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The landmark decision could transform the treatment of sickle-cell disease and beta-thalassaemia — but the technology is expensive.
A study in mice reports a CRISPR/Cas9 gene-editing delivery system, capable of bypassing the blood-brain-barrier and modulating neuronal receptor pathways, to treat chronic anxiety.
Simple, efficient and well-tolerated delivery of CRISPR genome editing systems into primary cells remains a major challenge. Here we describe an engineered Peptide-Assisted Genome Editing (PAGE) CRISPR–Cas system for rapid and robust editing of primary cells with minimal toxicity. The PAGE system requires only a 30-min incubation with a cell-penetrating Cas9 or Cas12a and a cell-penetrating endosomal escape peptide to achieve robust single and multiplex genome editing. Unlike electroporation-based methods, PAGE gene editing has low cellular toxicity and shows no significant transcriptional perturbation. We demonstrate rapid and efficient editing of primary cells, including human and mouse T cells, as well as human hematopoietic progenitor cells, with editing efficiencies upwards of 98%. PAGE provides a broadly generalizable platform for next-generation genome engineering in primary cells. Peptide-assisted genome editing enables efficient single and multiplex editing in hematopoietic cells.
November 18th, 2022. Today, Applied Cells Inc. and GenScript USA Incorporated announced their strategic collaboration to deliver combined cell isolation solutions for cell therapy drug development worldwide. Under this collaboration, GenScript will develop and supply its proprietary research and cGMP grade CytoSinct™ reagents for use in developing CAR-T and other Cell Therapy products on the Applied Cells MARS® Platform.
A team of researchers at Northwestern University has devised a new platform for gene editing that could inform the future application of a near-limitless library of CRISPR-based therapeutics.
In a new paper, University of California, Irvine researchers explain how precision genome editing agents have enabled precise gene correction and disease rescue in inherited retinal diseases (IRDs).
A Penn State-led team of interdisciplinary researchers has developed techniques to improve the efficiency of CRISPR-Cas9, the genome editing technique that earned the Nobel Prize in 2020.
DNA-based information is a new interdisciplinary field linking information technology and biotechnology.
Genetic mutations which cause a debilitating hereditary kidney disease affecting children and young adults have been fixed in patient-derived kidney cells using a potentially game-changing DNA repair-kit. The advance developed by University of Bristol scientists is published in Nucleic Acids Research.
We designed a unique nanocapsule for efficient single CRISPR-Cas9 capsuling, noninvasive brain delivery and tumor cell targeting, demonstrating an effective and safe strategy for glioblastoma gen
Estrogen and progesterone receptor (ER, PR) signaling control breast development and impinge on breast carcinogenesis. ER is an established driver of ER + disease but the role of the PR, itself an ER target gene, is debated. We assess the issue in clinically relevant settings by a genetic approach and inject ER + breast cancer cell lines and patient-derived tumor cells to the milk ducts of immunocompromised mice. Such ER + xenografts were exposed to physiologically relevant levels of 17-β-estradiol (E2) and progesterone (P4). We find that independently both premenopausal E2 and P4 levels increase tumor growth and combined treatment enhances metastatic spread. The proliferative responses are patient-specific with MYC and androgen receptor (AR) signatures determining P4 response. PR is required for tumor growth in patient samples and sufficient to drive tumor growth and metastasis in ER signaling ablated tumor cells. Our findings suggest that endocrine therapy may need to be personalized, and that abrogating PR expression can be a therapeutic option. The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.
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Large genes including several CRISPR-Cas modules like gene activators (CRISPRa) require dual adeno-associated viral (AAV) vectors for an efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids, and in vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, REVeRT enabled the reconstitution of full-length ABCA4 after intravitreal injection in a mouse model of Stargardt disease. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications. Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.
FDA approves Hemgenix, an adeno-associated virus vector-based gene therapy indicated for treatment of adults with Hemophilia B (congenital Factor IX deficiency)
Irish-Indian company CyGenica is on a mission to solve the huge challenge surrounding targeted intracellular delivery of gene-editing and other therapies. In just five years since the company was founded, the first clinical trials for cancer are in sight. Here, CEO and CSO Dr Nusrat Sanghamitra PhD tells us about how a persona
Adeno-associated viruses (AAVs) are the safest and most effective gene delivery vehicles to drive long-term transgene expression in gene therapy. While animal studies have shown promising results, the translatability of AAVs into clinical settings has been partly limited due to their restricted gene packaging capacities, off-target transduction, and immunogenicity. In this study, we analysed over two decades of AAV applications, in 136 clinical trials. This meta-analysis aims to provide an up-to-date overview of the use and successes of AAVs in clinical trials, while evaluating the approaches used to address the above challenges. First, this study reveals that the speed of novel AAV development has varied between therapeutic areas, with particular room for improvement in Central Nervous System disorders, where development has been slow. Second, the lack of dose-dependent toxicity and efficacy data indicates that optimal dosing regimes remain elusive. Third, more clinical data on the effectiveness of various immune-modulation strategies and gene editing approaches are required to direct future research and to accelerate the translation of AAV-mediated gene therapy into human applications.
Gene editing has revolutionised research and is set to change the treatment landscape for genetic diseases, with >100 ongoing clinical trials across diverse disease areas. Here, medical doctor Silja Hansen, who is currently a PhD student at Aarhus University in Denmark, discusses the promise, challenges, and future of prime editing t
Patients with collagen VI-related disorders experience progressive and debilitating disease. New research findings from Spain’s Institut de Recerca Sant Joan de Déu (IRSJD) provides new hope for these diseases, demonstrating the power of CRISPR-Cas9 to silence a dominant negative mutation in patient fibroblasts.
The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the present study, we aimed t
More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential. The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy.
On August 18, 2021, the American Society of Gene and Cell Therapy (ASGCT) hosted a virtual roundtable on adeno-associated virus (AAV) integration, fea…
Unwanted immune responses threaten to derail some gene therapies. But researchers are seeking ways to combat harmful inflammation.
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A mouse study reports on a CRISPR/Cas9 gene-editing delivery system, capable of bypassing the blood-brain barrier and modulating neuronal receptor pathways, to treat chronic anxiety. Researchers targeted 5HT-2A, a serotonin receptor known to play a role in anxiety and depression. The authors used a vector based on an inactivated adeno-associated virus to deliver the vector via the nose. The vector delivers a guide RNA to the neurons. The guide RNA binds to the target receptor gene, HTR2A, which is then cleaved at a precise location by the Cas9 enzyme. Five weeks after intranasal administration of the vector and packaging, 75 mice were tested with standard behavioral tests measuring mouse anxiety. For example, anxious mice would choose to spend more time in dark areas and would tend to bury unfamiliar objects such as logs in sawdust rather than leave them alone. Treated mice spent 35.7% more time in light areas than controls and showed a 14.8% decrease in the number of logs buried compared to controls. Mice treated with the CRISPR package showed an 8.47-fold decrease in HTR2A expression in their brains, compared with control mice. According to the authors, non-invasive intranasal administration of CRISPR/Cas9 therapies may therefore help patients with treatment-resistant anxiety.