Partnering conferences are a great place to meet investors, in-licensors and strategic partners. These events tend to be segmented in the following ways:
1) Focus: General, Licensing/BD or Investment
2) Modality: Biotech, Device/Diagnostics, Digital Health
3) Therapeutic area: General or Therapeutic area-specific
4) Stage: General or Early Stage
While it seems obvious, it is critical to align your events (and your limited time and budget) with your company objectives. In my experience at dozens of different partnering conference, I’ve found that each of the above are largely binary. For example, while a Licensing/BD conference will have some investors attending, you’ll have many more meetings with investors at a investment-focused meeting. And vice-versa. Additionally, an interesting pattern that I’ve noticed is when it comes to stage, a partnering event that has a general focus tends to skew late-stage (clinical or later, with lots of players looking for phase 3 or commercial assets). This leaves companies with preclinical or early clinical assets scrambling to identify and meet the relatively few investors who are interested in early-stage companies.
Since partnering conferences allow for a limited number of outgoing meeting requests that can be in the ‘requested’ state, it’s important for you to be able to identify the attending investors that are a good fit for your company. This is complicated by the fact that investors typically don’t do a stellar job populating their profile with information that makes their remit clear. While it may be tempting to use the filters provided by the partnering system to identify best-fit investors, this ONLY works if every investor profile is consistently populated. Why? Because blank values are not returned in filtered searches. What does that mean? That means that if you use the filters in the partnering system to look for those who invest in oncology, and there are some oncology investors who have not filled out their therapeutic area field in their profile, those investors will not be returned in the results. Some partnering conference providers, such as RESI, prevent this issue by having the staff populate the investor profiles on behalf of the investors, ensuring that all profiles are complete and searchable.
All that said, what do you need to look for to find the investors that fit your company best? The most important criteria (that you probably know already if you’ve done any investor outreach) is stage. “Too early” is a response that every pre-clinical and phase 1 company has heard a million times. At RESI it’s easy. You can filter accurately on stage. But at other conferences that depend on the investor to self-populate their profile, you’ll have to read the profile carefully and visit the website. If it doesn’t say explicitly, then look at the portfolio companies.
The next aspect is the assets under management and the check size range. This kind of information not only shows if the investor is appropriate for the amount you’re raising, but also shows if the investor is indeed an investor and not a financial consultancy or investment bank (in some conferences, such entities end up being classified as investors).
Next, and as alluded to above, is the therapeutic area focus. While many investors go across therapeutic areas, some focus on only one or a few.
Next is the modality. Of course if you’re a med tech investor you don’t want to target a biotech-only investor. Within biotech, there are some investors that only do advanced therapies and some who do everything except advanced therapies. Etc.
Next there is the geographic focus. Some investors target specific geographies.
Finally, there is the investor type or model. Not all investors are equity investors. Some are debt, some royalty, some are venture builders, some are CROs that provide services for equity, etc.
If you have access, looking up the investor in Life Science Nation’s investor database will return all the details you need with regard to the above. Other databases have information on investments a given investor made, which provides some insight. By ensuring the investor you send a meeting request to is actually suitable for your company, you’ll maximize your ROI and, with any luck, extend your cash runway.
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 theĀ New England Journal of MedicineĀ report from the groups of Rebecca Ahrens-Niklas and Lindsey George at the Childrenās 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 Ī²-actin promoter (B). Axial and coronal MRI of the patientās 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:Ā NEJMā
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 aĀ predominantly episomalĀ vector. More than five years ago, a paper on hemophilia A dog studies published in Nature Biotechnology reportedĀ 1,741 unique AAV integration eventsĀ 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 onĀ RegenxbioāsĀ gene therapy for Hurler, which wasĀ reported back in January. The takeaway for the investment community is that this is not entirely unexpected and should be viewed in the context ofĀ >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 encounteredĀ problemsĀ 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, includingĀ chronic kidney disease,Ā glaucomaĀ and evenĀ obesity, again with limited clinical success. It will be interesting to see whether drugging a downstream signaling pathway will bring greater reward.
While cannabinoids havenāt exactly set the world of company formation alight, platforms leveraging autophagy biology are another story. In the past five years,Ā Lysoway Therapeutics,Ā Retro Biosciences,Ā Casma Therapeutics,Ā Automera Therapeutics,Ā PAQ TherapeuticsĀ andĀ AUTOTAC BioĀ have all received funding for platforms leveraging auto-phagosomal pathways, such asĀ ATTEC,Ā AUTAC,Ā AUTOTAC,Ā chaperone-mediated autophagyĀ orĀ 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 Alzheimerās 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.Ā AcurastemĀ andĀ QuralisĀ 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, Ionisā transferrin-receptor 1 targeted ASO for downregulating phospholamban in R14-deleted dilated cardiomyopathy justĀ entered phase 1 testingĀ 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 antibodyāsiRNA 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.Ā 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/Genentechās Pulmozyme (dornase alpha) isĀ 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, withĀ Brink Therapeutics,Ā Seamless TherapeuticsĀ andĀ Stylus MedicineĀ 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 Zhangās 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 āPRIME-Inā, 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 āprime assemblyā 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 CRISPRāCas effectors capable of targeting and manipulating cells at the level of transcripts rather than nuclear DNA. A paper from I-Ming Hsingās group at Hong Kong University of Science and Technology describes the first use of DNA-guided CRISPRāCas12a effectors for programmable RNA recognition and cleavage (Nature Biotechnology). In a second paper, Yang Liuās team at the University of Utah, Chase Bieselās group at University of WĆ¼rzburg and scientists fromĀ Akribion TherapeuticsĀ and BRAIN Biotech engineer CRISPRāCas12a2 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,Ā May 11ā15.
If youāre interested in commercializing your science,Ā get in touch. We can help you figure out the next steps for your startupās translational research program and connect you with the right investor. Follow us on X, BlueSky and LinkedIn. Please send feedback; weād love to hear from you (info@haystacksci.com).
As partnering activity ramps up ahead of convention week in San Diego, early-stage life science companies are preparing for a critical week of fundraising, licensing, and strategic business development. To help companies better understand how large pharmaceutical companies evaluate new opportunities, Life Science Nation is hosting a webinar featuring leaders from Merck, Servier, and Meiji Pharma USA.
The webinar, Large Pharma BD & Investment: Merck, Servier & Meiji Pharma Prep You for RESI & Convention, will take place on June 2, 2026 at 1:00 PM ET and will be moderated by Sougato Das.
Carla BauerDirector, Search and Evaluation, BD & Licensing Merck
Irene Blat, PhDHead of External Innovation, NA Servier
Sho TakahataSenior Director, Venture Investment Meiji Pharma USA
The discussion will explore how pharma companies source and evaluate external innovation, what teams look for during initial meetings, how internal screening processes work, and what makes a company stand out for continued engagement. Topics will also include licensing, R&D partnerships, strategic investment, platform collaborations, and practical tips for improving partnering conversations during convention week.
For companies preparing for RESI San Diego and broader convention week activity, the webinar offers an opportunity to hear directly from pharma business development and investment leaders before arriving in San Diego.
RESI San Diego begins June 22 with an in-person conference day followed by four days of virtual partnering on June 23ā24 and June 29ā30, connecting early-stage companies with active investors, pharma scouts, strategic partners, and global healthcare stakeholders.
The fourth week of June is one of the largest gatherings of life science business development and investment professionals on the calendar, second only to JPM. If you are an early-stage company raising anywhere from $250K to $75M, that week in San Diego is not optional. The question most founders are asking right now is whether attending RESI means missing BIO.
The short answer is no. Here is why.
RESI partnering starts early morning on June 22. BIO Convention partnering does not start until early afternoon. That means you can run a full morning of investor meetings at RESI before BIO gets going. The two venues are about 15 minutes apart, making it straightforward to move between them in the afternoon. RESI has virtual days both that week and the following week, so any meetings that do not fit in person can be held on Zoom with no schedule conflicts.
If you find yourself double booked across both events on Monday afternoon, the partnering systems give you real options. Move the Convention meeting to another day. Move the RESI meeting to the morning or to a virtual slot. Or simply decide which meeting matters more for your specific raise. Having choices is better than not having them.
Fundraising is a numbers game. Companies with tight budgets need to maximize every hour and dollar spent in San Diego each week. RESI is not a scheduling conflict. It is more meetings with investors and pharma external innovation teams that are specifically focused on early-stage deals. Add it to your agenda.
Bonus: Increase your networking ROI by attending the many side events and receptions during Convention week. Luckily we’ve assembled the most complete list for you! Click here.
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 ā¦ delivery! Lipid nanoparticle (LNP) technology andĀ 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.Ā Recode Therapeutics,Ā Vertex PharmaceuticalsĀ andĀ ArcturusĀ are the main players, while other firms such asĀ 4DMTĀ andĀ Krystal BiotechĀ are focusing on viral gene therapies for lung delivery.
Just a few days ago, one of these LNP programsĀ 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 toĀ 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 wereĀ 569.2 million casesĀ of chronic respiratory diseases and 4.2 million deaths from respiratory disease.
Recode now isĀ enrolling patients into the phase 2 trialĀ of its Selective Organ Targeting (SORT), LNP platform (RCT2100) that delivers an mRNA encoding CFTR in combination with the small-molecule CFTR potentiator ivacaftor (theĀ SORT technologyĀ was originallyĀ licensed outĀ of Daniel Siegwartās group at UT Southwestern). The other LNP platform, Arcturusā LUNAR LNP technology, also has encouragingĀ interim dataĀ from its phase 2 trial in cystic fibrosis patients and from itsĀ programĀ 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 Arcturusā LUNAR LNP, distearoylphosphatidylcholine (DSPC) performs the helper lipid function, whereas in Recodeās 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 beĀ 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:Ā Mucosal Immunologyā
In a recent article inĀ Nature Biomedical Engineering,Ā 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 CRISPRāCas9 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 structureāactivity relationship analysis, they identified key features in the lipids that most effectively targeted the lung: a distinctive ātripod-likeā 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.Ā 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.Ā 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:Ā Nature Biomedical Engineeringā
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 CRISPRāCas9 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 āsurfaceomesā. 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 Āµm) 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 ādeepā 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 mĀ²) isĀ nearly 8.500 timesĀ larger than a mouse’s (~82 cmĀ²), and human tidal volume isĀ roughly 6,000 times greater. This requires significant dose scaling and affects how ādilutedā 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 doesnāt 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 Siegwartās 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.
The approval of multiple anti-amyloid monoclonal antibodies (mAbs) ā aducanumab (Aduhelm; nowĀ withdrawn), lecanemab (Leqembi) and donanemab (Kisunla) ā over the past five years has opened the era of disease-modifying Alzheimerās drugs, albeit with only modest benefits in addressing cognitive decline (30% slowing) and associated serious safety risks,Ā 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 AĪ².
Different mechanisms being targeted in Alzheimerās 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:Ā Alzheimerās & Dementia: Translational Research & Clinical Interventionsā
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 firmĀ ScitarisĀ (you donāt 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 inĀ managing these adverse events,Ā atypical non-ICANS neurotoxicities (NINTs)Ā 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 (āCAR-Asā), a strategy not unlike the one used in cancer immunotherapy. Although bothĀ macrophages (CAR-Ms)Ā andĀ conventional CAR-TsĀ have been tested in preclinical models of Alzheimerās 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 AĪ², 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:Ā Scienceā
In broad terms, the construct used to generate CAR-As consisted of an AĪ²-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 AĪ²-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 Alzheimerās disease (FAD) mutations, driving rapid AĪ² plaque formation, synaptic loss, and cognitive decline starting around 2ā4 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-AĪ² antibodies. This is of interest becauseĀ this disease profile of microglial cellsĀ has been suggested toĀ contribute to the inflammatory reactionĀ sometimes seen after Alzheimerās 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 donāt 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 Alzheimerās is a disease associated with an elderly population, immunogenicity is likely to be exacerbated. Similarly, the delivery of 1013ā1014Ā viral genomes to elderly patients living with Alzheimerāsāmany of whom will already have a brain prone to neuroinflammationāmakes the specter of unwanted side effects a major concern. In this respect, finding Alzheimerās 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.
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, includingĀ AIffinityĀ (Brno-MedlĆ”nky, Czech Republic),Ā NexMRĀ (ZĆ¼rich, Switzlerand),Ā CryoCloudĀ (Utrecht), andĀ IntelliculeĀ (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 āundruggableā targets are renowned shape shifters ā 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 ā a lot of therapeutic startup activity has recently focused around so-called āintrinsically disordered proteinsā (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 ā 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 ādruggableā 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 inĀ Science,Ā the team of Charalampos (Babis) Kalodimos at St. Jude Childrenās 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 (~1ā2 Ć ) resolution atomic information to identify non-covalent interactions between a drug and a protein target. Starting fromĀ 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 proteinādrug complexes. Source:Ā Communications Chemistryā
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 frequentlyĀ 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 inhibitorĀ Sprycel (dasatinib)Ā 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 SH3āSH2 module, a kinase domain, and a disordered C-tail. All can carry out processive phosphorylation ā 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-releaseāconstrained kinases achieve sufficiently rapid turnover to successfully perform their function.
Using NMR spectroscopy with cryogenic probes ā which reduce electronic/thermal noise and increase sensitivity up to five-fold compared with room-temperature probes ā 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 Ī±C 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 Ī³-phosphate to the substrate and ADP release, followed by a new cycle without dissociation of the complex. To sustain processive phosphorylation, the catalytic turnover ā limited by ADP release ā must be sufficiently fast to complete multiple phosphorylation events before dissociation of the SH3āsubstrate 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:Ā Scienceā
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 CD3Ī¶ 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 developerās 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 arenāt enough.
The firm is focused on therapeutics companies and does not invest in medical devices, diagnostics, or digital health. The firm is open to considering assets of very early stages, even those as early as lead optimization phase. The firm considers various modalities, including antibodies, small molecules, and cell therapy. Currently, the firm is not interested in gene therapy. Indication-wise, the firm is most interested in oncology and autoimmune diseases but has recently looked at fibrotic diseases and certain rare diseases as well.
The firm is opportunistic across all subsectors of healthcare. Within MedTech, the firm is most interested in medical devices, artificial intelligence, robotics, and mobile health. The firm is seeking post-prototype innovations that are FDA cleared or are close to receiving clearance. Within therapeutics, the firm is interested in therapeutics for large disease markets such as oncology, neurology, and metabolic diseases. The firm is open to all modalities with a special interest in immunotherapy and cell therapy.
A strategic investment firm of a large global pharmaceutical makes investments ranging from $5 million to $30 million, acting either as a sole investor or within a syndicate. The firm is open to considering therapeutic opportunities globally, but only if the company is pursuing a market opportunity in the USA and is in dialogue with the US FDA.
The firm is currently looking for new investment opportunities in enterprise software, medical devices, and the healthcare IT space. The firm will invest in 510k devices and healthcare IT companies, and it is very opportunistic in terms of indications. In the past, the firm was active in medical device companies developing dental devices, endovascular innovation devices, and womenās health devices.
A venture capital firm founded in 2005 has multiple offices throughout Asia, New York, and San Diego. The firm has closed its fifth fund in 2017 and is currently raising a sixth fund, which the firm is targeting to be the largest fund to date. The firm continues to actively seek investment opportunities across a […]
Partnering conferences are a great place to meet investors, in-licensors and strategic partners. These events tend to be segmented in the following ways:
Next Phase Newsletter 