By Momo Yamamoto, Senior Investor Research Analyst, LSN
At RESI San Diego, the “New Frontiers in Diagnostics: Investing in Technologies Enabling Earlier Disease Detection” panel will bring together investors and industry leaders to explore one of the most rapidly evolving areas in healthcare innovation: diagnostics.
As advances in liquid biopsies, molecular diagnostics, AI-enabled imaging, and point-of-care technologies continue to reshape healthcare, diagnostics are increasingly moving beyond simple detection tools and becoming central to disease prevention, monitoring, and personalized treatment strategies. Earlier and more precise detection has the potential to improve patient outcomes, reduce healthcare costs, and create entirely new models of care delivery.
Meet the Panelists
Priya Balachandran
Life Science Angels (Moderator)
Randy Berholtz
Mesa Verde Venture Partners
Yaron Daniely
aMoon Fund
Debbie Lin
T.Rx Capital
Soyoung Park
1004 Venture Partners
The panel will examine where investors and strategic partners see the greatest opportunities emerging across the diagnostics landscape, particularly in oncology screening, cardiometabolic disease, and chronic disease monitoring. With healthcare systems placing greater emphasis on prevention and longitudinal patient management, diagnostic companies are facing growing demand—but also increasing pressure to demonstrate meaningful clinical and economic value.
For early-stage companies, the diagnostics space presents unique opportunities alongside complex commercialization challenges. Unlike many therapeutics companies, diagnostics startups must often navigate overlapping clinical validation, reimbursement, regulatory, and adoption hurdles simultaneously. Investors are increasingly looking for companies that can clearly demonstrate clinical utility, integrate effectively into provider workflows, and build compelling reimbursement strategies early in development.
Panelists are expected to discuss the milestones and study designs that help diagnostic companies stand out in a crowded and competitive market. Topics may include generating real-world evidence, designing validation studies that resonate with payers and providers, and establishing partnerships with laboratories, health systems, and pharmaceutical companies to accelerate adoption.
The rise of AI-enabled diagnostics is also expected to play a central role in the conversation. As machine learning tools become more integrated into imaging, pathology, and predictive analytics platforms, investors are paying close attention to how startups validate algorithms, manage regulatory considerations, and demonstrate measurable improvements in clinical decision-making.
Beyond the technology itself, the panel will likely explore broader market trends shaping investor interest in diagnostics. Healthcare systems worldwide continue shifting toward preventative care models, while aging populations and rising chronic disease burdens increase demand for scalable monitoring solutions. In this environment, diagnostics companies capable of delivering actionable insights earlier in the patient journey may be particularly well-positioned to attract strategic partnerships and investment.
For founders attending RESI San Diego, the session offers an opportunity to better understand how investors evaluate diagnostics opportunities in today’s market and what differentiates successful companies from the broader field. From regulatory and reimbursement strategy to commercialization planning and partnership development, the panel aims to provide practical insight into building investable diagnostic platforms in an increasingly competitive healthcare landscape.
The “New Frontiers in Diagnostics” panel is part of RESI San Diego’s broader programming focused on emerging healthcare technologies, investment trends, and strategies for early-stage companies navigating today’s life science funding environment.
This week, we provide some lightning takes on recent translational papers that caught our eye. We saw several preclinical advances in approaches for pain, neurodegeneration, cardiovascular disease and bone disorders. In the gene-editing arena, several new large DNA insertion technologies and RNA-targeting CRISPR systems came to the fore.
But before we dive in, we want to highlight the New England Journal of Medicine report from the groups of Rebecca Ahrens-Niklas and Lindsey George at the Children’s Hospital of Philadelphia that details a neuroepithelial tumor in a 5-year-old boy with severe mucopolysaccharidosis type I (MPSI, a.k.a. Hurler Syndrome) 4 years after receiving an intracisternal injection of an AAV-9 gene therapy.
Summary timeline (A) of a patient with severe Hurler Syndrome who developed a neuroepithelial tumor 4 years after intracisternal administration of AAV-9 delivering an a-L-iduronidase (IDUA) transgene under the control of a cytomegalovirus enhancer and a chicken β-actin promoter (B). Axial and coronal MRI of the patient’s head performed 4 years after treatment revealed an intraventricular mass associated with truncated and rearranged AAV vector sequences integrated into intron 4 of the PLAG1 (pleiomorphic adenoma gene-like 1) gene on chromosome 8. Source: NEJM
Needless to say, approved AAV-based gene therapy products have a long track record of safety, efficacy and long-term transgene expression, but the specter of insertional mutagenesis has always loomed, even though AAV is a predominantly episomal vector. More than five years ago, a paper on hemophilia A dog studies published in Nature Biotechnology reported 1,741 unique AAV integration events in liver and clonal expansions of transduced hepatocytes, with many integrations near growth-related genes. In that case, no tumors were seen. Human liver-biopsy studies after AAV gene therapy have similarly made clear that integration and clonal hepatocyte expansion can happen, while not showing obvious malignant transformation. The NEJM report stands out as providing the first well-documented case of human oncogenesis plausibly linked to AAV vector integration. We can expect it to lead to tighter regulatory and post-marketing oversight of AAV gene therapies, as illustrated by the clinical hold the US Food and Drug Administration (FDA) already placed on Regenxbio’s gene therapy for Hurler, which was reported back in January. The takeaway for the investment community is that this is not entirely unexpected and should be viewed in the context of >6,000 patients receiving AAV gene therapy to date without major long-term toxic effects.
Safety signals have also been a recurring theme for drugs targeting sodium voltage channels (Nav1.7) in different pain indications. Multiple industry programs have encountered problems with off-target effects and poor clinical translation. Now a team led by Wengsheng Zhang at Sichuan University has identified potent nonopioid analgesics targeting multiple voltage-gated sodium channel isotypes with improved efficacy when tested their efficacy in perioperative rat models (PNAS). We wonder how such a broad approach would mitigate some of the safety flags encountered by previous clinical trials of investigational drugs targeting this pathway. Elsewhere, Xiao-Ming Li and collaborators at Zhejiang University School of Medicine set out to mitigate some of the adverse events of cannabinoid 1 (CB1) agonists, such as reduced locomotion, hypothermia, addiction and analgesic tolerance using so-called biased signaling and targeting downstream signaling cascades mediated predominantly through inhibitory guanine nucleotide binding protein (Gi), rather than beta-arrestin. They show their Gi-biased inhibitors display analgesic properties, but with reduced side effects when tested in mice (Cell). Over recent years, industry has explored cannabinoids to treat a wide range diseases, including chronic kidney disease, glaucoma and even obesity, again with limited clinical success. It will be interesting to see whether drugging a downstream signaling pathway will bring greater reward.
While cannabinoids haven’t exactly set the world of company formation alight, platforms leveraging autophagy biology are another story. In the past five years, Lysoway Therapeutics, Retro Biosciences, Casma Therapeutics, Automera Therapeutics, PAQ Therapeutics and AUTOTAC Bio have all received funding for platforms leveraging auto-phagosomal pathways, such as ATTEC, AUTAC, AUTOTAC, chaperone-mediated autophagy or AUTAB. The latest instantiation of ATTEC is described in a paper by Einar Sigurdsson and researchers from New York University, who develop single-domain antibodies to promote autophagy-mediated tau degradation in patient-derived neurons, improving motor function in tauopathy mice (Science Translational Medicine). Autophagy is also the focus for a collaboration between the Jia-Hong Lu team at the University of Macau and MindRank AI, which developed an AI-based screening platform using a variational autoencoder trained on a library (from MedChemExpress and TSBiochem) of over 1 million compounds to identify brain-penetrant small molecule autophagy enhancers effective in mouse models of Alzheimer’s disease (Nature Biomedical Engineering).
Elsewhere in the neurodegenerative disease field, TDP-43 aggregation is a hallmark of disorders like amyotrophic lateral sclerosis and frontotemporal dementia. Acurastem and Quralis have been tackling these diseases using antisense oligonucleotides (ASOs) to modulate splice-switching of genes affected by mutant TDP-43. But new research from the groups of James Shorter at the University of Pennsylvania, Christopher Donnelly at the University of Pittsburgh, Nicolas Fawzi at Brown University, Brigid Jensen at Thomas Jefferson University and Jeetain Mittal at Texas A&M reveals that short 34-nucleotide RNAs can act as chaperones to inhibit TDP-43 aggregation and prevent neurodegeneration in the mouse. This potentially opens up short RNA chaperones as a new therapeutic modality for protein-folding disorders (Science).
Moving away from the CNS, some intriguing advances in other therapeutic areas popped into our inbox. One of the new frontiers for oligonucleotide therapies is common cardiovascular indications, such as heart failure and atrial fibrillation. For example, Ionis’ transferrin-receptor 1 targeted ASO for downregulating phospholamban in R14-deleted dilated cardiomyopathy just entered phase 1 testing in a development partnership with AstraZeneca. Along these lines, two teams headed by Matthias Nahrendorf and Maarten Hulsman at Harvard Medical School report another target, osteopontin (Spp1), downregulation of which with an antibody–siRNA conjugate targeting TREM2+ cardiac macrophages suppresses atrial fibrillation in mice (Nature Cardiovascular Research).
Another area likely to attract more commercial activity going forward is metabolic bone disease. Last December, the US Food and Drug Administration (FDA) made a landmark regulatory shift, formally qualifying percentage change from baseline at 24 months in total hip bone mineral density (BMD) via imaging as a validated surrogate endpoint (previously, bone disease trial times typically took anywhere from two to five years). Two recent papers discuss new therapeutic approaches to heterotopic bone formation after injury. In the first, two teams led by Benjamin Levi and Michael Dellinger from UT Southwestern show that vascular endothelial growth factor D (VEGF-D)-induced lymphangiogenesis can promote heterotopic bone resorption in mice (PNAS). And across the Atlantic, the groups of Johan Keller and Anke Baranowsky at the University Medical Center Hamburg-Eppendorf target extracellular traps from myeloid cells using an FDA-approved recombinant DNAse 1 Pulmozyme to inhibit traumatic heterotopic ossification in mice (Science Translational Medicine; Roche/Genentech’s Pulmozyme (dornase alpha) is approved only for the pulmonary indication cystic fibrosis).
Moving onto advanced genetic therapeutics, several advances caught our attention in the gene-editing space. While programmable recombinases/integrases capable of introducing genetic cargoes >10 kb have been prominent in journals, momentum in commercializing these approaches has proceeded at a moderate pace, with Brink Therapeutics, Seamless Therapeutics and Stylus Medicine all raising funding in the past three years. The ability of recombinases to introduce large constructs has been touted as a key advantage over prime editing, which traditionally can only achieve desired edits no larger than ~300 bp. In this context, three recent papers disclose alternative prime-editing approaches for the genomic insertion of large sequences, overcoming the sequence size limitation. First, research patented by Ying Zhang’s group at Wuhan University shows that quadruple paired pegRNAs enable prime editing based genomic insertion of sequences as long as 26 kb in vitro (Nature). Second, the teams of Haoyi Wang, Chenxin Wang and Wei Li at the Chinese Academy of Science developed “PRIME-In”, a genome editing platform for the integration of up to 3 kb-long DNA sequences in human T cells independent of double-stranded DNA breaks (Nature Biomedical Engineering). Last, the groups of Erik Sontheimer and Wen Xue at the University of Massachusetts Chan Medical School described a “prime assembly” approach for the insertion of DNA fragments as long as 11 kb (Nature).
Finally, in the area of RNA editing, two recent studies expand the palette of CRISPR–Cas effectors capable of targeting and manipulating cells at the level of transcripts rather than nuclear DNA. A paper from I-Ming Hsing’s group at Hong Kong University of Science and Technology describes the first use of DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage (Nature Biotechnology). In a second paper, Yang Liu’s team at the University of Utah, Chase Biesel’s group at University of Würzburg and scientists from Akribion Therapeutics and BRAIN Biotech engineer CRISPR–Cas12a2 for the selective, DNA-triggered killing of virally infected human cells on the basis of their transcriptional profile (Nature).
Conference roundup
Selected startups raising funds in past three years presenting data at the American Society for Cell and Gene Therapy (ASCGT), Boston, May 11–15.
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An old adage in drug development states that any successful program for an advanced medicine must overcome three central challenges: first, delivery; second, delivery, and third … delivery! Lipid nanoparticle (LNP) technology and N-acetyl galactosamine-(GalNAc) conjugates have opened the liver to a wide range of genetic medicines, and transferrin 1 receptor (TfR1) conjugates are beginning to access the CNS via intravenous delivery with brain-shuttle technology. But tissues like the lung, kidney, muscle and heart remain very much a work in progress.
In the pulmonary space, a small cadre of companies are pursuing inhaled LNP delivery technologies. Recode Therapeutics, Vertex Pharmaceuticals and Arcturus are the main players, while other firms such as 4DMT and Krystal Biotech are focusing on viral gene therapies for lung delivery.
Just a few days ago, one of these LNP programs got the chop. The Vertex/Moderna phase 1/2 study of VX-522, an aerosolized LNP to deliver mRNA encoding full-length cystic fibrosis transmembrane conductance regulator (CFTR) to the lungs of cystic fibrosis patients, which had been paused due to tolerability issues, is now permanently discontinued. According to reports, the Moderna LNP was the culprit, leading to lung inflammation. That leaves Recode and Arcturus as the frontrunners, a rather small field, given the entire market opportunity for a pulmonary delivery solution. All told, in 2023, there were 569.2 million cases of chronic respiratory diseases and 4.2 million deaths from respiratory disease.
Recode now is enrolling patients into the phase 2 trial of its Selective Organ Targeting (SORT), LNP platform (RCT2100) that delivers an mRNA encoding CFTR in combination with the small-molecule CFTR potentiator ivacaftor (the SORT technology was originally licensed out of Daniel Siegwart’s group at UT Southwestern). The other LNP platform, Arcturus’ LUNAR LNP technology, also has encouraging interim data from its phase 2 trial in cystic fibrosis patients and from its program delivering ornithine transcarbamylase mRNA.
These LNPs (and most other LNP delivery platforms) are built around the same four common components: an amino ionizable lipid, a helper lipid, a polyethylene glycol lipid and cholesterol. The formulations follow this scheme but with different combinations of proprietary lipid forms; thus, in Arcturus’ LUNAR LNP, distearoylphosphatidylcholine (DSPC) performs the helper lipid function, whereas in Recode’s SORT LNP, it is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Overall, however, just a handful of novel lipid components have gone into humans so far.
According to Siegwart, the field is in dire need of developing a broader palette of cationic lipids that are both efficient and non-toxic for the pulmonary epithelium; ultimately, the goal would be a delivery technology capable of targeting specific cell types in the lung (with many new cell subtypes continuing to be identified).
The respiratory epithelium contains a diverse set of cell subtypes important in maintaining respiratory homeostasis. Dysfunction in these cells can lead to disease. PNEC, pulmonary neuroendocrine cell; PCD, primary ciliary dyskinesias; CGRP, calcitonin gene related peptide; SIDS, sudden infant death syndrome; SCLC, small cell lung carcinoma; Mtb, Mycobacterium tuberculosis; COPD, chronic obstructive pulmonary disease. Source: Mucosal Immunology
In a recent article in Nature Biomedical Engineering, Siegwart and his group at UT Southwestern introduce the design and evaluation of a new class of lung-targeting (LuT) lipids that enable the highly efficient and selective delivery of mRNA and CRISPR–Cas9 gene-editing systems to the lungs.
They synthesized and screened a library of 444 lipids using a combinatorial approach, systematically varying amine head groups and hydrophobic tails. Through in vivo testing and structure–activity relationship analysis, they identified key features in the lipids that most effectively targeted the lung: a distinctive ‘tripod-like’ structure, consisting of a quaternary amine head, three long alkyl chains and a short fourth chain.
Design, synthesis and multi-round evaluation of LuT lipids for pulmonary delivery. a, LuT lipids were chemically synthesized by one-step combinatorial conjugation of diverse amine heads and alkyl/alkenyl bromide tails, formulated into LuT LNPs and intravenously administrated into mice for in vivo evaluation. SARs governing the function of LuT LNPs were carefully analyzed. b, After in vivo evaluation, the top-performing LuT lipids with a tripod-like structure were identified and showed exceptional mRNA delivery efficiency, which inspired the in-depth investigation into their performance in specific cell type targeting, mechanisms and gene editing. Source: Nature Biomedical Engineering
Compared to benchmark formulations, the best-performing LuT-containing LNPs achieved up to a 25.5-fold increase in mRNA delivery and a 9.2-fold improvement in gene-editing efficiency, with >90% of delivery localized to the lungs. These LuT-LNPs successfully transfected multiple lung cell types, including endothelial, epithelial and immune cells, with some formulations showing preferences for specific cell populations.
Mechanistically, the improved performance was attributable to two main factors. First, the tripod-like structure of lipids promoted endosomal escape by facilitating membrane fusion and LNP disassembly, allowing efficient release of genetic cargo into cells. Second, LuT LNPs formed distinct protein coronas in the bloodstream, particularly enriching for vitronectin, a protein that enhances targeting to lung cells via receptor-mediated uptake.
Siegwart and his team went on to show the therapeutic potential of LuT LNPs. The lead formulation, 1A7B13, enabled effective delivery of IL-10 mRNA in a mouse model of acute lung injury and achieved robust CRISPR–Cas9 gene editing in lung tissue. The LNPs showed minimal toxicity and no significant adverse effects in vivo.
This research establishes clear design principles for lung-targeting LNPs and markedly expands the available toolkit for pulmonary gene delivery. It is just the beginning of the translational path, however.
The Siegwart LuT-LNPs must home through the vasculature to the lungs after being delivered intravenously. This is very different from the aerosolized LNP delivery approaches of Recode and Arcturus currently in clinical testing. There may be a case to be made that some pulmonary vascular disease, lung endothelial targets, lung fibrosis, immune-cell or vascular-compartment targets might warrant the intravenous route, but aerosolized LNP delivery provides lower systemic exposure (and thus higher therapeutic index), is more patient-friendly, and rapidly/directly reaches the airway lumen.
Regardless of the route of administration, the translational challenges associated with targeting the lung remain very difficult. In terms of testing formulations in different models, anatomical differences between mouse, ferret and human airways, including physiological size and branching complexity, impact LNP design and aerosol physics.The formulations used for mice may simply not work for people because of differences in cell composition, and lung epithelial and endothelial membranes and “surfaceomes”. As humans age and develop disease, cell protein and lipid composition may also change, requiring further optimization of LNP formulations. Mice have more narrow airways and faster breathing rates than humans, requiring smaller diameter aerosol droplets (often <2 µm) to ensure particles bypass the upper respiratory tract and reach the alveolar regions.
Moreover, humans have ~23 branches in their airways, whereas mice have only 13, meaning an aerosol optimized for a ‘deep’ reach in a mouse might only reach mid-level bronchi in a human. Furthermore, ferrets are not a widely available model system to study the biodistribution and efficacy of LNPs. Indeed, there are just a few labs in the United States that upkeep ferret colonies.
Last, a human lung’s surface area (~70 m²) is nearly 8.500 times larger than a mouse’s (~82 cm²), and human tidal volume is roughly 6,000 times greater. This requires significant dose scaling and affects how ‘diluted’ the LNPs become once they deposit.
Designing in vitro and in vivo systems representative of human biology and capable of predicting LNP biodistribution is also a tall order (especially with such a small cadre of companies working on the problem). For small molecules, the measurement of efficacy in human basal epithelium-derived patient cells carrying a mutation of interest by and large will translate into what you see in the clinic. The pharmaceutical industry has amassed a lot of data to bolster pharmacology.
Unfortunately, that correlation doesn’t necessarily hold for genetic modalities like mRNA or CRISPR/Cas9 constructs. For these medicines, it is very hard to figure out PK/PD. And so, the translation from preclinical work to the clinic can be tricky for an inhaled LNP technology delivering mRNA. It is difficult to really know the degree of protein expression from an inhaled LNP genetic medicine intracellularly without doing a bronchial biopsy (which is of course highly intrusive). And if you need to test your LNP in patients via biopsy, clinicians historically have been very resistant to carrying out such procedures, particularly in very sick patients like some of people with cystic fibrosis who carry nonsense mutations in CFTR. Thus, there is a need for alternative approaches. Certainly, there is an opportunity for more work on organoids or simpler patient cell-derived assays: 2D or 3D alternatives to large animal models like the ferret.
What is clear is that there are enough patients worldwide living with lung disease that further research in this area needs to be encouraged. In this respect, the findings from Siegwart’s group are a step in the right direction, with broad implications for treating lung diseases by enabling safer and more precise delivery of RNA-based therapeutics and genome-editing technologies.
By Momo Yamamoto, Senior Investor Research Analyst, LSN
For early-stage life science companies, securing seed capital is often only the first step. The greater challenge is successfully transitioning from early fundraising into institutional venture rounds, a critical phase where companies must prove not only the strength of their science or technology, but also their ability to deliver meaningful milestones, manage capital strategically, and build toward scalable growth.
At RESI San Diego 2026, this pivotal transition will be the focus of the panel discussion “Crossing the Venture Gap: Moving from Seed Funding to Venture Rounds,” scheduled for 4:00 PM as part of the conference’s investor programming.
This session will examine how companies can position themselves for larger venture rounds in a more demanding capital environment. Panelists will discuss what investors now expect from companies seeking their first significant institutional financing, including the level of scientific validation, regulatory planning, commercial readiness, and operational maturity required to stand out. The conversation will also address how founders can build credible leadership teams and boards, structure capital strategy effectively, and present a compelling long-term vision that aligns with near-term execution.
The panel features an experienced group of venture investors and strategic leaders actively engaged in funding and evaluating emerging life science companies:
Mahesh Narayanan
Neuvation Ventures
Nicolas Cindric
Yahara Ventures
Preetha Ram
Pier 70 Ventures
Chris Yoo
Xcellerant Ventures
Bob Sweeney
Global Health Impact Fund
Ole Henrik Bang-Andreasen
Avant Bio
Together, these panelists bring valuable perspectives on what it takes for startups to successfully move beyond seed-stage financing and into larger venture-backed growth.
For founders preparing for this next stage, the session offers practical insight into how investors assess risk, evaluate progress, and identify companies with the strongest potential for long-term success.
RESI San Diego 2026 provides a concentrated environment for early-stage companies to engage with investors, strategic partners, and industry stakeholders through targeted partnering, educational programming, investor panels, and pitch opportunities. With five days of partnering, access to active investors across the 4Ds, and specialized programming designed around early-stage fundraising and growth, the conference remains focused on helping companies navigate the realities of capital formation in life sciences.
Early bird rates are currently available through May 8, offering discounted access for companies looking to maximize both strategic insights and investor engagement opportunities at one of the sector’s leading partnering events.
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.
Different mechanisms being targeted in Alzheimer’s human testing. Although amyloid has long dominated drug-development efforts, there are now more neuroinflammatory targets in phase 2 trials than anti-amyloid treatments. Source: Alzheimer’s & Dementia: Translational Research & Clinical Interventions
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.
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.
CAR-A treatment of amyloid pathology in an AD-related model. The left panel shows the study design. The beneficial effect of CAR-A treatment depends on its improvement of astrocytic phagocytosis of Aβ, which results in reduced microglial burden and neuronal dystrophy (top right). The team tested two different CAR-As, which acted by different mechanisms converging on the same therapeutic effect (bottom right). Source: Science
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.
By Momo Yamamoto, Senior Investor Research Analyst, LSN
Life Science Nation (LSN) has announced the investor panel lineup for RESI San Diego 2026, taking place June 22 at the JULEP Venue in San Diego during Convention Week, followed by four days of virtual partnering on June 23–24 and June 29–30. The hybrid format combines in-person networking with extended virtual partnering, giving founders and investors additional opportunities to continue conversations and schedule meetings beyond the live event.
Investor panels are a cornerstone of the RESI conference series, bringing together active investors and strategic partners to share perspectives on the evolving life science funding environment. These sessions offer founders and executives the opportunity to hear directly from investors about how they evaluate opportunities across drugs, devices, diagnostics, and digital health.
This year’s discussions will explore several key themes shaping early-stage investment. Topics will include how emerging companies can successfully engage pharmaceutical partners, what strategic investors and corporate venture capital groups are prioritizing in today’s market, and how medtech innovators can position themselves to attract both financial and strategic partners. Panels will also examine investment trends in diagnostics and oncology, the growing role of artificial intelligence in healthcare innovation, and the challenges many startups face when moving from seed capital to institutional venture funding.
RESI San Diego 2026 Investor Panels
Time
Panel Title
9AM
Inside Pharma Partnering How Early-Stage Companies Can Engage Pharma
10AM
Strategic Partnerships in Medtech What the Next Generation of Device Companies Must Deliver
11AM
Strategic Capital: The Role of CVCs Investing Where Innovation Meets Industry
1PM
New Frontiers in Diagnostics Investing in Technologies Enabling Earlier Disease Detection
2PM
Emerging Approaches in Cancer Therapies How New Modalities Are Standing Out in a Competitive Market
3PM
AI at the Frontlines of Healthcare Innovation Building Scalable Companies at the Intersection of Data and Medicine
4PM
Crossing the Venture Gap Moving from Seed Funding to Venture Rounds
In addition to investor panels, RESI San Diego will feature the Innovator’s Pitch Challenge, where selected startups present their technologies directly to investor judges in an interactive pitch format. The conference also offers extensive one-on-one partnering opportunities, allowing attendees to schedule meetings with investors, strategic partners, and industry leaders through the RESI partnering system.
Held during San Diego’s broader biotech Convention Week, RESI San Diego provides a focused environment for early-stage companies to connect with active healthcare investors and strategic partners. The event brings together venture capital firms, family offices, corporate venture groups, and industry leaders seeking opportunities across drugs, devices, diagnostics, and digital health.
Register today to secure your place at RESI San Diego 2026 and connect with investors shaping the future of healthcare innovation. Super Early Bird rates are available through April 17.
X-ray crystallography has long been the go-to workhorse for providing atomic structures of drugs interacting with their protein targets. Increasingly, those static snapshots are being complemented by readouts from experimental analytical tools based on nucleic magnetic resonance (NMR) spectroscopy and cryoelectron microscopy (cryo-EM), offering drug developers a broader window into proteins as dynamic, breathing molecules. This is spurring a raft of new service provider startups, including AIffinity (Brno-Medlánky, Czech Republic), NexMR (Zürich, Switzlerand), CryoCloud (Utrecht), and Intellicule (West Lafayette, IN), all of which aim to supply drug-discovery teams with state-of-the-art platforms providing structural data with rapid turnaround times and low cost.
As many of the most compelling ‘undruggable’ targets are renowned shape shifters — aggregation-prone proteins like Tau, amyloid precursor protein (APP) or huntingtin in neurodegenerative diseases, or transcription factors like P53, KRAS and c-MYC in oncology — a lot of therapeutic startup activity has recently focused around so-called ‘intrinsically disordered proteins’ (IDPs). The ability to attain markedly different conformations under different conditions allows IDPs not only to play moonlighting roles or serve as hubs in signaling networks, but also to localize into liquid- phase condensates (or membrane-less organelles — attributes that make them acutely sensitive to mutations that can compromise specificity and lead to nonspecific binding, resulting in toxicity and disease.
An important postscript to the startup activity targeting undruggable IDPs is that more conventional ‘druggable’ target classes, like tyrosine kinases, may also represent a fruitful hunting ground for dynamic conformational states that may have been missed by traditional crystallographic approaches. Given that conventional drug targets have relatively well-trodden clinical and commercial development paths, they may also represent simpler starting points and testing grounds for commercial programs aiming to apply the new analytical approaches to support medicinal chemistry programs around validated targets.
In a paper recently published in Science, the team of Charalampos (Babis) Kalodimos at St. Jude Children’s Research Hospital use high-resolution NMR spectroscopy to gain structural insight into how SRC family tyrosine kinases (Src, Hck, and Lck) achieve processive phosphorylation of multisite substrates.
NMR spectroscopy offers direct access to (~1–2 Å) resolution atomic information to identify non-covalent interactions between a drug and a protein target. Starting from 13C-labeled amino acids/precursors (left), a backbone and side-chain amino acids in a protein of interest (up to 80 kDa in size) can be selectively labeled for NMR structure determination. Substantial chemical shift changes of protein signals induced by aromatic ligand ring-systems can be directly incorporated into 3D structural calculations of protein–drug complexes. Source: Communications Chemistry
The SRC enzyme family is essential for rapid and coordinated signaling in processes such as cell migration and T-cell activation. In addition, SRC family kinases are frequently overexpressed in tumors, contributing to the activation not only of multiple scaffold or signaling proteins, such as receptor tyrosine kinases (e.g., EGFR, FGFR, PDGFR or IGF1R), but also of downstream effectors (e.g., MAPKs, FAK, paxillin, p130Cas, ELMO1 and RAC1). Although there are approved drugs like the multikinase inhibitor Sprycel (dasatinib) that bind the SRC active site, these drugs have such extensive off-target and adverse side effects that there is a pressing need for new paths to more-selective SRC inhibitors.
SRC enzymes share a conserved domain organization, with a disordered N-tail, a tandem SH3–SH2 module, a kinase domain, and a disordered C-tail. All can carry out processive phosphorylation — a phenomenon where the enzyme phosphorylates multiple residues in a substrate during a single encounter. Each of these catalytic cycles typically requires ATP binding, phosphate transfer and ADP release, and ADP release is often the rate-limiting step. So, a question that has long puzzled structural biologists is how ADP-release–constrained kinases achieve sufficiently rapid turnover to successfully perform their function.
Using NMR spectroscopy with cryogenic probes — which reduce electronic/thermal noise and increase sensitivity up to five-fold compared with room-temperature probes — the St. Jude team characterized the conformational ensemble of the Src kinase domain and identified three interconverting states: a predominant active state, a previously described inactive Src/CDK-like state, and a hitherto unknown low-populated intermediate state positioned linearly between the other two. Structural determination revealed that this intermediate state displays features that are distinct from the active and inactive states. Its activation loop is partially folded, the P-loop is displaced inward, and the αC helix is shifted upward. This conformation binds ADP poorly relative to the active and inactive states, suggesting that it facilitates nucleotide release.
(A) Schematic representation of processive phosphorylation by an SFK. Substrate binding through the SH3 domain prolongs the residence time of the complex, allowing the kinase to phosphorylate multiple sites in a single binding event. Each catalytic cycle involves ATP binding and hydrolysis, transfer of the γ-phosphate to the substrate and ADP release, followed by a new cycle without dissociation of the complex. To sustain processive phosphorylation, the catalytic turnover — limited by ADP release — must be sufficiently fast to complete multiple phosphorylation events before dissociation of the SH3–substrate complex. (B) Energy landscape of the ground (G) and excited (E1 and E2) states of Src KD determined by NMR. Populations and kinetics of interconversion determined by fitting the relaxation data are shown. Structures of the (C) active state, (D) intermediate state and (E) inactive state. Source: Science
Using mutational analyses, the researchers then confirmed the functional importance of this intermediate state. Variants that eliminated this intermediate state while stabilizing the active state showed slower ADP dissociation, reduced catalytic turnover and impaired processive phosphorylation of the multisite Src substrate p130Cas. Instead of generating a fully phosphorylated substrate in a single binding event, these mutants accumulated partially phosphorylated intermediates. Equivalent mutations in other kinases of the SRC family, Lck and Hck, similarly reduced catalytic efficiency and impaired multisite phosphorylation of their respective physiological substrates CD3ζ and ELMO1 in Jurkat cells. Furthermore, these mutations compromised cellular functions measured via in vitro assays, including T-cell activation using Lck-deficient Jurkat cells and migration of mouse embryo fibroblasts lacking Src, Yes and Fyn in the presence of fibronectin. These molecular and functional findings indicate that the intermediate state is evolutionarily conserved and essential for processive activity across the SRC family.
Mechanistically, the work establishes that rapid ADP release, enabled by transient sampling of a structurally constrained intermediate, is critical for sustaining catalytic turnover rates that exceed the speed of substrate dissociation. More broadly, it shows that kinase conformational landscapes are tuned not only for switching between active and inactive states, but also for optimizing specific kinetic steps within the catalytic cycle.
From a drug developer’s standpoint, because Sprycel and other inhibitors target the active or inactive conformations of the SRC active site, the identification of a low-populated, functionally indispensable intermediate suggests a completely new strategy to target tyrosine kinases: selectively stabilize or destabilize the intermediate state to fine-tune catalytic turnover and processivity rather than simply blocking activity. Targeting such transient conformations could enable more precise modulation of signaling output, potentially improving selectivity and reducing off-target effects in kinase-directed therapies.
We look forward to seeing how many more of these intermediate states are uncovered in other kinase targets and whether pharmacological inhibitors targeting this state have advantages over orthosteric or allosteric chemotypes that conventionally have been used to inhibit the kinase active site or lock it in an inactive conformation. What is clear is that ultrafast NMR measurements of binding and state behavior are a powerful differentiating tool for understanding kinase activity where static structures aren’t enough.
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