Welcome to a special edition of my blog that summarizes all the big news from the summer. I hope you’ve all been able to soak up (safely) as much sun as possible.
Below, I cover the latest in aging, global trends in clinical trials for engineered biomaterials, emerging data on the FDA’s black box warning for CAR T-cell therapy, and more.
Pick of the summer
Please use the link to view the video: https://www.eurekalert.org/multimedia/1034831. IL-11 genetic knockout mice (left) strongly contrast control animals that are aging normally (right). Timepoint captured is 90-95 weeks of age. Credit: MRC Laboratory of Medical Science / Duke-NUS Medical School.
A not-so-hidden gem? Interleukin 11’s implications on life span
The science of aging and longevity has become a hot topic in recent years, as exemplified by the launch of Nature Aging in 2021. Inflammation is also widely researched, coming up again and again across disease contexts. A point of convergence for these streams is interleukin 11 (IL-11); this cytokine has stimulated quite the buzz, both in mainstream scientific forums and chat forums alike. (Why chat forums, you ask? I’ll circle back to this below.)
A lab at Duke–NUS Medical School noticed that expression of IL-11 increases as rodents age, laying the groundwork for their subsequent discovery: In rodent experiments, both genetic knockout (KO) and pharmacological blockade of IL-11 extended lifespan by up to 25 per cent. The genetic experiment was their proof of principle, while the pharmacological experiment demonstrated translational potential. In the latter case, the authors administered anti-IL-11 antibodies to 75-week-old mice (equivalent to middle-aged humans at approximately 55 years old). The question was, in the future, could you administer such a therapy to individuals who have already begun accumulating age-related cellular damage, and still produce a lifespan extension? And, the preclinical answer was yes – lifespan was increased from 120.9 weeks (wildtype average) to 155.6 weeks, right on par with genetic KO animals, which lived an average of 151 weeks.
While these findings could have enormous implications if they hold up in humans, the side effects still aren’t clear. This is really important to emphasize. Also, as mentioned in this insightful Nature News article, testing a drug for lifespan extension in humans would take much longer than your average clinical trial, and it could be incredibly expensive. Instead, some have suggested focusing on a specific condition. This is possible because anti-IL-11 treatment also ameliorated other age-related factors in rodents, including frailty (e.g. tremor, gait disorder), muscle strength, fibrosis and metabolism, amongst other indices. In addition, autopsies revealed significantly fewer tumours in these animals by the time they had died.
Luckily, there are already clinical trials testing anti-IL-11 antibodies:
- Phase I trial by Boehringer Ingelheim currently involves healthy subjects, disease targets will eventually include pulmonary fibrosis and non-alcoholic steatohepatitis.
- Phase I trial by Mabwell Therapeutics currently involves healthy subjects, disease targets will eventually include pulmonary fibrosis and cancer.
- Phase I/IIa trial by Lassen Therapeutics currently involves both healthy subjects and patients with pulmonary fibrosis or thyroid eye disease. Note that the Phase I portion is complete.
It’s going to be important to wait for the results of these safety trials to better understand the effects of lowered IL-11 in humans. I mentioned chat forums earlier because this type of research tends to be followed closely by biohackers. Some forms of this practice are relatively safe, but others are quite dangerous. In this case, the science is already progressing, and answers are on the way. It’s best to wait and see how these trials go, and to discuss with your doctor before experimenting with your body’s complex molecular pathways.
Other drugs have previously been implicated in anti-aging studies, including rapamycin and metformin. The side effect profile of each drug is going to have to be cross-compared and evaluated to determine which options are ultimately best for this application, and whether the reward is worth the risk. Another element to this is that anti-IL-11 antibodies are thought to block multiple signalling pathways that grow dysfunctional as an organism ages, rendering it a promising candidate in cases of multimorbidity. This could mean a broader-spectrum therapeutic solution but, again, time is needed to confirm this in humans.
I’ll be keeping a close eye on this line of inquiry; hopefully, there will be more to report soon.
New data following the boxed warning issued to CAR T-cell therapy
In my May 2024 edition, I mentioned that CAR T-cell treatment is not without potential risks. I linked the FDA’s statement announcing a black box warning to accompany the therapy, highlighting concerns regarding secondary malignancies. Considering just how many conditions CAR T-cell therapy is being considered for, it’s going to be important to ascertain exactly what the risks are.
A new study out of Stanford reviews 724 patients who received CAR T-cell therapy. They report that unfortunate side effects are probably rare. The authors find a three-year risk of 6.5 per cent. There was a single fatal case; however, it’s suggested that this death was most likely caused by the immunosuppression required for CAR T-cell therapy, rather than the cells themselves. With the patient’s immune system in a weakened state, pre-existing cancer that had evaded the care team’s detection was free to grow unchecked.
As more data emerge, there will be interest in determining how secondary malignancy risks for CAR T-cell treatments will compare to other stem cell transplants designed to treat cancer. As of now, the authors of this study suggest they’re similar. More generally, further assessment of the issue will help guide clinicians in determining which patients run a greater risk of developing secondary cancers, the type of monitoring that needs to happen following the procedure, and the need to screen for other potentially fatal cancers prior to treatment.
If you’re interested in reading more, Krista Conger has also written about this work for Stanford Medicine News Center.
Engineered biomaterials in clinical trials: Global trends
Engineered biomaterials are being investigated for use in many medical contexts, including (but certainly not limited to) regenerative applications and tissue engineering. Lele et al. review global trends in clinical trials related to engineered biomaterials, out in Science Advances this past July. Surveying 834 studies pulled from CinicalTrials.gov, they generated quite the collection of interesting insights.
The United States, Canada and Italy seem to be leading the way. Both synthetic and natural polymers appear to dominate, with silicone and collagen reigning as the most popular choices.
The majority of trials are focused on ophthalmology, vascular medicine and dentistry, but tend to enrol fewer than 100 patients, leaving room for progress here. In addition, the integration of cells into biomaterials is highlighted as an under-explored area. That being said, two opportunities for growth in this field include larger trial sizes, plus the development of innovations that might enhance cell-material interactions.
On this note, I’ve recently come across work being done on nanocellulose that might address the latter opportunity. In fact, nanocellulose products are being developed globally by several notable companies for applications across a wide array of disciplines, including those mentioned above. We could be hearing more about this biomaterial in the coming years. Another great example is highlighted a few stories down in the context of cartilage repair.
I’m only scratching the surface here. There is lots of information packed into this paper, so don’t miss this read.
VX-880: Promise for type 1 diabetes
You may have heard about Vertex Pharmaceuticals as a result of their recent FDA approval for Casgevy, a CRISPR-based cure for sickle cell disease. Or maybe you learned of them prior to that, given their successes tackling cystic fibrosis (here and here) and the controversy surrounding how these products are priced. Relevant to the case at hand, however, are headlines from October 2021 announcing that the first patient with type 1 diabetes in their VX-880 trial began producing insulin. VX-880 is a fully differentiated, stem cell-derived pancreatic islet cell therapy. The goal is to replace destroyed beta cells in a patient with type 1 diabetes, enabling them to produce their own insulin again. Vertex acquired the therapy in September 2019 as part of its buyout of Semma Therapeutics (for a cool $950 million).
Clinical results for VX-880 thus far are promising, and Vertex is also working on newer versions of the drug that won’t require immunosuppressants; this new product is called VX-264, and a corresponding Phase I/II trial is already underway.
Blogger Peace Chukwu also just wrote about VX-880 in her post asking whether diabetes has been cured. If you’re looking for more details, make sure to bookmark her piece!
Optogenetics, triboelectric nanogenerators, and intervertebral disc degeneration
It’s always exciting to see optogenetics applied in creative solutions. I wrote about this exciting technique years ago for Signals, and it was the beating heart of my doctoral thesis work.
Optogenetic tools allow us to genetically engineer living cells so that they can respond to specific wavelengths of light. Since its inception in 2005, this idea of a cellular “response” has taken on many forms: the earliest strategies allowed neuroscientists to induce electrical impulses in specific populations of neurons, generating different types of brain activity at will. This is an incredible superpower – some of my all-time favourite examples include the implantation of artificial memories (in rodents, but yes, that’s inception) and intelligently patterned optogenetic stimulation to improve Parkinsonian motor impairments. Optogenetic tools have continued to alter the course of neuroscience, but have also been deployed in a wide array of other research fields. A few examples include the heart, muscles, various molecular pathways and protein-protein interactions.
Optogenetic toolkits are now being applied to intervertebral disc degeneration (IVDD) – a debilitating condition wherein the intervertebral discs break down, leading to pain and mobility issues. Current treatment options are limited, ranging from intense physical therapy to invasive surgical procedures for more severe cases.
Zhang et al. employ a minimally invasive system that harnesses energy generated from the body’s movement in a way you might not expect: the triboelectric effect is the type of static electricity most of us have personal experience with. Rub different materials together, and that friction causes a transfer of electrons from one material to the other, creating a charge imbalance. A triboelectric nanogenerator harvests this energy, here powered by exercise, and controls the release of optogenetically engineered extracellular vesicles (EVs). These EVs are designed to tackle IVDD from an inflammatory perspective. They specifically target a protein called TREX1, which has been implicated in inflammatory senescence, a hallmark of both the initiation and progression of IVDD. The EVs are then delivered via microneedles to the discs in need of treatment.
Optogenetics allowed the researchers to load EVs with their therapeutic protein, TRAM1. By fusing both an anchoring membrane protein and TRAM1 to light-inducible binding partners, TRAM1 becomes bound to the interior of the EV. The TRAM1-containing EVs can then be delivered to nucleus pulposus cells within the disc, where freed TRAM1 binds TREX1, essentially holding it back to alleviate senescence.
It’s nice to see attention paid to IVDD – I think we all know someone who knows someone suffering from it, yet the condition is not discussed nearly enough! If this is of interest to you, read about cell therapies that are also in the works for disc degeneration.
Promoting cartilage regeneration in active joints
Cartilage, an invaluable component of our joints, has a limited capacity for self-healing. If it deteriorates, whether due to damage or time, our health and mobility will inevitably suffer. A notable example of this would be osteoarthritis, a degenerative condition where the cartilage lining the joint is worn down. With a prevalence of 16.1 per cent in Canadian women and 11.1 per cent in Canadian men, this is a significant problem. In fact, advanced osteoarthritis can often lead to total joint replacements.
A new biomaterial, introduced in PNAS this August, was designed to address cartilage repair using a two-factor approach. The first is a modified hyaluronic acid, which is naturally found in the body as a component of the joint’s synovial fluid and cartilage. The second ingredient is a peptide that binds to TGFβ-1, an isoform of TGF-β. In Lewis et al.’s cartilage cocktail, TGFβ-1’s role was to encourage chondrogenesis.
Interestingly, this biomaterial shapeshifts. It’s described as an injectable slurry that, upon contact with local calcium ions, transforms into a porous, rubbery material. Together, the bioactive peptide and the modified hyaluronic acid self-organize in such a way that mimics the fine structure of cartilage and creates an ideal regenerative scaffold for host cells to colonize. In sheep – whose joint biomechanics bear similarity to humans – the biomaterial not only remained in place despite delivery to resected, actively moving, knee joints, but it also successfully stimulated significant chondrocyte growth as it degraded (relative to a TGFβ-1-only controls).
Of course, this promising new biomaterial will have to be evaluated in clinical trials before it becomes an acceptable treatment option. Anybody claiming to offer such a treatment before then is not doing so legitimately.
Additional recommendations
So much interesting work this summer – see more below. If you scroll all the way to the end, I’ve also included a separate section for Regenerative Medicine Advanced Therapy (RMAT) designations handed down over the past few months.
Seventh person likely ‘cured’ of HIV, doctors announce. Daniel Lawler for Medical Xpress. Really nice to see the numbers increasing on these cases – see my coverage from this year’s April edition for more.
An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease. Kassim et al. in Blood. Also see coverage of this story by Jessica Pasley for Vanderbilt University Medical Center News. According to the Vice Chair of Clinical Research and Professor of Pediatrics at Monroe Carell Jr. Children’s Hospital at Vanderbilt, although there are already FDA-approved gene therapy and gene editing trials for sickle cell disease, this one could be more affordable, while being just as safe and, importantly, also curative.
Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice. Zhou et al. in Nature Communications. If you’re interested in this line of investigation, also have a look at this paper: Split intein-mediated protein trans-splicing to express large dystrophins. Tasfaout et al. in Nature.
Preclinical evaluation of transaxial intraputaminal trajectory for enhanced distribution of grafted cells in Parkinson’s disease. Emborg et al. in Journal of Neurosurgery. Aspen Neuroscience is behind this paper; apparently, data from this preclinical work helped secure the clinical trial I highlighted in the May edition. This one’s interesting because they’re going in at a different angle. Rather than approaching the putamen from the top of the skull, they’re going in through the back in an attempt to decrease infection risk, trauma and time required. Note that monkeys are the subjects here. If you’re looking for a longer summary, try this one by Chris Barncard for the University of Wisconsin-Madison News.
Enhancing volumetric muscle loss (VML) recovery in a rat model using super durable hydrogels derived from bacteria. Niknezhad et al. in Bioactive Materials. Yet another bacteria-derived product with potential in regenerative medicine (see notes on cellulose above). It will be interesting to see how these biomaterials compare across different applications.
In vivo editing of lung stem cells for durable gene correction in mice. Sun et al. in Science.
Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in haematopoietic stem and progenitor cells. Luna et al. in Nature Biomedical Engineering.
Serotonin reuptake inhibitors improve muscle stem cell function and muscle regeneration in male mice. Fefeu et al. in Nature Communications.
Unlocking cellular plasticity: enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation. Yang et al. in Stem Cells.
Comparative single-cell transcriptional and proteomic atlas of clinical-grade injectable mesenchymal source tissues. Ruoss et al. in Science Advances.
Multilevel neurium-mimetic individualized graft via additive manufacturing for efficient tissue repair. Kong et al. in Nature Communications.
Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence. Cappabianca et al. in Molecular Therapy.
Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1. Pereira et al. in Nature Neuroscience.
Novo Nordisk Foundation to Focus on Stem-Cell Therapies in Shift. Christian Wienberg for Bloomberg.
Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine. Shen et al. in Cell Death and Differentiation.
Lab-grown embryo models: UK unveils first ever rules to guide research. Smriti Mallapaty for Nature.
Redefining vascular repair: revealing cellular responses on PEUU—gelatin electrospun vascular grafts for endothelialization and immune responses on in vitro models. Rodríguez-Soto et al. in Frontiers in Bioengineering and Biotechnology.
PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Dorff et al. in Nature Medicine.
Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells. Capdevila et al. in Cell.
Epigenetic maintenance of adult neural stem cell quiescence in the mouse hippocampus via Setd1a. Zhao et al. in Nature Communications.
Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. Edman et al. in Cell.
Electromagnetic Cellularized Patch with Wirelessly Electrical Stimulation for Promoting Neuronal Differentiation and Spinal Cord Injury Repair. Wang et al. in Advanced Science.
CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice. Colella et al. in Nature Communications.
tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling. Zuo et al. in Nature Communications.
Hematopoietic stem and progenitor cell membrane-coated vesicles for bone marrow-targeted leukaemia drug delivery. Li et al. in Nature Communications.
Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells. Thangaraj et al. in Cell Stem Cell.
Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy. Chadarevian et al. in Neuron.
Landmark University of Minnesota papers on Alzheimer’s disease and stem cells retracted. Jeremy Olson for The Minnesota Star Tribune.
Human iPSC-derived CD4+ Treg-like cells engineered with chimeric antigen receptors control GvHD in a xenograft model. Yano et al. in Cell Stem Cell.
Lung Institute found guilty of selling patients ‘sham’ stem cell treatment for incurable lung disease. Katie LaGrone for WPTV.
Low-dose TED-A9 cell therapy eases Parkinson’s motor symptoms: Study. Margarida Maia for Parkinson’s News Today.
Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue. Jevans et al. in Gut.
Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation. Zhu et al. in Science Translational Medicine.
A maternal brain hormone that builds bone. Babey et al. in Nature.
A CAR enhancer increases the activity and persistence of CAR T cells. Rakhshandehroo et al. in Nature Biotechnology.
Pfizer takes $230M hit after axing failed DMD gene therapy—and tosses out RSV combo vaccine. Nick Paul Taylor for Fierce Biotech.
Q&A: How a stem cell bank is helping scientists understand psychiatric disorders. Allessandra DiCorato for Broad Institute News.
Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation. Laurie et al. in Nature Communications.
Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors. Shaffer et al. in Journal of Clinical Oncology.
An aptamer-mediated base editing platform for simultaneous knockin and multiple gene knockout for allogeneic CAR-T cells generation. Porreca et al. in Molecular Therapy.
Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis. Wang et al. in Cell.
Pfizer Announces Positive Topline Results From Phase 3 Study of Hemophilia A Gene Therapy Candidate. Pfizer Press Release.
A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial. Srinivasan et al. in PLOS ONE.
Ube3a unsilencer for the potential treatment of Angelman syndrome. Vihma et al. in Nature Communications.
Mostly discouraging trial of MSC-NPs or purported neural cells from MSCs for MS. Paul Knoepfler for The Niche.
Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells. Dietrich-Zagonel et al. in Scientific Reports.
Switching anti-EGFR antibody re-sensitizes head and neck cancer patient following acquired resistance to cetuximab. Khattri et al. in Cancer Gene Therapy.
A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa. Neumayer et al. in Nature Communications.
Cell atlas of the regenerating human liver after portal vein embolization. Brazovskaja et al. in Nature Communications.
Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype. Thananthirige et al. in Acta Neuropathologica Communications.
Cell and gene therapy accessibility. Rayne Rouce and Matthew Porteus for Science.
Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair. Saraswathy et al. in Nature Communications.
Regulation of the hematopoietic stem cell pool by C-Kit–associated trogocytosis. Gao et al. in Science.
Pelage Pharmaceuticals Advances Clinical Program with First Patients Dosed in Phase 2 Study for Hair Loss and GV-Led $14M Series A-1. PR Newswire.
Discoveries from human stem cell research in space that are relevant to advancing cellular therapies on Earth. Ghani and Zubair in npj Microgravity.
Whistleblowing in science: this physician faced ostracization after standing up to pharma. Sara Reardon for Nature Career Features.
Pulmonary Function After Non-Myeloablative Hematopoietic Cell Transplant for Sickle Cell Disease. Ruhl et al. in Annals of the American Thoracic Society.
Primitive macrophages enable long-term vascularization of human heart-on-a-chip platforms. Landau et al. in Cell Stem Cell.
Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis. Clayton et al. in Cell Stem Cell.
BEAM or cyclophosphamide in autologous haematopoietic stem cell transplantation for relapsing-remitting multiple sclerosis. Silfverberg et al. in Bone Marrow Transplantation.
Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in the OIM model of osteogenesis imperfecta. Li et al. in Bone Research.
Comprehensive evaluation of the mechanism of human adipose mesenchymal stem cells ameliorating liver fibrosis by transcriptomics and metabolomics analysis. Ji et al. in Scientific Reports.
Human microglial cells as a therapeutic target in a neurodevelopmental disease model. Mesci et al. in Stem Cell Reports.
MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber’s hereditary optic neuropathy. Wang et al. in Science China Life Sciences.
CellProthera inches closer to Phase III trial for heart attack cell therapy. Robert Barrie for Clinical Trials Arena.
Biofabrication of prevascularized spheroids for bone tissue engineering by fusion of microvascular fragments with osteoblasts. Wrublewsky et al. in Frontiers in Bioengineering and Biotechnology.
Optimizing cell therapy by sorting cells with high extracellular vesicle secretion. Koo et al. in Nature Communications.
RMAT Designations:
Lyla El-Fayomi
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