CMN Weekly (8 March 2024) - Your Weekly CRISPR Medicine News
By: Gorm Palmgren - Mar. 8, 2024
Top picks
- Chinese researchers have developed an exosomal CRISPR intervention system for Parkinson's disease (PD), utilising focused ultrasound to deliver targeted CRISPR machinery into the brain. This approach methylates explicitly the α-synuclein (SNCA) gene, reducing SNCA levels and improving motor functions in PD mice. It demonstrates a novel method for brain disease treatment through epigenetic regulation, offering insights into targeted nano-delivery systems for neurological disorders.
- CRISPR-Cas9-based research in Sweden reveals that the tumour suppressor p53 negatively regulates FOXQ1, a transcription factor implicated in tumour metastasis. Loss of p53 function, a common feature in cancers, leads to increased FOXQ1 expression, promoting cancer progression. This was confirmed through genomic locus proteomics, promoter-reporter constructs, and pharmacological activation of p53, highlighting a critical molecular mechanism in cancer development.
Research
- An in vivo CRISPR genome-wide screen has pinpointed the transcriptional modulator CITED2 as a pivotal driver in the progression of prostate cancer to bone metastasis. The discovery not only enhances our understanding of the disease's molecular underpinnings but also opens new avenues for targeted therapies, potentially revolutionising treatment paradigms for patients battling advanced prostate cancer.
- In another study, two independent high-throughput CRISPR-Cas9 screenings identified PRMT7 as a key regulator of metastatic castration-resistant prostate cancer (mCRPC) cell invasiveness. PRMT7 acts by methylating transcription factors like FoxK1, and its inhibition significantly reduced the invasive, migratory, and proliferative capabilities of mCRPC cells in vitro and in vivo.
- Researchers in China have developed a high-throughput microdroplet-based single-cell transfection method for CRISPR-Cas9-based gene knockout. The process allows for high-efficiency delivery of genome-editing reagents into single living cells by accurately controlling the number of exogenous plasmids in microdroplets.
- A recent Italian has used advanced gene regulatory network (GRN) analysis to uncover the intricate mechanisms behind drug and CRISPR-Cas9 resistance in cancer cell lines. The study introduces a novel methodology to investigate multidrug resistance (MDR) and CRISPR-Cas9 resistance in cancer, focusing on constructing and analysing gene regulatory networks (GRNs). By examining the differential gene expression of cancer cell lines, researchers identified essential genes and pathways contributing to resistance mechanisms.
- A novel CRISPR-Cas9 delivery method using an internalising IgG antibody and a CL split intein for posttranslational ligation of IgG and Cas9 has been developed. This approach enables targeted delivery of the Cas9-RNP complex to cells, minimising side effects and avoiding permanent genetic modifications. This method represents a significant step towards more precise and safe CRISPR-Cas9 applications in genetic engineering.
- Japanese scientists have developed an in vivo CRISPR-Cas9 sgRNA library screening method to investigate spermatogenesis, using sperm capacitation as a marker. This led to the identification of the Rd3 gene, which is significantly expressed in round spermatids and interacts with mitochondria. A novel computational tool, Hub-Explorer, used alongside these analyses, showed Rd3's involvement in modulating oxidative stress via mitochondrial distribution during ciliogenesis.
Industry
- iECURE has announced approval from the UK Medicines & Healthcare products Regulatory Agency (MHRA) of the company's Clinical Trial Authorisation application (CTA) to expand the OTC-HOPE study into the UK. The OTC-HOPE study investigates ECUR-506, an investigational meganuclease-based in vivo gene insertion therapy, to treat Ornithine Transcarbamylase (OTC) deficiency in infants.
- Iovance Biotherapeutics announced that the FDA has lifted a partial clinical hold placed on the registrational IOV-LUN-202 trial investigating LN-145 TIL cell therapy in non-small cell lung cancer (NSCLC). Iovance can now resume patient enrollment in IOV-LUN-202.
- Precision BioSciences has agreed to sell 2,500,000 shares of its common stock and warrants to the public for total gross proceeds of $40.0 million.
2023 financial updates
- 2seventy bio has reported full-year 2023 financial results with a net loss of $218 million and $222 million in cash at the end of the year.
- Prime Medicine has reported full-year 2023 financial results with a net loss of $198 million and $135 million in cash at the end of the year.
- Poseida Therapeutics has reported full-year 2023 financial results with a net loss of $123 million and $212 million in cash at the end of the year.
Detection
- Scientists in China present an enhanced 3D DNA walker-induced CRISPR-Cas12a technology for highly sensitive detection of exomicroRNA associated with osteoporosis. Under optimal conditions, the devised technology demonstrated the capacity to detect target exomiRNA-214 at concentrations as low as 20.42 fM, encompassing a wide linear range extending from 50.0 fM to 10.0 nM.
- A new molecular assay for detecting norovirus - a major cause of diarrhoea - is based on recombinase polymerase amplification (RPA) combined with CRISPR-CAS12a targeting the conserved region of the GII norovirus genome. The results are displayed by fluorescence curves and immunochromatographic lateral-flow test strips. The reaction only required approximately 50 min, and the sensitivity reached 102 copies/μl.
- Chinese researchers have developed a method for genotyping for the ABO blood group by using CRISPR-Cas13a to differentiate SNPs of the ABO*O.01.01(c.261delG) allele (G for the A/B allele and del for the O allele) and ABO*B.01(c.796C > A) allele (C for the A/O allele and A for the B allele). The method reliably identified ABO blood group genotypes in a wide range of samples, eliminating the need to collect fresh blood samples in the traditional method.
- A novel CRISPR biosensor that detects ssDNA exclusively relies on an anti-CRISPR protein (AcrVA1). In this sensing strategy, AcrVA1 cuts the crRNA to inhibit CRISPR-Cas12a cleavage, and only ssDNA can recruit the cleaved crRNA fragment to recover the detection ability of the CRISPR-Cas12 biosensor.
Reviews
- Revolutionising cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology. This review focuses on the application of CRISPR/Cas9 technology in CAR-T cell therapy, including eliminating the inhibitory effect of immune checkpoints, enhancing the ability of CAR-T cells to resist exhaustion, assisting in the construction of universal CAR-T cells, reducing the manufacturing costs of CAR-T cells, and the security problems faced.
- Targeted nonviral delivery of genome editors in vivo. This review discusses recent advances, current applications, and future opportunities for delivering CRISPR-Cas genome editors as preassembled ribonucleoproteins or encoded in mRNA.
- Factors affecting the cleavage efficiency of the CRISPR-Cas9 system. This review explores several factors affecting the cleavage efficiency of the CRISPR-Cas9 system, including the GC content of the PAM proximal and distal regions, sgRNA properties, and chromatin state.
- Epigenome editing for targeted DNA (de)methylation: a new perspective in modulating gene expression. This review focuses on recent developments in epigenome editing tools/techniques, technological limitations, and future perspectives of this emerging technology in therapeutics for human diseases and plant improvement to achieve sustainable developmental goals.
- Nanoplatform-Based In Vivo Gene Delivery Systems for Cancer Therapy. This review provides an overview of the categories of nanoplatform-based non-viral gene vectors, the limitations on their development, and their applications in cancer therapy.
- Anti-CRISPR Proteins and Their Application to Control CRISPR Effectors in Mammalian Systems. This review discusses the diverse applications of anti-CRISPR (Acr) proteins in mammalian cells and organisms and the underlying engineering strategies.
- RNA-guided genome engineering: a paradigm shift towards transposons. This review explores the recent developments and uses of CRISPR-associated transposons (CASTs) and obligate mobile element-guided activity (OMEGA) in genome editing across prokaryotic and eukaryotic cells. The pros and cons of these transposon-based systems are deliberated in comparison to other CRISPR systems.
News from CRISPR Medicine News
- On Monday, we interviewed Brian Cosgrove from the US startup Tune Therapeutics. We heard about their lead candidate, TUNE-401, which can epigenetically silence all forms of the hepatitis B virus, providing hope for a functional cure. He also told about the company's TEMPO platform, which employs CRISPR as an epigenome-editing tool, using catalytically dead Cas9 (dCas9) fused to epigenetic effectors to reprogramme the epigenome in a site-specific manner.
- In a Clinical Update on Wednesday, we reported about AvenCell Therapeutics, which recently announced that the first patient had been dosed in a Phase 1A study with its lead product candidate, AVC-201. This novel allogeneic switchable CAR-T candidate targets CD123 and is being developed to treat relapsed or refractory acute myeloid leukaemia and other CD123-associated blood cancers.
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