GEG-Tech

In the fight against cancer, CAR-T cells have achieved remarkable results in treating blood cancers. However, they have proven largely ineffective against solid tumors. CAR-NKT cells, on the other hand, possess innate properties that make them particularly well-equipped to combat solid tumors. Specifically, they express a T cell receptor that recognizes glycolipid antigens presented by CD1d molecules. CAR-NKT cells effectively eliminate CD1d-expressing M2 macrophages in the tumor microenvironment. These macrophages promote tumor growth and suppress immune responses, making their elimination essential for strengthening antitumor immunity. By targeting these cells, CAR-NKT therapy effectively reprograms the tumor microenvironment from a pro-tumor to an anti-tumor state. CAR-NKT cells promote epitope spreading, a process by which the immune system recognizes and attacks new targets, activating T-cell responses. Researchers further demonstrated that combining CAR-NKT cells with PD1 blockade significantly enhances their antitumor activity, and that this activity can be further strengthened by vaccination approaches, such as those using dendritic cells loaded with alpha-galactosylceramide. 

The field of RNA editing may be in its infancy, but pharma companies are already testing its use in some types of eye disease and cancer.

The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common identified mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. This expansion leads to the production of repeat RNA and dipeptide repeat proteins (DPR), both of which contribute to disease and are recognised as important disease markers. In a recent study, a team in the United States demonstrated that CRISPR-Cas13d can be optimised to specifically target GGGGCC repeat RNA to minimise the translation of associated poly-dipeptides.The team shows that the optimised CRISPR-Cas13d system effectively reduced DPR production when delivered via lentiviral particles to various in vitro models, including C9orf72-ALS patient-derived induced pluripotent stem cells (iPSCs) and motor neurons derived from those iPSCs, and that the efficiency of RNA targeting corresponded to Cas13d expression levels. Intracerebroventricular injection of the C9orf72-targeting cargo (delivered via AAV9) in C9orf72 repeat transgenic mice revealed a significant reduction in DPR levels. The team reports that the approach exhibits specificity for expanded repeats, with minimal effect on wild-type C9orf72 transcripts and protein levels.

[#MabDesignMember]- ZOOM ON about [#GEG-Tech] GEG-Tech is a French deeptech company born from the CNRS and located on the Saclay Plateau, near Paris, France. GEG-Tech operates an Open Innovation research model to develop breakthrough nanoparticles enabling novel therapies, in collaboration with leading research institutes, pharma and biotechs. To know more : https://lnkd.in/edpE7waq

Glioblastoma is the most common and aggressive primary brain tumor, with an average survival after diagnosis of less than two years, and against which current treatments remain ineffective. In recent years, immunotherapies have given patients hope, albeit with relatively modest success. One research team has succeeded in identifying a specific marker, PTPRZ1, on the surface of tumour cells, and generating CAR-T cells to destroy them. Moreover, this CAR-T cell-based therapy appears to be able to target diseased tumor cells that do not carry this specific marker, while sparing healthy cells. The team tested the treatment in vivo on mouse models of human glioblastoma. Tumor growth was controlled, remarkably prolonging the life of the mice without signs of toxicity. These results, published in the journal Cancer Immunology Research, represent a first step towards the development of clinical trials with human patients. 

Scientists use a long, thin glass needle to inject eggs or embryos, a technique known as microinjection, which requires a great deal of time and expertise. However, a new delivery approach has been inspired by an egg yolk protein found in most animals, called vitellogenin, which provides an energy source for the growing egg. Vitellogenin is a large protein, but the team isolated the small part that binds to the receptor on the surface of the egg. This is a very small tag (around 10 amino acids) to which various fillers, such as Cas9, can be added. The team has successfully used VitelloTag on two distantly related species: the starfish (Patiria miniata) and the acorn worm (Saccoglossus kowalevskii). However, microinjection remains the method of choice for delivering CRISPR-Cas9 to many organisms. Penetration (the percentage of cells that successfully absorb the CRISPR load) can reach 90% with microinjection, while with VitelloTag, the team achieved around 30% penetration in starfish and acorn worms. 

Duchenne muscular dystrophy (DMD) is a rare, incurable muscular disease affecting around 1 in every 3,500 to 5,000 male births worldwide. The disease follows an X-linked pattern of inheritance, and exonic duplications of the gene coding for DMD dystrophin are frequently observed in DMD patients. Dystrophin is a cytoplasmic protein that plays a mechanical role in muscle. In a recent study, French researchers used the CRISPR-Cas9 gene-editing technique to target intronic regions of the DMD gene. Their aim was to delete certain duplicated regions in patients' immortalized myogenic (muscle progenitor) cells, in particular duplications of exon 2, exons 2 to 9 or exons 8 to 9, which are known hotspots for mutations in DMD patients.They confirmed restoration of the DMD open reading frame and rescued dystrophin expression by Western blotting and mytotube immunostaining after CRISPR-based deletion of the target duplications. RNA sequencing suggested gene rescue in dystrophin-related pathways. Off-target analysis based on predicted nearby off-targets revealed no significant unintended genetic changes at these loci.

The treatment’s success in three people raises hopes for mass production of cutting-edge CAR T therapies.

Clues to keeping the brain’s regenerative cells youthful and energetic into old age have emerged by applying CRISPR gene editing to mice

CAR-T cell therapy works very well in only about a third of cancer patients. One of the main factors in failure is T-cell depletion. This condition causes many patients to relapse within a year of CAR-T cell therapy. In search of new solutions, a research team compared data from patients in remission with those whose CAR-T cell therapy had failed. They also studied how CAR-T cells killed tumors grown in laboratory mice. They compared the results of mice that responded well to CAR-T therapy with those that did not. The team observed an increase in interleukin-4 (IL-4) protein in both human and mouse CAR-T cell depletion samples. The team then used CRISPR gene-editing technology to eliminate or modify the IL-4 protein causing CAR-T cell dysfunction. The researchers also tested monoclonal antibodies to block or neutralize the IL-4 protein. They found that they also rejuvenated CAR-T cells and their ability to block cancer.