Many in the life sciences research community were spooked when PubMed went down temporarily in March after the Trump administration cut $4 billion in “indirect costs” that supported medical research. More recently, an ominous message appeared on PubMed: “Because of a lapse in government funding, the information on this website may not be up to date, transactions submitted via the website may not be processed…” Many who use PubMed but not other government websites were probably panicked by this, but a quick look at clinicaltrials.gov, NIH Reporter and even NIH’s main site reveals the same message, while different versions of this message appear on the websites of HHS, CMS, etc.
Still, various EU governments have been quietly preparing for a PubMed shutdown by ensuring they will have a PubMed-alternative just in case. Of course, let’s be real: while they may be able to serve the existing content in PubMed, they will not be able to suddenly support the thousands of additional abstracts and articles added each day, along with MeSH tagging, journal selection, XML/JSON feeds, and other critical functions PubMed provides.
While PubMed is critical to nearly every life science researcher, even those with access to Web of Science, Embase, etc., it is especially critical to early-stage life science companies and investors. For basic research, competitive intelligence, due diligence and more, PubMed is indispensable for those without access to paid literature databases. PubMed is also an important source for pipeline database providers that investors and pharma use to find assets and perform CI.
The US government, for decades, has supplied a critical and reliable literature resource for worldwide audiences, both professional and non-professional alike. With the addition of the first and best clinical trial registry in 2000, continued funding for this resource is paramount for global biomedical research.
We have all heard about the recent 100% pharma tariff announcement, applicable mainly to manufacturers or marketed drugs unless they are in the process of building manufacturing facilities in the US. We know that early stage biotechs are generally not counting on investment to take them through manufacturing, for which they will seek a pharma partner. Nevertheless, these tariffs may still have an effect on early-stage biotech investments. Investment in early-stage (seed, Series A/B) biotech is likely to face increased headwinds under a 100 % pharmaceutical tariff regime. The tariff risk exacerbates existing structural challenges in biotech investing.
Overall Expected Effect (Short to Medium Term)
Slower fundraising pace
The number of deals may decline, particularly in the earlier stages. Biotech investors will likely become more selective, preferring de-risked assets, strong data, or compelling platforms with clear strategies to mitigate tariff exposure.
Higher effective cost of capital
Investors will demand more upside or stricter protections (e.g. liquidation preferences, anti-dilution) to compensate for the added risk.
Greater emphasis on capital efficiency / leaner burn models
Startups may need to conserve cash more, focus earlier on key inflection points, outsource less, and plan fallback strategies for supply chain risk.
Longer timelines / delayed exits
Because of the risk, uncertainty, and possible delays, the time to IPO, acquisition, or commercialization may stretch, further compressing IRR for investors.
Capital flow shift toward infrastructure and enabling technologies
Some portion of venture capital may redirect toward bioprocessing, domestic manufacturing, synthetic biology for local API production, supply-chain tools — companies that can help others evade tariff impact.
Public market investment in pharma may slow, leading to less IPOs
The tariffs could serve to further erode the attractiveness of the biopharma sector for public market investors, reducing the room for IPOs, and pressuring investment taking place more upstream.
In summary, while the recent 100% pharma tariffs certainly don’t have a direct effect on early-stage biotech investing, their dampening effects will nonetheless be felt.
Commercial interest in targeted epigenetic therapies — agents that target specific genes without altering bases in their sequence or causing double-strand breaks or even single nicks in the DNA — continues to grow, as underscored by the latest financing announced by Epigenic Therapies. The unique selectivity and specificity of targeted epigenetic therapeutics offers compelling advantages over small-molecule epigenetic drugs, which target a specific epigenetic reader, writer or eraser, but affect genes across the genome and affect many diverse tissues, leading to narrow therapeutic windows that make them difficult to develop for conditions outside of cancer.
All of these therapies are designed around an alluring set of simple principles: take a gene-specific DNA-binding domain — zinc-finger proteins (ZFPs), ‘dead’ Cas9 (dCas9) with mutations in its RuvC and HNH endonuclease domains, or transcription activator-like effectors (TALEs) — and tether it via an amino acid linker to an enzymatic effector module. This effector is either an enzyme that directly places or removes a specific epigenetic modification (e.g., TET, histone demethylases or the histone acetyltransferase p300) or a transcriptional activator (e.g., VP16) or repressor (e.g., KRAB).
Epigenetic editing approaches have recently focused on dead CRISPR (dCRISPR) domains fused to various epigenetic effectors, but transcription activator-like effectors (TALEs) and zinc finger proteins (ZFPs) also continue to be explored. Source: TINS
A particularly compelling application for such treatments is genetic disorders of haploinsufficiency (like Dravet’s) or imprinting disorders (like Angelman’s or Prader Willi). There are also many of these diseases where the therapeutic genes would be too large (>4.0 kb) for a traditional AAV gene-therapy approach; in contrast, epigenetic editing machinery can be packaged into an AAV vector.
In a first paper published in Nature, the groups of Kevin Bender and Nadav Ahituv at UCSF (scientific co-founders of Regel Therapeutics) sought to test a targeted epigenetic therapy in patients with SCN2A mutations that exhibit decreased NaV1.2 function. These individuals have impaired action potentials, synaptic transmission and manifest diverse neurological symptoms and seizures, with few therapeutic options, beyond symptomatic anti-seizure medications that have a dizzying range of debilitating side effects.
The UCSF teams leveraged conditional genetic knock-in technolgoy or CRISPRa technology — an AAV-delivered SCN2A-promoter-targeting dCas9 fused to a VP16 activator domain — to upregulate transcription of the SCN2A gene. Using either approach, they were able to boost transcript levels from the healthy SCN2A allele, ameliorating electrophsiological deficits and chemical-induced seizure activity in Scn2a+/− mouse models. Importantly, these effects were seen in adolescent mice, which conventionally have been thought to be too old to respond to treatment. This suggests that rescue of normal dendritic excitability with epigenetic agents at later stages of life might be capable of restoring neuronal function, with implications for patients.
In a separate set of experiments, the authors showed that their epigenetic approach was able to rescue neurophysiological activity in haploinsufficient neuron-like cells from SCN2A-knockout human embryonic stem cells. This cross-species reproducibility provides further confidence that CRISPRa-mediated upregulation could be translated into human treatments.
In a second paper in Nature Biotechnology, a team from Epigenic Therapeutics (Shanghai, China) describes the design and validation of optimized epigenetic regulators (EpiRegs) to silence genes in a precise, durable way without altering genomic DNA. Epigen’s Shaoshai Mao and his collaborators at the Chinese Academy of Sciences and the First Affiliated Hospital of Anhui Medical University tested combinations of TALE- and dCas9-based systems, systematically optimizing effector domains and fusion architectures, looking for effective regulators of gene expression. The best-performing variant, EpiReg-T (a TALE-based system, which eliminates the need for a guide RNA), achieved 98% silencing of target genes in mice, substantially outperforming dCas9-based versions.
Using lipid nanoparticles (LNPs) for delivery, a single administration of EpiReg-T in macaques induced long-term repression of the PCSK9 gene, which encodes a validated target for the treatment of hypercholesterolemia. EpiReg-T reduced PCSK9 expression by >90% and LDL-cholesterol by about 60%, with effects persisting for nearly a year (343 days).
Mechanistically, the team used whole-genome bisulfite sequencing and cleavage under targets and tagmentation (CUT&Tag) to show that EpiReg-T induced stable DNA methylation and repressive histone marks at the PCSK9 promoter. The silencing persisted even after liver regeneration and could be reversed by targeted epigenetic activation. Multiomic analysis in mice, macaques and human hepatocytes confirmed high specificity of the manipulation and minimal off-target effects. Overall, these finding, as well as similar results reported in April by Chroma Medicine, establish epigenetic editing as a promising therapeutic platform for durable and reversible gene silencing.
Overall, targeted epigenetic therapies offer clear safety advantages over small molecules that indiscriminately target all genes under the control of an epigenetic eraser or writer enzymes. They avoid the potential risks associated with creating single- or double-strand DNA breaks associated with CRISPR/Cas9 gene, base or prime editing therapies. And they avoid the insertional mutagenesis risks associated with traditional viral gene therapies. What’s more, in applications requiring gene upregulation in haploinsufficient disease, these approaches maintain the endogenous regulatory context of the functional allele. This is in stark contrast to traditional gene-therapy replacement approaches, where overexpression of an introduced therapeutic gene can often lead to toxicities and immunogenecity.
Of course, questions still linger around the persistence of the changes elicited by these epigenetic agents. Will they persist in patients for long periods — for years or even decades? If they can, then epigenetic therapy may offer compliance advantages over small molecules, antibodies, ASOs or even siRNAs, which have treatment durations of six months or less.
Like all genetic medicines, though, delivery remains the key headache. Thus far, AAV vectors, lipid nanoparticles or ribonucleoproteins (RNP) have all been explored to deliver epigenetic therapies (with some evidence that RNPs might have advantages because they can result in higher dCas9 dosages within target cells). For AAV vectors, the fact that targeted epigenetic therapy might only need to be given once might be an advantage in terms of immunogenicity/neutralization concerns against the vector.
A broader point is that the safety profile of targeted epigenetic editors may offer advantages if AAV vectors are used as delivery vehicles: if the epigenetic agents themselves can be delivered at high dosage (given their intrinsic favorable safety profile and presumed maximal tolerated dose), perhaps AAV vector dosages could be lower than current practice. With many current gene therapies requiring dosages of 1013 or more viral particles/kg in patients, it is increasingly becoming clear that unacceptable liver toxicities arise from the virus at these levels in clinical studies. It will be interesting to follow this space as more agents enter human testing.
Life Science Nation’s Redefining Every Stage of Investments (RESI) conferences are designed to connect life science companies with global investors and strategic partners. Two major upcoming events, RESI London and RESI JPM, are now open for registration at Super Early Bird rates through October 3. By registering early, attendees can save £300 on RESI London and $800 on RESI JPM.
RESI London 2025
The first week of December marks the largest life science partnering and venture week in the UK. If you are raising pre-seed, seed, round A or round B, or are in phase 2 or earlier development, Life Science Nation’s RESI London, One Nucleus’ Genesis, and ELRIG/SLAS events offer stronger partnering, investment, learning, and procurement opportunities compared to the health care week in late November that runs alongside the Jefferies investment banking event. That November week typically focuses on recent IPOs, companies close to IPO, and phase 3 or more advanced companies seeking partnerships. For companies not yet at that stage, December’s conference series is a more strategic use of critical conference and travel budgets.
RESI London and Genesis are joining to provide a multi-day investment, partnering, and thought leadership event for venture-stage companies pursuing funding and strategic alliances. RESI London will take place on December 4 at 1 Wimpole Street and 11 Cavendish Square, followed by two days of virtual partnering on December 5 and 6. Super Early Bird registration is now open, offering a savings of £300 until October 3.
RESI JPM 2026
RESI JPM will be held January 12–13, 2026, at the San Francisco Marriott Marquis. The program features two days of in-person investor panels, workshops, networking, and one-on-one partnering, followed by three days of online partnering on January 14, 19, and 20.
Previous RESI JPM conferences have drawn more than one thousand attendees, including over 500 investors, innovators, and industry experts from across the globe. The conference is held concurrently with JP Morgan Healthcare Week, January 12–15, 2026, which takes place at the Westin St. Francis. Known as the largest healthcare investment symposium worldwide, JPM attracts thousands of life science professionals each year.
Super Early Bird registration for RESI JPM offers a savings of $800 when completed before October 3.
Both conferences provide access to global investors and in-licensors, strategic partners, and hundreds of early-stage innovators across therapeutics, medical devices, diagnostics, and digital health. Register now to take advantage of Super Early Bird discounts for RESI London and RESI JPM before October 3.
In healthy epithelial lung cells (top), the CFTR chloride channel translocates from the endoplasmic reticulum to the cell surface, where it participates in the production of mucus to help protect against pathogens. In cells carrying mutant ΔF508 CFTR (bottom), misfolded CFTR cannot reach the membrane and is degraded, resulting in abnormal mucus, microbial infection and lung inflammation. Trikafta restores CFTR function through a dual mechanism: the small molecules elexacaftor and tezacaftor help CFTR fold correctly, whereas ivacaftor improves its gating properties. Source: Lasker Foundation, Michael Welsh
But what about the other 10% of patients who don’t respond to Trikafta, many of whom carry so-called Class I alleles that cannot be rescued by this drug combination? Although a lot of progress has been made, several obstacles lie in the path of effective medicines for people who produce no, or negligible amounts of, CFTR protein.
Class I CFTR alleles. The first three account for ~70% of all patients who don’t respond to Trikafta. Ultra-rare alleles include Y122X, Q1412X, Q493X, and many others.
It should come as no surprise that the main therapeutic strategies for Class I alleles aim to put missing CFTR back into lung cells. Among these strategies, mRNA delivery is the most advanced. VX-522, an RNA therapeutic program from Vertex and Moderna currently in Phase 2, is an inhaled drug that aims to deliver full-length CFTR mRNA to the lung using lipid nanoparticles (LNPs). Two related, competing mRNA delivery programs are at a similar stage of clinical development: ARCT-032 by Arcturus Therapeutics using their LUNAR LNPs; and RCT-2100 by ReCode Therapeutics, which uses a lung-targeted SORT (selective organ-targeting) LNP.
A key feature of RNA-based therapies is that any therapeutic benefit would likely be transient, requiring periodic administration of the medicine to achieve sustained effects. Gene therapy and gene editing have the potential to be a curative, “one and done” procedure. Thus far, however, only gene therapy programs have advanced far enough to be in human testing.
Of these, 4D Molecular Therapeutics’ 4D-710 and Spirovants’ SP-101 use different AAV subtypes designed to optimize delivery to airway basal epithelial cells of a CFTR minigene that lacks the regulatory domain. Both projects are in Phase 1/2 of clinical development.
As the large size (6.2 kb) of the CFTR transgene exceeds the packaging capacity of AAV vectors, Krystal Biotech and Boehringer Ingelheim have launched Phase 1/2 clinical programs using viral vectors with a greater payload capacity: KB407 is a re-dosable herpes simplex virus (HSV)-1 vector with a cargo capacity >30 kb that delivers two copies of the CFTR gene to lung epithelial cells using a nebulizer. BI 3720931 is Boehringer’s inhaled lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) engineered to deliver a single copy of the CFTR gene. Further behind in the pipeline, Carbon Biosciences’ CGT-001 is a nebulized non-AAV parvovirus-based vector capable of delivering full-length CFTR gene. Thus far, it has been tested in nonhuman primates and in human bronchial cells in culture.
Companies are also pursuing oligonucleotide therapies to modify disease-causing mutations at the RNA level. SPL84 is an inhaled antisense oligonucleotide (ASO) addressing a splicing defect (cryptic exon; class V mutation) in the ~1,600 CF patients who carry the 3849+10kb C→T mutation. SpliSense has advanced the ASO into phase 2 testing, but it also has in preclinical development an exon-skipping ASO against the class I mutant W1282X. By masking the mutant premature termination codon in exon 23, SP23 induces the splicing machinery to skip exon 23 and stitch together exon 22 and exon 24, forming a partially functional CFTRΔex23 protein.
Gene editing is also beginning to appear on the therapeutic horizon. In July, Prime Medicine announced it had received $25 million in funding to advance prime editors, with a lead program focusing on G542X. Last year, Intellia Therapeutics and ReCode Therapeutics also announced a strategic collaboration to combine the CRISPR pioneer’s Cas9 DNA ‘writing’/insertion technology with Recode’s SORT LNPs. Academic groups have now shown that G542X correction is possible using inhaled LNP- or virus–like particle-delivered adenine base editors. And for RNA editing, at this year’s American Society of Gene & Cell Therapy Wave Life Sciences reported their oligo-based ADAR editors could achieve 21% correction (EC50 = 376nM) of CFTR W1282X nonsense mutations. This is likely a sliver of all the therapeutic activity underway; other programs are targeting mucus itself, which is much thicker than in healthy individuals. If we missed any drug-discovery projects in this space, please let us know!
Despite the plethora of programs, developing genetic therapies against cystic fibrosis patients with class I CFTR mutations faces some stiff translational challenges. For starters, targeted delivery of drugs to lung tissue remains a work in progress. The optimal cell type to be targeted by gene therapy/editing remains an open question, especially as the community continues to identify new cell types in the lung; is it enough to target the more prevalent epithelial cells (alveolar type 2 cells), or will it be necessary to target rarer stem cells (alveolar type 1 cells) to see a long-lasting therapeutic effect? What about the contribution of genetic modifiers and other ion channels known to affect airway dysfunction in CF airway epithelial cells? Also, how to figure out the pharmacokinetics and pharmacodynamics of these disease-modifying therapies in lungs and measure delivery in patients? Specifically, establishing protein expression levels after inhaling a DNA- or RNA-based product would likely require a bronchial biopsy, which is impractical particularly in this fragile patient population.
Last, not unlike most pathologies, new animal and in vitro models with predictive value need to be developed. The use of human bronchial epithelium culture is not as predictive of the efficacy of genetic therapies as it has been for small molecules. At present, the ferret is the gold standard disease model. But it is a time-consuming, challenging animal model, which is only supported by a few groups. All of which slows the path to clinical translation.
Six years after the approval of Trikafta, patient foundations like the CF Foundation, Emily’s Entourage, and the Cystic Fibrosis Trust are devoting increasing resources to translational research to push forward treatments for patients with CFTR Class I mutations who do not respond to potentiators and correctors. The Lasker recognition of the science that led to Trikafta will surely inspire researchers working on those projects to overcome the remaining hurdles.
Given the ‘pipeline in a product’ potential of drugs targeting this pathway, big pharma has shown considerable interest, with Genentech/Roche snapping up Jecure Therapeutics for an undisclosed amount, and both Novartis and Roche splashing out hundreds of millions of dollars for pioneer companies IFM Tre and Inflazome, respectively. In 2022, Novo Nordisk licensed Ventus Therapeutics’ peripherally restricted NLRP3 inhibitor in a deal worth up to $703 million, lending weight to pharmacological inhibition of NLRP3 as a complement to glucagon-like peptide-1 agonists (GLP-1s) in cardiometabolic disease. And with several programs now entering the clinic, investment activity in the area has continued, with Enveda’s announcement last week of a $150 million series D round to fund a phase 1 trial for ENV-6946, an orally delivered gut-restricted small molecule targeting the NLRP3/tumor necrosis factor-like cytokine 1A (TL1A) pathway in inflammatory bowel disease.
While drugmakers have traditionally targeted downstream extracellular mediators of the inflammasome pathway (canakinumab or rilonacept against IL-1β or anakinra to block IL-1 receptor), NLRP3 represents a key upstream intracellular signaling hub, activated by innate immune pattern-recognition receptor (Toll like receptors 2/4) signaling via MyD88 and NFkappaB. Once activated, NLRP3 monomers unfold and associate into a massive 1.2 MDa oligomeric supracomplex with three other proteins: ASC, NEK7 and caspase 1. The mature complex then cleaves and activates proinflammatory cytokines interleukin (IL)-1β and IL-18 and primes gasdermin D to instigate cell pore formation and cell death via pyroptosis.
Mechanisms of NLRP3 inflammasome activation and inhibition. In priming, lipopolysaccharide (LPS) or IL-1β activates NF-κB, and induces the expression of proinflammatory cytokines and NLRP3. Activation mediated by ATP, nigericin, and particulate matter causes ion fluxes, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage. NLRP3 binds to oxidized mitochondrial DNA (ox-mtDNA) released through the mitochondrial permeability transition pore (mPTP), leading to inflammasome assembly. Inhibition mechanisms are shown for drugs that prevent NLRP3 activation or inflammasome formation (red boxes). CARD, caspase activation and recruitment domain; LRR, leucine-rich repeat domain; MCU, mitochondrial calcium uniporter; MSU, monosodium urate; NACHT, nucleotide-binding and oligomerization domain. Source: TIPS.
But it has been less than straightforward to identify compounds with sufficient potency to target this pivotal innate immune signaling pathway without debilitating off-target effects. Indeed, several of the first wave of compounds entering the clinic have been dogged by serious toxicities, including liver problems (MCC950 and GDC-2394) and hypoglycemia (glyburide). Now, a team led by Rebecca Coll (Queen’s University Belfast) and Kevin Wilhelmsen (of BioAge Labs) reports in TheJournal of Experimental Medicine the discovery and characterization of BAL-0028, a novel and selective small-molecule inhibitor of the human NLRP3 inflammasome.
Unlike previously studied inhibitors, BAL-0028 acts through a unique mechanism of action; it binds NLRP3’s NACHT domain at a site distinct from other inhibitors that act by directly interfering with ATPase activity. BAL-0028 has nanomolar potency against human and primate NLRP3 but, remarkably, has weak activity against the mouse target, highlighting species-specific differences.
As BAL-0028 showed very high plasma protein binding in mice, limiting its use in vivo, the team developed a derivative, BAL-0598, with improved pharmacokinetic properties. In a humanized NLRP3 mouse peritonitis model, BAL-0598 effectively reduced IL-1β and IL-6 production, confirming its anti-inflammatory activity in vivo. Importantly, both BAL-0028 and BAL-0598 inhibited hyperactive NLRP3 mutants associated with autoinflammatory diseases, in some cases more effectively than Vertex’s VX-765, a caspase 1 inhibitor, and compounds like MCC950, one of the best characterized NLRP3 inhibitors available.
The novel mechanism of action of BAL-0028 and BAL-0598 would suggest their off-target effects may be different from those associated with other NLRP3 inhibitors blocking ATP hydrolysis. The concern that such compounds might also bind other members of the NOD/NLR family (e.g., NLRP1, NLRP4 or AIM2 inflammasomes) is mitigated by most published studies indicating that NLRP3’s unique fold around the ATP binding site makes small-molecule binders selective for this family member alone. The most likely explanation from trials published to date is that the observed toxicities are associated with small molecule chemotype rather than any NLRP3 class-specific problem. In any case, the findings from this study support further investigation of these compounds as candidates for treating inflammatory and age-related diseases where NLRP3 plays a role. The race to develop a safe and effective NLRP3 inhibitor is on, with big pharma billion-dollar bets and startups jostling to create best-in-class assets across cancer, cardiovascular, neurodegenerative and metabolic disease.
While most parts of biotech early-stage financing have been in the doldrums in the past two or three years, so-called tech-bio startups have been thriving. Since the posterchild $1.0 billion mega series A round last April of Xaira Therapeutics, which was founded by scientists out of Nobel prize winner David Baker’s group at the University of Washington, several startups seeking to develop machine learning models for designing miniproteins or peptide binders of challenging or ‘undruggable’ targets have emerged, including Enlaza Therapeutics, Vilya, and UbiquiTx. All of these have been developing their own proprietary models based on Alphafold 3, Boltz-1 or Chai-1 for structure prediction and tools based off RFdiffusion, Bindcraft and ProteinMPNN for peptide design. Predicting CDR loops for de novo antibody design is a considerably more challenging task than for simple peptides, but Nabla Bio, founded last year by scientists out of George Church’s lab at Harvard, claims it is doing just that for GPCRs and ion channels. Earlier this month, Chai Discovery also launched with a $100 million series A from Menlo Ventures to optimize multimodal generative models such as Chai-2, which, according to the company, already “achieves a 16% hit rate in de novo antibody design.”
Designing peptides that can selectively bind to a protein target and show therapeutic activity remains a challenge, however, as it often depends on the availability of high-quality structural information about the target molecule, which is seldom available for many disease-relevant proteins that are unstructured or conformationally disordered. Similarly modeling protein-protein interactions like antibody-antigen interactions that are extremely dynamic and floppy also poses problems. All of which raises the question as to whether binders could be predicted simply using amino acid sequence information instead of structural data.
Now, a team led by Pranam Chatterjee from Duke University has addressed this question. In a recent paper in Nature Biotechnology, Chatterjee and his collaborators report the creation of PepMLM, a peptide binder design algorithm based on masked language modeling. A key feature of the algorithm is that it depends exclusively on protein sequence, not structure. Built upon the ESM-2 (Evolutionary Scale Modeling 2) protein language model, PepMLM masks and reconstructs entire peptide regions appended to target protein sequences. This design compels the model to generate context-specific binders. To train PepMLM, the team used high-quality curated datasets from PepNN and Propedia comprising ~10k putative peptide-protein sequence pairs. PepMLM output was consistently found to outperform RFDiffusion on held-out/structured targets, with a higher hit rate (38% to 29%) and low perplexities that closely matched real binders, with generated sequences showing target specificity, even in stringent permutation tests.
The PepMLM model is trained by labeling with ~10k putative target protein-peptide sequence pairs and is built with a target protein sequence and a masked binder region. During the generation phase, the model has a target protein sequence and then mask the binder to facilitate the prediction of peptides of specified lengths. (Source: Nature Biotechnology)
The model generated binders predicted to have higher binding scores than native and structure-based binders designed through other methods. Indeed, in vitro validation experiments confirmed the high affinity and specificity of PepMLM-generated binders.
Structural comparison of PepMLM-designed binders (red) and experimental test binders (blue), with contact residues in target proteins H-2Kb MHC complex (2OI9)and Lck tyrosine kinase (1LCK) (gray) shown in corresponding colors. (Source: Nature Biotechnology).
Chatterjee and his colleagues went on to turn their binders into degraders by fusing them to E3 ubiquitin ligase domains, such as CHIP/STUB1. When tested in vitro, over 60% of these degraders knocked down their target proteins. PepMLM peptides achieved nanomolar binding affinity on the drug targets neural cell adhesion molecule 1 (NCAM1), a key marker of acute myeloid leukemia, and anti-Müllerian hormone type 2 receptor (AMHR2), a critical regulator of polycystic ovarian syndrome (where RFDiffusion-predicted peptides failed to bind). The authors also demonstrated that PepMLM-predicted peptides fused to E3 ubiquitin ligases not only degraded MSH3 but completely eliminated mutant huntingtin protein exon 1 containing 43 CAG repeats in Huntington disease patient-derived fibroblast cells. Similar results were obtained for a PepMLM-predicted peptide binder of MESH1, a protein controlling ferroptosis, in collaboration with Ashley Chi Jen-Tsan’s group at Duke University (RFDiffusion again gave no hits). And with Madelaine Dumas and Hector Aguilar-Carreno’s group, in collaboration with Matt Delisa’s group at Cornell University, PepMLM-derived peptides bound and reduced levels of viral phosphoproteins from Nipah, Hendra, and human metapneumovirus (HMPV); indeed, in live HMPV infection models, the PepMLM peptide mediated high levels of P protein clearance.
The ability of PepMLM to design binders purely on the basis of target-protein sequence is an important advance towards designing therapeutic peptides against hitherto inaccessible targets that lack structural data. Future work should explore how to incorporate chemical modifications such as cyclization or stapling to enhance stability of the binders, as well as the evaluation of the strongest candidates in vivo. Another challenge will be to ameliorate the immunogenicity of these foreign de novo proteins. The use of protein engineering approaches, such as incorporation of mirror amino acids that can cloak foreign peptides from the immune system, may offer solutions. But it is likely that candidates discovered using sequence or structure prediction tools will still require lengthy development programs to be turned into safe and effective drugs, despite the hype.
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 women’s 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 […]
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