這一點至關重要，因為阿爾茨海默病存在顯著異質性：某些患者可能主要表現為免疫介導的病理特征，而另一些患者則存在溶酶體系統功能障礙。運用生物標志物精準篩選試驗對象并量化治療效果，將真正改變研發格局。

您特別強調了生物標志物的重要性，尤其是多重檢測組合這一發展趨勢。在開發這類復雜診斷工具的過程中，在科研以及患者可及性層面，我們面臨哪些關鍵挑戰？

Stacie Weninger博士：我認為多重生物標志物檢測組合是未來發展趨勢。單一標志物遠遠不夠，我們需要的是能夠一次性檢測數十種不同標志物的血液檢測方案。鑒于共存病理是普遍現象，我們真正需要的是能檢測與神經退行性病變相關的關鍵蛋白及多種生物系統的廣譜檢測組合，而非單一的"阿爾茨海默病檢測"或"帕金森病檢測"。

至于可及性，我并不擔憂這項技術。當我們依賴PET和MRI掃描這類昂貴影像學檢查手段時，我確實曾為可及性問題憂慮。然而，我毫不懷疑我們將獲得具有可及性的血液生物標志物檢測組合。

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您關注的另一個關鍵挑戰是臨床試驗本身。我們應如何重新設計神經病學試驗，使其能更真實地反映患者的日常生活狀態？

Stacie Weninger博士：在醫生診所里進行的低頻認知評估很難反映疾病的真實波動。我在照顧患有神經退行性疾病的父母期間，深切體會到患者病情每天的波動有多么劇烈，更不用說頻繁就診帶來的負擔。我們需要轉向使用可穿戴設備等技術采集的持續真實世界數據，并結合客觀生物標志物，作為臨床試驗終點。

能持續監測患者活動的無創可穿戴設備可能會非常有效，尤其是對于帕金森病等需要監測運動功能的疾病。相比醫生診所里三分鐘的評估，全天24小時監測用藥期與停藥期的活動數據能提供更全面的信息。我們確實需要更積極地采納這些創新工具。

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現在，讓我們將視角轉向企業構建與商業策略。考慮到神經科學領域研發周期長、成本高的特點，您認為哪些融資與合作模式最為有效？

Stacie Weninger博士：對小型生物技術公司而言，獨立將神經退行性疾病療法推進至3期臨床試驗非常困難，因此需要多元化的融資與合作模式。從早期階段的私募資金，到公開市場投資者，當然還包括大型藥企的合作，需要與各方建立合作關系。我們始終需要依靠大型藥企來開展大規模3期試驗。

慈善資金在降低早期風險方面也發揮著重要作用。神經科學研究難度高，往往需要漫長周期才能達到關鍵價值拐點。來自家族辦公室或大型公益慈善機構的額外資金，不僅能幫助降低早期項目風險，還能增強其他投資者的信心。關鍵在于組建能夠推動項目進展的頂尖團隊，而慈善資金能夠激勵這些頂尖團隊挑戰高風險靶點，而一旦成功，這些靶點或將帶來變革性突破。

回顧這一領域的發展，自《時代》周刊著名的阿爾茨海默病封面報道問世已過去25年。回顧往昔，您認為我們在哪些方面尚未達到預期？展望未來，神經退行性疾病與精神疾病領域有哪些進展最令您振奮？

Stacie Weninger博士：展望未來，讓我振奮的是我們對神經退行性疾病靶點的生物學理解不斷深化，尤其是外周免疫系統在大腦中的作用，這一方向長期以來被嚴重低估。在精神病學領域，令我欣喜的是我們正在超越過去"重錘式"的用藥方式。如今我們正逐步厘清關鍵受體的作用，進而設計出在保持療效的同時大幅降低副作用的治療方案。

回望過去，我希望我們當時能夠更快一些。然而，那時我們缺乏如今掌握的諸多技術手段。以有些早期阿爾茨海默病臨床試驗為例，我們甚至無法準確診斷患者，部分試驗招募了大腦中不存在淀粉樣蛋白沉積的受試者，因為當時缺乏可靠的檢測手段。PET掃描技術和現今的血液檢測改變了這一格局。通過生物標志物更早篩選受試者并縮短驗證藥物療效的臨床試驗時間，我們能夠全面加速研發進程。

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從個人經歷來看，您曾與家人共同面對這些疾病。基于這樣的體驗，您認為我們應當如何思考工作的最終目標？是延長壽命，還是致力于縮短壽命與健康壽命之間的差距？

Stacie Weninger博士：這是一個讓我深有感觸的話題。今年一月，我的父親因帕金森病相關癡呆離世，目前我也在照料患有額顳葉癡呆的母親。有時，人們會將延長癡呆癥患者壽命幾個月與腫瘤學領域的生存期延長相比較，但我認為二者之間存在巨大差異。正如你提到健康壽命與自然壽命之間的區別，我們的目標應該是延長健康壽命。當患者處于癡呆癥晚期時，在我看來，重點并不是延長壽命本身。

我希望我們能在預防和早期干預領域投入更多努力。這意味著我們需要更早開始治療，往往在癥狀顯現之前就采取行動。如果能將神經退行性疾病癥狀的出現推遲五到十年，那么即便對患者最終壽命影響有限，也足以顯著改善他們的健康壽命。對我來說，讓患者在認知功能完好、能夠獨立生活的狀態下度過更多時間，才應該是我們的目標。

De-Risking the Brain: A Conversation with Dr. Stacie Weninger, President of the F-Prime Biomedical Research Initiative

Editor’s Note:In the high-stakes, rapidly advancing field of neuroscience, few leaders have been as instrumental in shaping the landscape as Dr. Stacie Weninger. As President of the F-Prime Biomedical Research Initiative (FBRI) and a Venture Partner at F-Prime, she operates at the nexus of foundational science and company creation, identifying transformative research and building world-class teams to translate it into new medicines. With a track record that includes co-founding industry pillars like Denali Therapeutics and Neumora, and recently co-leading a $200 million financing for Tenvie Therapeutics, Dr. Weninger has developed a clear thesis for success: de-risk novel targets, double down on the enduring power of small molecules, and re-focus clinical trials on biomarkers and real-world data. We spoke with Dr. Weninger to understand her strategy for building the next generation of neuroscience companies, and her vision for ushering in a new era of therapies for devastating brain disorders.

Stacie, thank you for speaking with us. We'd like to start with your recent work, beginning with a $200 million round for Tenvie Therapeutics that you co-led. What made that specific opportunity stand out, and what does it say about the key characteristics you look for in neuro-focused companies?

Stacie Weninger:To me, it’s always a combination of science and team.Previously, I co-led the founding of Denali, and part of the excitement there was the broad scope: new technologies were emerging and our understanding of the biology was improving. While Denali decided to double down on its exciting blood-brain barrier platform, it also had a promising program of small molecules. We decided those programs would be better financed privately, so we spun them out with a stellar team to give them the attention they deserved. That created the ideal combination: a phenomenal team and exciting foundational programs.

There's a lot of excitement in neuroscience right now as new modalities emerge. For instance, I was just listening to the latest Huntington's disease data from uniQure, which involves an MRI-guided neurosurgical administration of gene therapy. While that kind of therapy is a heavy lift and challenging to scale, it's an incredible proof of concept showing we can affect these diseases.Ultimately, however, small molecules are going to be among the best drugs.Once we de-risk targets and show that modulating them affects the disease, the ultimate goal will be a pill that can do the same.

You've made a strong case for refocusing on small molecules. At the same time, you mentioned the excitement around new modalities. What other therapeutic approaches for brain aging do you find most promising?

Stacie Weninger:Blood-brain barrier technology is proving to be quite powerful.The original idea was to deliver antibodies that can’t otherwise easily cross into the brain. We've since realized there's so much more we can deliver, such as oligos and enzymes. The data Denali has shown on delivering the missing enzyme to treat Hunter syndrome is very exciting. In addition,the ability to manipulate gene expression through technologies such as RNAi holds great promise.As these technologies achieve further POC with direct CNS administration, it will be exciting if we could further combine technologies to allow peripheral administration.

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If we could zoom in on a specific and challenging area like Alzheimer's, what do you see as the most impactful advances over the past decade, and where are the next big opportunities for investment?

Stacie Weninger:First,if we don't have the right targets, we can’t make the right drugs.The advancements in our biological understanding of these complex, multifactorial disorders have been key.I also think examining genes that affect the rate of disease progression will be transformational.To date, most genetic research has focused on what increases disease risk. But the biological pathways and genes that affect rate of progression might be more tractable as therapeutic targets for patients who are already symptomatic. We've barely scratched the surface there.

Biomarkers are also completely changing drug development. I can't stress their importance enough.Trying to measure a drug's efficacy based on a cognitive test in a doctor's office is extremely noisy and difficult. Many factors influence the result, like how well you slept or how stressful traffic was getting there.We need objective, quantitative biomarkers of disease subtypes and disease progression. This is crucial because Alzheimer's isn’t the same across all patients;for example some may have a more immune-mediated disease while others have issues with their endolysosomal system.Using biomarkers to identify the right patients for a trial and measure the therapeutic effect will be truly game-changing.

You've highlighted the power of biomarkers, particularly the move towards multiplexed panels. As we develop these complex diagnostics, what are the key challenges, both in terms of the science and in ensuring they remain affordable for patients?

Stacie Weninger:I think the future is multiplexed panels of biomarkers.It’s not going to be one single marker; you're going to want a blood test that can measure dozens of different markers at once. As co-pathologies are the norm, not the exception, we really need broad neurodegeneration panels that examine key proteins and various biological systems, not just an "Alzheimer's panel" or a "Parkinson's panel".

As for affordability, I’m not worried about that with this technology. I was worried about how to keep things affordable when we were relying on PET scans and MRI scans, which are very expensive. But I have no doubt that we will have affordable blood biomarker panels.

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Another hurdle you’ve focused on is the clinical trial itself. How can we redesign neurology trials to better reflect the day-to-day reality of living with a disease?

Stacie Weninger:Infrequent cognitive tests in a doctor's office aren't particularly meaningful.Having cared for both my parents with neurodegenerative diseases, I've seen how massive the daily fluctuations are, not to mention the burden of care appointments.We need to move toward using continuous, real-world data from technologies such as wearables, combined with objective biomarkers, as our endpoints.

Noninvasive wearables that continuously measure activity could be very effective, particularly for diseases like Parkinson’s where you want to monitor motor function. Measuring activity 24 hours a day, on meds, off meds, etc., is much better than a three-minute assessment in a doctor’s office. We really need to embrace these tools.

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Shifting to the business side, let’s discuss the strategy behind building these companies. Given the notoriously long and expensive timelines in neuroscience, what financing and partnership models do you see working best?

Stacie Weninger:It's difficult for small biotech companies to take a therapy all the way through a Phase III trial in a neurodegenerative disease, so it requires a combination of models.You need a partnership among everyone, from private investment in early-stage work to public investors and, of course, big pharma. We will always rely on big pharma for large Phase III trials.

Philanthropy also plays a big role in early-stage de-risking.Neuroscience is hard, and it can be a long time before you reach those high-value inflection milestones. Additional financing, whether from family offices or large public charities, helps de-risk projects in the early stages and convinces other investors this is worth investing in. It’s about assembling an A-plus team that can move the needle, and philanthropic funding can encourage these A-plus teams to work on higher-risk targets that could be transformative if they succeed.

Looking at the state of the field, it’s been 25 years since that famous Time Magazine cover on Alzheimer's. When you look back at that time, where do you feel we have fallen short? And when you look forward, what developments in neurodegeneration and psychiatry get you most excited?

Stacie Weninger:When I look forward, I'm excited by our improved biological understanding of targets in neurodegeneration, especially the role of the peripheral immune system in the brain,which has been woefully underappreciated. In psychiatry, I’m excited that we’re moving beyond the "sledgehammer" drugs of the past. We're now understanding the specific receptors that matter, so we can design therapies that maintain efficacy with far fewer side effects.

When I look back, I wish we had been faster. However, we were lacking so many tools that we have now. In some of the early Alzheimer's trials, for example, we couldn't even definitively diagnose someone; some trials enrolled people who didn’t have amyloid in their brains because we didn't have the tools to detect it. PET scans, and now blood tests, have changed that.Using biomarkers to enroll people earlier and run shorter trials to see if a drug is working will accelerate everything.

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On a more personal note, you’ve spoken about your family’s experience with these diseases. From that perspective, how should we think about the ultimate goal of our work? Is it about extending lifespan or closing the gap between lifespan and healthspan?

Stacie Weninger:This is very personal to me. I lost my dad in January to Parkinson's Disease Dementia, and I care for my mother, who has Frontotemporal Dementia. People sometimes compare extending life by a few months in dementia to doing so in oncology, and I think there's a huge difference.To your point on healthspan versus lifespan, we want to extend healthy life. When someone is in the late stages of dementia, to me, it is not about extending life.

I want to see us doing more prevention and early-stage slowing. That means we need to be treating people earlier, often before symptoms appear.If we could delay the onset of neurodegenerative disease symptoms by five or ten years, it would significantly change an individual’s healthspan, even if it doesn't dramatically alter their lifespan.To me, giving people more years of being cognitively intact and living independently should be our goal.

參考資料：

[1] A Trailblazer in Neuroscience and Biotech Leadership. Retrieved JNovember 4, 2025, from https://www.targetals.org/2025/03/28/a-trailblazer-in-neuroscience-and-biotech-leadership/

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