Tag Archives: wellness

The Needle Issue #27

27 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

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.

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.

Preclinical financings (from April 21 to May 4)

Preclinical financings (from May 5 to May 11)

Preclinical financings (from May 12 to May 14)

Preclinical deals (from April 16 to April 29)

Preclinical deals (from April 30 to May 13)

Stay in touch

We hope you enjoyed this issue of The Needle and hit the button below to receive forthcoming issues into your inbox

If you’re interested in commercializing your science, get in touch. We can help you figure out the next steps for your startup’s translational research program and connect you with the right investor. Follow us on X, BlueSky and LinkedIn. Please send feedback; we’d love to hear from you (info@haystacksci.com).

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

12 May

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

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The Needle Issue #26

12 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

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).

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.

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.

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

14 Apr

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

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The Needle Issue #25

14 Apr
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.

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Novotech at RESI JPM: Strategic Early Clinical Development for Biotech Sponsors 

3 Mar

As a sponsor of RESI JPM, Novotech joined the RESI community during JPM Week to engage with emerging biotech companies at pivotal stages of development. Marina Mullins, VP of Early Clinical Development at Novotech, shared insight into the company’s biotech-focused model, global execution strategy, and evolving approach to early-phase clinical development. 

Marina Mullins
 CaitiCaitlin Dolegowski

Caitlin Dolegowski (CD): Can you briefly describe Novotech’s mission and core capabilities as a global CRO and scientific advisory partner? 

Marina Mullins(MM) : Novotech is a global full-service clinical research organization and scientific advisory partner focused on accelerating the development of innovative therapeutics for biotech and small- to mid-sized pharmaceutical companies. The company provides integrated clinical trial services across Phase I–IV, with particular strength in early clinical development, regulatory strategy, medical oversight, biometrics, and operational execution. 

With offices across Asia-Pacific, North America, and Europe, and long-standing site partnerships globally, Novotech combines regional expertise with global coordination to support sponsors from preclinical planning through proof-of-concept and beyond. Its model integrates scientific advisory and operational delivery, enabling sponsors to move efficiently from strategy to execution. 

CD: What differentiates Novotech from other CROs in terms of clinical execution, expertise, or client support? 

MM: Novotech differentiates itself through a biotech-centric approach and deep regional execution expertise. Rather than operating as a transactional service provider, the company works as a strategic partner, aligning development strategy with operational planning from the outset. 

Key differentiators include strong early-phase capabilities, particularly in first-in-human and proof-of-concept studies; deep regulatory and operational experience across high-performance regions such as Australia, Asia, and North America; therapeutic expertise spanning oncology, infectious diseases, obesity, CNS, endocrine, rare diseases, and emerging modalities; and a partnership model designed to provide agility, senior oversight, and milestone-aligned execution. 

This integrated structure allows sponsors to make data-driven decisions while maintaining timeline discipline and regulatory alignment. 

CD: How does Novotech’s global footprint support biotech and pharma companies as they advance clinical development? 

MM: Novotech’s global presence enables sponsors to strategically select development regions based on speed, regulatory pathway, patient access, and capital efficiency. 

For example, Australia offers an established regulatory framework that allows certain first-in-human studies to proceed under the Clinical Trial Notification scheme without requiring an Investigational New Drug submission to the U.S. Food and Drug Administration. This can provide an efficient pathway to first patient while maintaining internationally recognized ethical and regulatory standards. 

At the same time, Novotech’s footprint across Asia, North America, and Europe supports seamless program expansion into multi-regional trials. Sponsors benefit from consistent governance, harmonized data standards, and coordinated regulatory strategy as programs advance. 

CD: As a sponsor of RESI during JPM Week, what were your key objectives for participating this year? 

MM: Novotech’s objectives were centered on early engagement and strategic dialogue. The company aimed to connect with emerging biotech companies preparing for first-in-human or proof-of-concept studies, provide guidance on early development strategy and regulatory pathways, explore long-term partnerships beyond single studies, and support investor-backed companies in aligning clinical milestones with financing objectives. 

RESI provided a focused environment to engage with innovative sponsors at critical inflection points in development. 

CD: Who is Novotech most interested in connecting with? 

MM: Novotech is particularly interested in engaging with early- to mid-stage biotech companies transitioning from preclinical to first-in-human studies, and companies seeking an integrated CRO partner that combines regulatory advisory, scientific strategy, and operational execution. The emphasis is on building strategic relationships with sponsors who value early alignment between scientific design, regulatory positioning, and clinical operations. 

CD: Are there particular trends in early clinical development shaping Novotech’s ECD strategy? 

MM: Regulators are placing greater emphasis on optimized dose selection and robust early-phase data packages, increasing the use of adaptive designs, expansion cohorts, and integrated pharmacokinetic and pharmacodynamic modeling in first-in-human studies. 

There is also growing strategic use of healthy volunteer studies, where scientifically appropriate, to better characterize safety, pharmacokinetics, and target engagement before patient expansion. This can reduce downstream risk and improve capital efficiency. 

Biotech sponsors are under pressure to generate milestone-defining data efficiently. As a result, early programs increasingly incorporate translational biomarkers, seamless SAD and MAD structures, and optional proof-of-concept expansion pathways within unified protocol frameworks. 

Together, these trends reinforce a shift toward positioning early clinical development as a strategic foundation for the entire program lifecycle. 

Interested in sponsoring an upcoming RESI conference? 

To explore sponsorship opportunities, please contact resi@lifesciencenation.com. Life Science Nation would welcome the opportunity to meet and discuss organizational goals for connecting with the global RESI investor and innovator community.

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The Needle Issue #24

24 Feb
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

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.

As IDPs frequently resist attack by conventional drug discovery approaches, a slew of startups has sprung up to try to go after this target class, many using new structural techniques. These include Peptone (London, UK), Dewpoint Therapeutics (Boston, MA), brainQR Therapeutics (Göttingen, Germany), and Kodiform Therapeutics (Oxford, UK). Just last month, Topos Bio secured a $10.5 million seed round to “tackle ‘undruggable’ proteins driving Alzheimer’s and cancer”. Dewpoint also just announced it has dosed its first patient in a phase 1/2a trial of its lead beta-catenin program in gastric cancer and elected its MYC development candidate to take forward.

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.

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.

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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