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Category: genetics – Page 50

Engineering chimeric antigen receptor CD4 T cells for Alzheimer’s disease

Recent advancements in immunotherapy have led to the first successful application of chimeric antigen receptor (CAR) T-cell therapy in treating neurodegenerative diseases, specifically Alzheimer’s disease. In a study conducted by researchers at Washington University in St. Louis and the Weizmann Institute of Science, T-cells were genetically engineered to recognize and target toxic beta-amyloid plaques. When tested on mouse models, three injections of these modified cells resulted in a significant reduction of protein aggregates within just ten days of the final administration. Beyond plaque clearance, the treatment successfully mitigated neuroinflammation, as evidenced by decreased microglial and astrocytic activity. These findings demonstrate the potential of CAR-T technology to rapidly clear pathological protein deposits and restore nervous tissue function, offering a promising new frontier for the treatment of Alzheimer’s and other proteinopathies.

Alzheimer’s disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8+ cells, CD4+ T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4+ T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4+ T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4+ T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4+ CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.

Keywords: Alzheimer’s disease; CAR T cells; T cell; chimeric antigen receptors; neurodegeneration.

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A giant tortoise, extinct for over a century, has reappeared alive after several failed expeditions, reviving a historic plan to save the species, a symbol of evolution

Genetic sleuthing has now confirmed that she belongs to the Fernandina Island Galápagos giant tortoise, Chelonoidis phantasticus, a lineage thought lost since a lone male was collected in 1906.

Only two individuals of this lineage have ever been found, the museum specimen from the early twentieth century and Fernanda. To make sure she was not a stray tortoise washed in from another island, researchers sequenced her entire genome and compared it with DNA extracted from the century-old male and from all other living Galápagos tortoise species.

The analyses showed that Fernanda and the museum male form their own distinct branch, separate from the rest of the archipelago’s giants.

A single oncolytic virus injection may help T cells infiltrate glioblastoma

A team led by investigators at Mass General Brigham and Dana-Farber Cancer Institute has shown that a single injection of an oncolytic virus—a genetically modified virus that selectively infects and destroys cancer cells—can recruit immune cells to penetrate and persist deep within brain tumors. The research, which is published in Cell, provides details on how this therapy prolonged survival in patients with glioblastoma, the most common and malignant primary brain tumor, in a recent clinical trial.

“Patients with glioblastoma have not benefited from immunotherapies that have transformed patient care in other cancer types such as melanoma because glioblastoma is a ‘cold’ tumor with poor infiltration by cancer-fighting immune cells,” said co-senior author Kai Wucherpfennig, MD, Ph.D., chair of the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute.

“Findings from our clinical trial and our mechanistic study show that it is now feasible to bring these critical immune cells into glioblastoma.”

Neural crest cells: Miniature electric muscles that colonize embryonic organs

Neural crest cells are a population of stem cells that invade the embryo in early development. They play a big role in what you look like: the pigments of your eyes, of your skin, and the bone structure of your face are all neural crests. Inside your body, the neural crest will form the myelin sheath of your peripheral nervous system and the entire nervous system of your intestine, the so-called “second brain.”

Neurocristopathies are a range of pathologies resulting from defective neural crest migration. One of the most frequent ones is Hirschsprung disease; it affects 1 in 5,000 newborns. These babies lack a nervous system inside their colon because the neural crest cells didn’t make it all the way to the end of the digestive tract during embryogenesis. The condition is lethal if not surgically treated at birth and its causes remain unknown in more than half of cases.

Among the identified genes involved in Hirschsprung disease, one has stood out for more than half a century: the peptide endothelin 3. Mice and humans with genetic defects in either endothelin 3 or its receptor EDNRB develop the disease, in some cases accompanied with pigmentation or craniofacial defects.

DNA-binding proteins from volcanic lakes could improve disease diagnosis

Scientists have uncovered new DNA-binding proteins from some of the most extreme environments on Earth and shown that they can improve rapid medical tests for infectious diseases. The work has been published in Nucleic Acids Research. The international research team, led by Durham University and working with partners in Iceland, Norway and Poland, analyzed genetic material from Icelandic volcanic lakes and deep-sea vents more than two kilometers below the surface of the North Atlantic Ocean.

Nature is the world’s largest source of useful enzymes, but many remain undiscovered. By using next-generation DNA sequencing, the researchers were able to search huge databases containing millions of potential proteins.

This approach allowed them to identify previously unknown proteins that bind to single-stranded DNA and remain stable under harsh conditions such as high temperatures, extreme pH or high salt levels.

Natural history of craniocervical alignment in Chiari patients and the impact of posterior fossa decompression

Chiari malformation (CM) involves a broad disease spectrum, where rare complex CM cases can be associated with craniocervical junction (CVJ) instability and require occipitocervical fusion. However, the natural progression of CVJ alignment in the general CM type I and 1.5 populations treated with posterior fossa decompression (PFD) remains insufficiently characterized. The authors aimed to compare CVJ alignment changes in patients who underwent PFD versus patients with CM who did not undergo surgery.

The authors conducted a retrospective cohort study at their institution of all patients diagnosed with CM I and 1.5 from 2000 to early 2023. Demographic, clinical, and surgical data were collected, along with preoperative and postoperative MRI measurements, including tonsillar herniation, brainstem descent, clivoaxial angle (CXA), and condylar-C2 sagittal vertical alignment (C-C2SVA).

A total of 241 patients were included, with 201 undergoing PFD and 40 managed conservatively (controls). No significant differences were observed between groups in age at diagnosis, sex, or genetic diagnoses. In the PFD group, 55% underwent duraplasty and 45% underwent bone-only decompression. Baseline craniocervical alignment measurements showed a lower CXA in the PFD group (144.4° ± 13.4°) compared to controls (148.5° ± 14.2°) (p = 0.04) but no difference in C-C2SVA. Changes over time showed a small but significant decrease in CXA at < 1 year after surgery in the PFD group (−2.7°) compared to controls (−2.0°) (p = 0.008), but no differences were noted at 1–2 years. No differences in C-C2SVA were observed over time in either group.

How Epigenetic Reprogramming Makes Cells Act Young Again

Aging doesn’t rewrite your DNA, it scrambles how your cells read it.

This clip explains epigenetic drift and how Life Biosciences’ therapy, ER100, uses Yamanaka factors to restore youthful epigenetic patterns in aged cells. By resetting the chemical marks that control gene expression, cells can behave as if they’re young again without changing the underlying DNA.

It’s the same biological process that happens early in embryonic development, applied in a controlled way to adult cells.

Why only a small number of planets are suitable for life

For life to develop on a planet, certain chemical elements are needed in sufficient quantities. Phosphorus and nitrogen are essential. Phosphorus is vital for the formation of DNA and RNA, which store and transmit genetic information, and for the energy balance of cells. Nitrogen is an essential component of proteins, which are needed for the formation, structure, and function of cells. Without these two elements, no life can develop out of lifeless matter.

A study led by Craig Walton, postdoc at the Center for Origin and Prevalence of Life at ETH Zurich, and ETH professor Maria Schönbächler has now shown that there must be sufficient phosphorus and nitrogen present when a planet’s core is formed. The study is published in Nature Astronomy.

“During the formation of a planet’s core, there needs to be exactly the right amount of oxygen present so that phosphorus and nitrogen can remain on the surface of the planet,” explains Walton, lead author of the study. This was exactly the case with Earth around 4.6 billion years ago—a stroke of chemical good fortune in the universe. This finding may affect how scientists search for life elsewhere in the universe.

‘Remnant’ Cholesterol Cut by More Than 60 Percent in New Drug Trial

Hopes are high for a powerful new compound aimed at lowering blood fat levels responsible for potentially fatal heart disease. In a recent trial, the oral drug, TLC-2716, lowered blood triglycerides by almost 40 percent and remnant cholesterol by more than 60 percent.

The drug was tested in a clinical trial involving 100 healthy adults to assess its effects on a metabolic switch that is active in the liver and gut, and involved in making and handling fats. The trial was the first of its kind on humans, and more testing is required.

Researchers initially isolated the switch, called Liver X Receptor ⍺ (LXR⍺), through analysis of large human genetics databases. Then they linked it to blood-fat-related metabolic disorders using Mendelian randomization, a powerful technique for linking gene expression and outcomes.

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