LongeCityNews Last Updated: 25 March 2026 - 09:11 AM

Myostatin is a circulating inhibitor of muscle growth. It has been an area of research interest for some time, long enough for myostatin loss of function mutants to have been identified or engineered in a range of mammalian species: mice, dogs, cows, and so forth. Complete loss of function in the myostatin gene throughout life is accompanied by exceptional muscle growth and strength, alongside a lesser amount of visceral fat tissue. All told it seems a benefit with little to no downside.

Since muscle mass and strength is lost with advancing age, there have been efforts to develop therapies based on inhibition of myostatin, such as via monoclonal antibodies. The popularity of GLP-1 receptor agonist drugs that produce loss of muscle mass in addition to visceral fat tissue by reducing calorie intake has resulted in an even greater pharmaceutical industry interest in developing ways to avoid this loss of muscle.

There are many possible points of intervention beyond direct inhibition of myostatin expression, circulating levels, or activity. One possibility presently in clinical trials is the inhibition of myostatin receptors. Another example is the upregulation of follistatin, a circulating molecule that acts in opposition to myostatin, and comes with a similar body of work in mouse studies, where genetic engineering or gene therapies have produced heavily muscled mice. A number of therapies claim to improve follistatin levels, and follistatin gene therapies are now used to some degree in the medical tourism industry. Data on human efficacy is thin to non-existent, however.

Meanwhile, research into myostatin continues as the range of possible muscle growth therapies expands. Today's open access paper is a very interesting tour of what can be learned from the very large genetic databases that now exist. Only the one convincing human myostatin mutant with very evident effects is known to the scientific community, but these large databases allow the discovery of other individuals with mutations that produce a weaker loss of function in the myostatin gene. Since genetic data is coupled with a large amount of other health data in the UK Biobank, one can actually map mutation to muscle strength and other characteristics known to be affected by myostatin.

Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity

Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health.

Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%.

Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.

BioAge Labs, Inc. (“BioAge”, “the Company”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today provided financial results for the full year ended December 31, 2025 and business updates for the fourth quarter ended December 31, 2025.

“The past few months have been a defining period for BioAge as we delivered positive interim Phase 1 data for BGE-102 demonstrating potential best-in-class reductions in inflammatory biomarkers of cardiovascular risk, including hsCRP, IL-6, and fibrinogen,” said Kristen Fortney, PhD, CEO and co-founder of BioAge. “These results support BGE-102’s potential to deliver injectable-like anti-inflammatory efficacy in a convenient oral therapy, and we are advancing toward a Phase 2a proof-of-concept study in the first half of this year. We also expanded BGE-102 into ophthalmology, where its unique profile positions it as a potential ‘pipeline in a pill’ across cardiovascular, CNS, and ocular diseases. In parallel, we are actively advancing a follow-on NLRP3 inhibitor program to create optionality to address the many diseases driven by the inflammasome. With our upsized $132.3 million follow-on offering, we have further strengthened our balance sheet to support our expanding clinical programs.”

Business Highlights

NLRP3 inhibitor clinical development

• In December 2025, BioAge announced positive interim data from the ongoing Phase 1 single ascending dose (SAD) / multiple ascending dose (MAD) trial of BGE-102, its oral, brain-penetrant NLRP3 inhibitor. BGE-102 was well tolerated across all doses, with dose-proportional pharmacokinetics supporting once-daily dosing, 90–98% suppression of IL-1β in an ex vivo whole blood assay at Day 14, and cerebrospinal fluid concentrations exceeding the IC90 at doses of 60 mg and above — a key differentiator from other NLRP3 inhibitors in development. The Company expanded the trial to include MAD cohorts in participants with obesity and elevated hsCRP.
• In January 2026, BioAge announced additional positive interim Phase 1 data from the first MAD cohort in participants with obesity and elevated hsCRP. At Day 14, BGE-102 120 mg once daily achieved an 86% median reduction in hsCRP, with 93% of participants reaching levels below 2 mg/L, a threshold for reduced cardiovascular risk.
• BGE-102 also achieved a 58% reduction in IL-6 and a 30% reduction in fibrinogen.
• Full Phase 1 data are anticipated in the first half of 2026.
• The Company plans to initiate a Phase 2a proof-of-concept trial in cardiovascular risk in the first half of 2026. The trial has been expanded to incorporate dose-ranging, with the goal of potentially enabling initiation of a Phase 3 registration study by the end of 2027. Phase 2a data are expected in the second half of 2026.

BGE-102 indication expansion into ophthalmology

• BioAge announced the expansion of its BGE-102 development program into ophthalmology, with an initial proof-of-concept study planned in patients with diabetic macular edema (DME). NLRP3 inflammasome activation is a central pathological feature in a range of retinal diseases. In preclinical models, oral BGE-102 demonstrated dose-dependent preservation of retinal vascular integrity, achieving near-complete protection from vascular leakage.
• The Company plans to initiate a Phase 1b/2a proof-of-concept trial in patients with DME in mid-2026, with results anticipated in mid-2027. The DME trial will run in parallel with the BGE-102 Phase 2a cardiovascular risk trial.

APJ agonist program advancement

• The Company continued to advance its oral and parenteral APJ agonist development strategy. Under the exclusive option agreement with JiKang Therapeutics announced in June 2025, BioAge and JiKang are jointly advancing a novel APJ agonist nanobody demonstrating at least 10-fold greater potency than apelin toward Investigational New Drug (IND)-enabling studies.
• In parallel, BioAge is progressing its proprietary portfolio of orally active APJ agonists for which it filed a U.S. provisional patent application in May 2025.
• BioAge intends to file the first IND for an APJ program by 2026 year end.

Upsized follow-on public offering

• In January 2026, BioAge completed an upsized follow-on public offering of 5,897,435 shares of common stock at a public offering price of $19.50 per share, generating gross proceeds of approximately $115.0 million. In February 2026, the underwriters exercised their overallotment option in full, purchasing an additional 884,615 shares of common stock at the public offering price, resulting in total gross proceeds from the offering of approximately $132.3 million. The offering was led by Goldman Sachs, Piper Sandler, and Citigroup. The Company estimates that the proceeds from this financing, together with our $285.1 million in cash, cash equivalents, and marketable securities as of December 31, 2025, will be sufficient to fund operations through 2029 based on its current operating plan.

Strategic partnerships and discovery platform

• BioAge’s multi-year research collaboration with Novartis, focused on discovering novel therapeutic targets at the intersection of aging biology and exercise physiology, continued to advance, with multiple targets under evaluation.
• The Company progressed its strategic collaboration with Lilly ExploR&D for the development of therapeutic antibodies targeting novel metabolic aging targets identified through BioAge’s discovery platform.
• BioAge continued to advance its initiative to comprehensively profile and analyze samples from the HUNT Biobank in Norway through its collaboration with Age Labs AS, generating molecular insights from more than 17,000 individual samples tracking the transition from health to disease over decades of lifespan.

For more information, read the full release here.

In a new study, an ingenious CRISPR-based tool was used to create CAR T cells in vivo instead of the usual in vitro approach. It showed higher efficacy across three cancer types, including a solid tumor [1].

CAR T therapies: promising but imperfect

Ideally, T cells, the killer cells of our adaptive immune systems, should be able to eliminate cancerous cells. In most cases, however, T cells either fail to recognize tumor cells as abnormal or are suppressed by the tumor microenvironment [2].

CAR T cell therapy solves this by genetically engineering T cells to express an artificial receptor – specifically, a chimeric antigen receptor (CAR) – that “instructs” them to attack cancer cells expressing a particular target protein (for example, CD19 on leukemia cells). Seven such therapies are now FDA-approved, and they can induce durable remissions in patients with blood cancers who had no other options [3].

The standard process works like this: the patient-derived T cells are taken to a specialized facility, a gene for the CAR is delivered into them using a retroviral or lentiviral vector, then the cells are expanded in culture and infused back into the patient. This process takes 3-5 weeks, costs hundreds of thousands of dollars per treatment, and produces results of variable quality; often, the cells just don’t expand well. Affordability issues aside, patients can simply die waiting.

Who ordered CRISPR delivery?

In a new study published in Nature, a group of researchers from the University of California San Francisco reports forgoing the standard process entirely by creating CAR T cells in vivo. A 2017 study demonstrated a CRISPR-based precision DNA-cutting system, combined with a DNA repair template, that can be used to insert the CAR sequence at a specific address in the T cell genome: the T cell receptor alpha constant (TRAC) locus [4]. Inserting the CAR gene here has several important advantages, such as tighter regulation of expression, which slows T cell exhaustion. However, until now, the system has not been deployed in vivo.

The authors achieved this feat by using two delivery systems. The first part used enveloped delivery vehicles (EDVs), virus-like particles engineered from viral structural proteins. EDVs delivered the CRISPR-based targeting and cutting complex. Another system, based on a different, adeno-associated, virus (AAV), delivered the CAR gene flanked by sequences matching the regions on either side of the CRISPR cut. When the cell’s own DNA repair machinery repairs the CRISPR-induced break, it uses the AAV-delivered template, and voilà: the CAR gene is inserted precisely at the TRAC locus.

After testing their concept in vitro, the researchers engrafted immunodeficient mice with a mix of human immune cells, including T cells, B cells, and monocytes (peripheral blood mononuclear cells, PBMCs). Then the mice received an intravenous injection of the EDV + AAV combination carrying the CD19-CAR.

Two weeks later, spleens were collected. The team found that TRAC-CAR T cells were present in the spleen, and those mice showed depletion of CD19-expressing B cells, demonstrating that the CAR T cells were indeed killing their targets. After several ingenious steps to tweak their design, the team achieved high levels of transfection with no evidence of systemic inflammation.

The phenotypic data suggested that the cells were not just present but functional, proliferating, and maintaining a memory-like profile (i.e., ready to engage the same antigen on rechallenge). The paper claims that this is the first targeted integration of a large DNA payload in primary human T cells in a living animal.

Knocking out real cancers

Next, the team challenged mice with aggressive leukemia. Three days later, human PBMCs were injected, and the experimental therapy was injected a day after that. This was repeated across four independent PBMC donors to assess reproducibility. 18 out of 20 mice achieved complete response (total tumor elimination) across all four donors.

The team then pitted their design against competition: a lentivirus-based design for in vivo CAR T generation, which is currently in Phase I clinical trials [5]. In vitro variants of both designs were tested as well. The TRAC-CAR T in vivo therapy vastly outperformed the rest of the field, with 6 out of 6 mice achieving complete response. In vivo TRAC-CART T expanded many times faster than in vivo lentiviral CAR T cells and showed higher and more uniform CAR expression. The authors suggest this is a direct consequence of random integration (the LLV approach) compared to site-specific integration at a single regulated locus (the TRAC-CAR T approach).

“What was especially remarkable was that the cells we’re generating in vivo actually look better than what we make in the lab,” said Justin Eyquem, PhD, an associate professor of medicine at UCSF and the senior author of the new paper. “We think that when cells are taken out of the body and grown in the lab, they lose some of their ‘stemness’ and proliferative capacity and that doesn’t happen here.”

The team then threw their invention at multiple myeloma: a different cancer type with a different CAR antigen. Here, too, the treatment led to complete responses in all eight mice.

The final test was against sarcoma. Solid tumor treatment has been much harder for CAR T therapy due to poor T cell infiltration, immunosuppressive tumor microenvironment, and antigen heterogeneity. Despite that, with one of the two donors, five out of six mice achieved complete responses. With the second donor, however, only three out of eight did, proving that donor variability remains a challenge.

“If we can translate this to humans, we could dramatically reduce costs, eliminate waiting times, and potentially allow community hospitals – not just major cancer centers – to offer these life-saving therapies,” said Eyquem. “That would truly democratize access to CAR-T cell therapy.”

Literature

[1] Nyberg, W. A., Bernard, P. L., Ngo, W., Wang, C. H., Ark, J., Rothrock, A., … & Eyquem, J. (2026). In vivo site-specific engineering to reprogram T cells. Nature, 1-10.

[2] Chen, D. S., & Mellman, I. (2013). Oncology meets immunology: the cancer-immunity cycle. immunity, 39(1), 1-10.

[3] Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., … & Grupp, S. A. (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), 439-448.

[4] Eyquem, J., Mansilla-Soto, J., Giavridis, T., Van Der Stegen, S. J., Hamieh, M., Cunanan, K. M., … & Sadelain, M. (2017). Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature, 543(7643), 113-117.

[5] Xu, J., Liu, L., Parone, P., Xie, W., Sun, C., Chen, Z., … & Mei, H. (2025). In-vivo B-cell maturation antigen CAR T-cell therapy for relapsed or refractory multiple myeloma. The Lancet, 406(10500), 228-231.

The dominant amyloid cascade hypothesis for Alzheimer's disease broadly states that amyloid-β aggregation occurs early in the progression of the condition, setting the stage for later and much more damaging neuroinflammation and tau aggregation. There remains a great deal of room to debate the details of this progression, how exactly amyloid-β and tau aggregation are linked. Is it as simple as a matter of chronic inflammation generated by amyloid-β aggregation slowly rising to the level of inciting a feedback loop between tau aggregation and further inflammatory signaling? Or some other more direct connection between the biochemistry of amyloid-β aggregation and tau aggregation? Here, researchers advance a novel theory on this topic.

Alzheimer's disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid β (Aβ) and tau, yet existing models of AD fail to provide a simple connection between Aβ and tau. However, microtubules provide an intriguing nexus for pathological interactions between the two. Tau binds to microtubules and is critical to maintaining their proper function. We demonstrate that Aβ also binds to microtubules with affinity comparable to that of tau itself.

We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of Aβ is not the primary cause of toxicity, which allows many of the apparent contradictions between Aβ pathology and cognition to be rationalized. This model highlights the importance of both tau and Aβ and enables additional therapeutic and intervention strategies to be considered.

Link: https://doi.org/10.1093/pnasnexus/pgag034