Tag: mental health

From the Innovator’s Pitch Challenge Podium to the Clinic: FELIQS Advances Vision Saving Therapies 

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Third Place winner of the RESI San Diego Innovator’s Pitch Challenge, FELIQS is developing innovative therapies for neonatal ophthalmology and other serious retinal diseases with the goal of preserving vision at the earliest stages of life. In this interview, Kenichiro “Nobu” Kuninobu discusses the company’s lead clinical program, the value of participating in the RESI Innovator’s Pitch Challenge, and the milestones that will shape FELIQS’ next phase of growth.

Kenichiro “Nobu” Kuninobu
Co-founder & CEO, FELIQS
 Caitlin Dolegowski
Program Director, LSN

Caitlin Dolegowski (CD): FELIQS is focused on developing therapies for neonatal ophthalmology and other serious retinal diseases. Can you tell us about your lead program and the impact it could have on patients and their families?

Kenichiro Kuninobu (NK): FELIQS’ lead program, FLQ-101, is being developed for the prevention of retinopathy of prematurity, or ROP, a serious retinal disease affecting premature infants that can lead to lifelong visual impairment or blindness. Today, treatment is generally initiated after ROP has already progressed to a clinically significant stage. Our goal with FLQ-101 is to intervene earlier and prevent disease progression before invasive treatment becomes necessary. If successful, this approach could give premature infants the best possible opportunity for healthy visual development. For families, the impact could be profound. Preserving vision at the very beginning of life can influence a child’s development, independence, and quality of life, while potentially reducing a lifelong burden of care for families and healthcare systems.

CD: Your work bridges scientific innovation and international collaboration. How has that global perspective influenced the company’s development?

NK: FELIQS was founded on scientific discoveries originating in Japan, but from the beginning we have approached drug development with a global perspective. Our lead clinical program is being developed in the United States, while we continue to work closely with researchers, clinicians, regulators, and partners across Japan and other regions. That international approach has shaped how we think about clinical development, regulatory strategy, patient access, and partnerships. It also allows us to bring together complementary expertise from different regions. For diseases such as ROP, which affect premature infants around the world, we believe that building a globally relevant development strategy from an early stage is particularly important.

CD: Earning Third Place in the RESI San Diego Innovator’s Pitch Challenge highlights the strength of your innovation. What did this recognition mean to your team?

NK: Earning Third Place at the RESI San Diego Innovator’s Pitch Challenge was very meaningful to the FELIQS team. It provided encouraging external recognition of both our scientific approach and our mission to address serious retinal diseases in vulnerable patient populations, particularly premature infants. For our team, it was especially valuable to see investors and industry experts respond positively to our strategy and the potential of our programs. The recognition gave us additional confidence that FELIQS is pursuing an important and differentiated approach, while also increasing our visibility within the global life sciences community.

CD: Were there any conversations with investors, judges, or strategic partners at RESI that stood out or created new opportunities?

NK: RESI created a valuable forum for high-quality conversations with investors, judges, and potential strategic partners who understood both the unmet need in retinal disease and the importance of early intervention in ROP. Several discussions helped us refine our communication of the clinical and commercial opportunity, and some opened the door to follow-up conversations about financing, development strategy, and potential collaboration. The event was particularly useful because the feedback was practical, thoughtful, and directly relevant to our next stage of growth.

CD: What are the most important clinical, regulatory, or business milestones FELIQS hopes to achieve over the next 12 to 18 months?

NK: Over the next 12 to 18 months, our highest priority is to advance FLQ-101 clinically and build the foundation for its next stage of development. This includes progressing our ongoing clinical study in ROP, expanding our clinical network, generating additional data, and continuing regulatory discussions to define an efficient path forward.

At the same time, we plan to advance our broader pipeline, including FLQ-103 and FLQ-105, while continuing to strengthen the company financially and strategically.

From a business perspective, we are actively engaging with investors and potential strategic partners who can help us accelerate these programs. Ultimately, each of these milestones is focused on one objective: moving promising science into meaningful therapies for patients as efficiently and rigorously as possible.

CD: What qualities are you looking for in investors or strategic partners as you continue to grow?

NK: We are looking for investors and strategic partners who share our commitment to developing meaningful therapies for serious retinal diseases and who understand that building innovative medicines requires both scientific rigor and long-term perspective.

Beyond financial support, we particularly value partners who can contribute strategic insight, experience in ophthalmology, rare diseases, or global drug development, and access to networks that can help accelerate clinical and commercial progress.

Most importantly, we want partners who are collaborative and aligned with our mission. We believe the strongest partnerships are built when both sides share a long-term commitment to creating meaningful value for patients.

CD: Looking ahead, what is your long-term vision for FELIQS, and what advice would you offer companies considering participating in a future RESI Innovator’s Pitch Challenge?

NK: Our long-term vision is to establish FELIQS as a leading biotechnology company in neonatal ophthalmology and rare diseases. Building from our work in ROP, we aim to expand into additional diseases where early and innovative therapeutic intervention could preserve vision and meaningfully change patients’ lives.

For companies considering participating in a future RESI Innovator’s Pitch Challenge, my advice would be to come with a clear story, a focused objective, and an openness to feedback. RESI is not simply an opportunity to pitch your company. It is a platform to refine your strategy, understand how investors perceive your opportunity, and build relationships that may continue well beyond the event.

Additional Innovator’s Pitch Challenge (IPC) slots are now available, giving companies the opportunity to pitch directly to investors, receive live feedback, and boost visibility ahead of the event. Applications close August 26.

Apply to Pitch at RESI Boston

Cross-Border Investor Luncheon at RESI Boston 2026

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A private, screened luncheon for regional and international investors seeking syndicate partners.

RESI Boston | Wednesday, September 23 | 75 Seats


RSVP for Cross-Border Investor Luncheon Today

By Dennis Ford, Founder & CEO, Life Science Nation (LSN)

DF-News-09142022

Nearly nine out of ten life science startups fail. Not because the science is poor, but because they never connect to the right capital and strategic partners. Solving that is the reason Life Science Nation exists, and for more than fifteen years our work has come down to one thing: finding parties who need each other and matching them.

As some readers know, LSN has been addressing this pervasive dilemma through the LSN Labs Anchor Node Program. An Anchor Node combines LSN’s commercialization methodology and global capital formation network with a regional partner’s laboratories, entrepreneurial programs, and operating platform to produce investment-ready life science companies.

As we expanded the Anchor Node Program across Boston, Australia, Japan, Korea, the UK, and Brazil, a clear pattern emerged: regional partners constantly brought their local VCs to the table seeking international capital. At the same time, our own data across five global RESI events revealed that twenty percent of all partnering meetings were already investor-to-investor.

So we decided to formalize it, and provide a dedicated room for these partners to connect.

The Cross-Border Investor Luncheon, CBIL, is a private luncheon at RESI Boston for regional and international investors seeking syndicate partners. Regional investors have access to exceptional companies that often never reach international investors. International investors have access and reach that regional funds cannot build alone. Both are looking for the same thing across Asia, Europe, North America, and South America.

Attendance is screened. CBIL is for active investors seeking syndicate partners outside their own region, whether that means bringing international capital into local deals or gaining access to deal flow in regions where they have no presence.

Taking place on Wednesday, September 23, CBIL follows the format of the Global Family Office BioForum luncheon (GFOB luncheon takes place on Tuesday, September 22), now in its eighth year. Across those eight years, GFOB has brought family offices together to find each other, form alliances, and build syndicates. CBIL is the natural next step, applying the same private, curated format to the international investor community.

“The future of life science investing is not just finding great companies. It is finding great syndicate partners in the global arena.”


Dennis Ford, Founder and CEO, Life Science Nation

Wednesday, September 23   |   Private luncheon   |   Screened RSVP   |   75 seats

Every RSVP is reviewed. Request your seat today!


RSVP for Cross-Border Investor Luncheon Today

RESI San Diego 2026 Program Guide Released 

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By Dennis Ford, Founder & CEO, Life Science Nation (LSN)

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Life Science Nation (LSN) is pleased to release the RESI San Diego 2026 Program Guide for its upcoming hybrid conference, taking place June 22 in person at the JULEP Venue in San Diego, followed by four days of virtual partnering on June 23–24 and June 29–30. 

RESI San Diego brings together early-stage life science companies, active investors, strategic partners, and industry leaders during one of the most important weeks in biotechnology. The conference features the Innovator’s Pitch Challenge, investor panels, educational workshops, company showcases, and a dynamic partnering platform designed to facilitate meaningful fundraising and business development conversations. 

The Program Guide provides a comprehensive look at this year’s agenda, including sessions covering therapeutics, medtech, diagnostics, digital health, corporate venture capital, artificial intelligence in healthcare, strategic partnerships, and emerging investment trends. Attendees can also explore participating investors, sponsors, exhibitors, and networking opportunities available throughout the five-day partnering event. 

With partnering already underway and meeting calendars continuing to fill, RESI San Diego offers a unique opportunity for innovators to connect directly with the investors and strategic stakeholders shaping the future of healthcare. 

View the RESI San Diego 2026 Program Guide and secure your place today at RESI San Diego.

Register for RESI San Diego

Don’t Underestimate the Importance of the Line 

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By Dennis Ford, Founder & CEO, Life Science Nation (LSN)

DF-News-09142022

There is a line between deciding to pursue investors and partners and pursuing them. Most people believe they cross it the moment they decide. They don’t. Deciding is private. The line is the part the market can see, and the market only sees behavior. You can be completely certain you are committed and still be, as far as anyone outside your own head can tell, standing exactly where you were a year ago.

The market doesn’t care what you declare. It responds to what you do. What it reads is presence, whether you are in the room when it counts. There are moments when it counts more than others, when the people who fund and license and partner are not scattered across a thousand calendars but gathered in one place at one time, looking for their next opportunity. Those moments are real, and they are on the calendar. The wave forms whether you are ready or not. The only question it puts to you is whether you are in the water when it arrives.

Here is the part that surprises people. The companies that are serious about this do not try to be efficient about it. You would think the sophisticated move is to be selective, to take only the meetings that obviously matter and skip the rest. It isn’t, and there is a hard reason why. The meeting that changes your company does not announce itself going in. The lead investor is hidden inside a large number of conversations that look, beforehand, exactly like the ones that lead nowhere. The licensing partner is buried in a stack of introductions you cannot tell apart until you are sitting in them. You cannot reason your way to the one that counts and avoid the others. The only way to reach it is to go through the volume. So the serious company does not look for reasons to take fewer meetings. It looks for reasons to take more, because every additional relevant room is another draw from the deck the one card is hidden in. Most of the draws are blanks. That is not a flaw in the method. That is the method.

Activity guarantees nothing, and no one who has done this for long will tell you otherwise. What inactivity guarantees is the opposite. The company that is not in the room is not weighed, and ends up passed over. It is simply never seen, and the market does not hold a seat open for the company that didn’t show. It gives the seat to one that did. Which brings me to the week of June 22 in San Diego. That is a week the market gathers. The city fills with meetings, events, and venues all competing for the same hours, and RESI, on June 22, is built for exactly the thing I have been describing, a room assembled out of investors, licensing teams, and business development people who came specifically to find companies like yours.

Some of you reading this are already going to be there. You have a reason to be in San Diego that week, and you still have not decided to be in this particular room. Sit with that for a second. You will be in the same city, on the same days, with the market gathered a few miles away, and you are on the fence about walking in. There is a word for standing that close to the water, dressed to swim, watching the set roll past. The word is not caution. It is hesitation, and from the outside the market cannot tell the difference between a company that hesitated and a company that was never there.

The line we started with is not crossed by deciding you are ready. It is crossed in the open, by being where the market is while the market is there. If you believe you are ready, the week of June 22 is where that belief becomes visible or doesn’t. Register for RESI San Diego, June 22.

Don’t underestimate the importance of the line.

Register for RESI San Diego

StimOxyGen on Advancing SGEN-33 Following First Place Win at RESI Europe 

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After securing 1st Place in the Innovator’s Pitch Challenge at RESI Europe, StimOxyGen is gaining momentum as it advances its lead program, SGEN-33, toward clinical development. In this interview, Sian Farrell discusses the science behind the platform, upcoming milestones, and how the RESI experience has accelerated investor engagement.

Sian Farrell
CEO, StimOxyGen
 Caitlin Dolegowski
Program Director, LSN

Caitlin Dolegowski (CD): For those new to StimOxyGen, how would you describe SGEN-33 and the problem it is solving in a way that resonates with investors?

Sian Farrell (SF): SGEN-33 is a pH-responsive, oxygen-generating nanoparticle designed to overcome tumour hypoxia, one of the biggest barriers limiting the effectiveness of radiotherapy and other cancer treatments. Many aggressive solid tumours, particularly pancreatic cancer, are severely oxygen deprived, making them highly resistant to therapy. SGEN-33 selectively activates within the acidic tumour microenvironment, releasing oxygen directly where it is needed to help re-sensitise tumours to treatment. What makes the opportunity particularly compelling is that we are addressing a fundamental biological resistance mechanism that impacts multiple high-value oncology indications. Rather than replacing existing therapies, SGEN-33 is designed to enhance them, positioning StimOxyGen within the growing combination of therapy landscape.

CD: What makes this approach particularly compelling from a commercial and clinical perspective compared to existing strategies?

SF: Clinically, our approach is differentiated because SGEN-33 generates oxygen directly within the tumour microenvironment rather than relying on systemic oxygen delivery methods, which have historically shown limited success. Existing hypoxia-targeting strategies such as hyperbaric oxygen therapy or intratumoural injections face significant limitations in practicality, scalability, or clinical adoption. In contrast, SGEN-33 is designed for intravenous administration and tumour-selective activation, offering a scalable and clinically feasible solution. Commercially, we believe this creates a highly attractive platform opportunity. Radiotherapy is used in approximately 60% of cancer patients worldwide, yet hypoxia remains a major unresolved challenge. By integrating into existing standards of care, SGEN-33 has the potential to enhance multiple treatment modalities across several solid tumour types without requiring clinicians to completely change current workflows. Importantly, we have already demonstrated strong preclinical efficacy and safety data in highly hypoxic tumour models, including pancreatic cancer, triple-negative breast cancer, and aggressive prostate cancer. Our studies have shown significant tumour growth reduction and survival benefit when SGEN-33 is combined with radiotherapy.

CD: What key milestones or inflection points should investors be watching as you move toward clinical development?

SF: The next 18–24 months represent a highly important period for StimOxyGen as we advance SGEN-33 toward clinical development. Our current focus is on completing key IND-enabling activities, including GLP toxicology and DMPK studies, GMP manufacturing scale-up, FDA regulatory engagement, and expansion of our radiotherapy-immunotherapy datasets. Alongside these milestones, we are progressing collaborations with leading translational oncology centres including Memorial Sloan Kettering Cancer Center (MSK), advancing early clinical strategy and trial design activities, and continuing to strengthen our scientific and clinical advisory network. A particularly exciting area is the growing evidence of immune-mediated effects observed in our preclinical studies, which may create future opportunities in combination with immunotherapy approaches.

CD: What are your current fundraising priorities, and what types of investors or partners are you looking to engage at this stage?

SF: We are currently raising $7.5 million to advance SGEN-33 through IND-enabling development and position the programme for First-in-Human clinical studies, with a target close by Q1 2027. The financing will support key value-creation milestones including GLP toxicology, DMPK studies, GMP manufacturing scale-up, FDA regulatory engagement, and continued expansion of our radiotherapy-immunotherapy datasets. In parallel, we are progressing clinical strategy and early trial design activities through collaborations with leading translational oncology centres, including Memorial Sloan Kettering Cancer Center (MSK). We are particularly interested in engaging with specialist life science investors, oncology-focused funds, and strategic partners with expertise in radiotherapy, immuno-oncology, nanomedicine, and translational drug development.

CD: How did participating in RESI Europe and the Innovator’s Pitch Challenge impact your visibility and conversations with investors?

SF: Participating in RESI Europe was hugely valuable for StimOxyGen from both a networking and visibility perspective. Having the conference based in Lisbon created an important opportunity to expand beyond the UK ecosystem and connect more directly with the broader European life science investment community. It allowed us to significantly grow our investor network and establish new relationships with international investors and strategic partners. Winning 1st Place in the Innovator’s Pitch Challenge increased our visibility and credibility within the global biotech community and created strong momentum in investor conversations. An additional benefit is the opportunity to attend future RESI conferences, including events in the United States, which will help us continue expanding our US investor and strategic partner network as we move toward clinical development. Beyond the exposure itself, the experience also provided a significant confidence boost for our team and reinforced that the work we are doing is resonating internationally.

CD: What stood out most about the Innovator’s Pitch Challenge experience compared to other pitch opportunities?

SF: What stood out most was the quality and relevance of the audience. I’ve participated in pitch competitions previously, but many were more sector-agnostic and included a broad mix of industries and technologies. At RESI, it was particularly meaningful to receive recognition in a highly relevant and competitive life sciences environment, surrounded by innovative biotech and healthcare companies tackling major clinical challenges. The discussions also felt far more relationship-driven than transactional. Conversations extended beyond the pitch itself and focused on clinical strategy, regulatory pathways, commercialization, and long-term value creation. Importantly, the support from the Life Science Nation (LSN) team did not feel like a “one-and-done” experience. The ongoing opportunities through future RESI events and the wider LSN network create continued momentum and provide a strong platform for us to further expand our international investor and strategic partner network moving forward.

CD: Following your win, what are the next key priorities for StimOxyGen as you move into your next phase of growth?

SF: Our biggest priority is maintaining the momentum we have built over the past 18 months as we advance SGEN-33 toward clinical development. Since completing our first VC financing round in January 2025, we have continued to de-risk the technology, expand our international investor network, progress collaborations with Memorial Sloan Kettering Cancer Center (MSK), and strengthen our translational and regulatory strategy. Winning the RESI Europe Innovator’s Pitch Challenge was another important milestone that reinforced the growing momentum around the company. Over the next phase of growth, our focus is on advancing SGEN-33 through IND-enabling development, progressing FDA engagement, scaling manufacturing capabilities, and continuing to strengthen our clinical strategy. Of course, securing the capital required to move the programme into the clinic remains a critical priority. We believe StimOxyGen is at a genuinely exciting inflection point, and we are actively looking to partner with investors who share both our ambition and our sense of urgency. At the heart of everything we do is the patient. We are working on therapies for people facing some of the most difficult-to-treat cancers, where treatment options are limited and outcomes remain devastatingly poor. That reality keeps our team focused every day and drives our determination to move as quickly and responsibly as possible toward the clinic. For us, this is about far more than building a company — it is about giving patients and families hope where too often there currently is very little. And, if our story resonates with you, we would love to continue the conversation.

Additional Innovator’s Pitch Challenge (IPC) slots are now available, giving companies the opportunity to pitch directly to investors, receive live feedback, and boost visibility ahead of the event. Applications close May 22.

Apply to Pitch at RESI San Diego

Innovator’s Pitch Challenge Winner Spotlight: Bram De Moor of You2Yourself 

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Following its recognition as a winner of the Innovator’s Pitch Challenge at RESI Europe, You2Yourself is advancing a new approach to early disease detection through longitudinal biomarker monitoring. In this interview, Bram De Moor discusses the science behind URIMON, the company’s commercialization strategy, and how RESI has supported its investor engagement. 

Bram De Moor
Founder & General Manager, You2Yourself
 CaitiCaitlin Dolegowski
Program Director, LSN

Caitlin Dolegowski (CD): For those new to You2Yourself, how would you describe URIMON and the value of longitudinal biomarker monitoring in a way that resonates with investors?

Bram De Moor (BD): URIMON is a personalized, non-invasive, urine-based liquid biopsy platform that uses urinary miRNA profiling to detect multiple serious diseases — including prostate cancer, lung cancer, and cardiovascular disease — before symptoms appear. One urine sample generates simultaneous risk scores across multiple conditions.

The longitudinal dimension is key: repeated monitoring detects biological drift months to years before clinical symptoms — the difference between catching cancer at stage I versus stage III. With no needles, no clinic visit, and at-home collection with mail-in capability, URIMON is designed for scalable, population-level adoption.

CD: What makes your approach to early disease detection fundamentally different from traditional diagnostic models?

BD: Traditional diagnostics are reactive and often focus on a single biomarker. URIMON differs in three key ways:

  • Multi-disease detection from a single sample, analyzing hundreds of miRNA species simultaneously
  • Focus on molecular signals rather than anatomical changes, enabling earlier detection
  • Use of urine as a scalable, patient-friendly biofluid that captures signals from across the body

This approach provides a unified molecular health view, reducing fragmentation across specialties.

CD: You have built a unique biobank of longitudinal samples — how does this dataset strengthen your technology and create a competitive advantage?

BD: The URIMON Biobank, developed since 2019 with over 6,500 participants under IRB-approved and GDPR-compliant protocols, is a significant strategic moat.

It enables algorithm training on longitudinal patient data, including individuals who later develop disease, supporting prospective validation. It also ensures robustness across cohorts, allowing classifiers to generalize beyond a single institution.

Replicating this dataset would require years and substantial capital, making it a durable barrier to entry.

CD: How do you think about commercialization, particularly your subscription-based model and the path toward broader reimbursement and population-level adoption?

BD: Our strategy is staged to de-risk scaling. We are entering the market under the EU IVDR Article 5(5) in-house LDT framework to accelerate time to revenue.

Our subscription model (€299–499/year) targets individuals, employer groups, and occupational health programs, aligning recurring revenue with longitudinal monitoring.

Reimbursement will follow through HTA submissions in Europe, with FDA De Novo clearance as a parallel pathway in the U.S.

CD: What key milestones or inflection points should investors be watching as you move toward your planned 2027 market entry?

BD: Key milestones include:

  • Clinical validation and publication of performance data
  • Regulatory progress under IVDR and FDA pathways
  • Launch of commercial infrastructure and first paying customers
  • Strategic partnerships and completion of financing rounds
  • These milestones will demonstrate both technical validation and commercial traction.

CD: How did participating in RESI Europe and the Innovator’s Pitch Challenge impact your investor visibility and strategic conversations?

BD: RESI provided direct access to European and transatlantic investors actively seeking early-stage diagnostic companies — a highly targeted audience that is difficult to reach through traditional outreach.

The Innovator’s Pitch Challenge offered structured validation in a competitive setting, signaling credibility to institutional investors. It also led to new investor conversations and follow-up meetings now underway.

CD: Following your recognition at RESI Europe, what are the next key priorities for You2Yourself as you move into your next phase of growth?

BD: Our focus over the next 12–18 months includes:

  • Expanding clinical evidence through continued biobank growth and prospective studies
  • Securing financing through grants and a seed-to-Series A bridge round
  • Scaling team and infrastructure across lab, regulatory, and business development functions

With favorable market conditions — including advances in NGS, growing demand for preventive health, and regulatory clarity — You2Yourself is well positioned to lead in this space.

Applications are now open for upcoming Innovator’s Pitch Challenges. Companies can apply to pitch at RESI San Diego 2026 and take the stage in front of a global network of investors and partners.

Apply to Pitch at RESI San Diego

The Needle Issue #25

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Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

The approval of multiple anti-amyloid monoclonal antibodies (mAbs) — aducanumab (Aduhelm; now withdrawn), lecanemab (Leqembi) and donanemab (Kisunla) — over the past five years has opened the era of disease-modifying Alzheimer’s drugs, albeit with only modest benefits in addressing cognitive decline (30% slowing) and associated serious safety risks, such as CNS inflammation and cerebral hemorrhages, which has limited clinical uptake. While many drug development programs target biological processes other than amyloid formation (e.g., tau and tangles, neurotransmitter receptors, neuroinflammation, autophagy, and mitochondrial or metabolic dysfunction), companies continue to optimize anti-amyloid monoclonals, but also look for alternative ways to therapeutically target Aβ.

One alternative therapeutic modality to antibodies is chimeric antigen receptor (CAR) immune cell therapy. In recent weeks, we have been thinking a lot about in vivo chimeric antigen receptor (CAR)-T therapies, which were one of the dealmaking trends in 2025, and we recommend readers check out an excellent summary of trends in the area from the consultancy firm Scitaris (you don’t even have to give them your details to download the report).

CAR-T treatments have established their clinical niche as last-ditch treatments for B-cell malignancies, with some remarkable outcomes for late-stage patients. In some cases, they have been shown to be at least twice as effective as T-cell engager bispecific antibodies in clinical studies. But they remain rather blunt instruments.

Despite advances in the clinical management of cytokine-release syndrome and immune effector cell neurotoxicity syndrome (ICANS), CAR-T treatments continue to be associated with serious risks. And while there have been advances in managing these adverse events, atypical non-ICANS neurotoxicities (NINTs) can also create serious clinical management issues, with risk factors predisposing patients to development still only poorly understood.

That said, over the past year, we have seen an increasing trend for the use of CAR-T treatments outside oncology. They have started to be applied with promising efficacy in various areas of autoimmunity (systemic lupus erythrematosus, lupus nephritis, systemic sclerosis, Sjögren’s syndrome, antisynthetase syndrome, myasthenia gravis and idiopathic inflammatory myopathies) and neuroinflammatory conditions (multiple sclerosis). In this respect, a recent paper in Science caught our attention. In it, Marco Colonna and his colleagues at Washington University in St. Louis harness astrocytes to clear amyloid plaques by promoting their ability to phagocytize Aβ.

To that end, they used in vivo gene therapy to generate astrocytes carrying chimeric antigen receptors (“CAR-As”), a strategy not unlike the one used in cancer immunotherapy. Although both macrophages (CAR-Ms) and conventional CAR-Ts have been tested in preclinical models of Alzheimer’s disease with limited success, this study reports the first attempt to directly engineer astrocytes in the body to generate CAR-As.

In broad terms, the construct used to generate CAR-As consisted of an Aβ-binding domain and the phagocytic signaling protein MEGF10 (multiple epidermal growth factor-like domains protein 10). The team examined a variety of constructs and chose two for in vivo testing. One of them combined a fragment from the Aβ-binding antibody crenezumab and MEGF10, which is primarily expressed in astrocytes. The second construct combined a fragment of aducanumab with the phagocytosis receptor Dectin-1, which is primarily expressed in microglia.

The authors packaged the constructs in an adeno-associated viral (AAV) vector under the control of an astrocyte-specific promoter and injected them intravenously into 5xFAD mice (which carry five familial Alzheimer’s disease (FAD) mutations, driving rapid Aβ plaque formation, synaptic loss, and cognitive decline starting around 2–4 months). Both CAR-As reduced amyloid burden and neuritic dystrophy, and the treatment worked both in the prophylactic and therapeutic settings.

Single-nucleus RNA sequencing and immunostaining showed that the CAR-As adopted the transcriptomic profile of activated astrocytes and readily clustered around amyloid plaques. Microglial cells, in turn, also responded to the treatment by showing a reduction of the disease-associated transcriptomic profile that is often seen after administration of monoclonal anti-Aβ antibodies. This is of interest because this disease profile of microglial cells has been suggested to contribute to the inflammatory reaction sometimes seen after Alzheimer’s immunotherapy.

A caveat of the study is that the authos saw no improvements in cognition following therapy, albeit behavioral results in mouse models have been notoriously poor at predicting outcomes in humans. However, the translational questions don’t stop there.

If in clinical practice the CAR-A approach would require an AAV vector, then immunogenicity of the treatment is going to be an issue. Pre-exposure to AAV is often a problem for gene-therapy programs, where patients are much younger. Given that Alzheimer’s is a disease associated with an elderly population, immunogenicity is likely to be exacerbated. Similarly, the delivery of 1013–1014 viral genomes to elderly patients living with Alzheimer’s—many of whom will already have a brain prone to neuroinflammation—makes the specter of unwanted side effects a major concern. In this respect, finding Alzheimer’s patients whose disease stage and age would be appropriate for a therapy with potentially highly toxic consequences for fragile recipients is also difficult to gauge.

That is not to say that CAR-immune cell therapy may not have a place in CNS disease. It just seems like neurological conditions, such as multiple sclerosis where patients are younger and potentially less fragile, are the place where much of the translational groundwork and clinical management for CAR-A or CAR-T therapies must be worked out before moving into neurodegenerative disease for elderly and cognitively compromised patients.