CMN Weekly (7 January 2022) - Your Weekly CRISPR Medicine News

Top Picks

• Hereditary hearing loss can now be detected in blood samples using a novel CRISPR-Cas12a-based assay. The fast and sensitive detection system identifies three pathogenic mutations in the SLC26A4 gene that lead to congenital sensorineural or mixed deafness. In 64 clinical samples, results from the CRISPR-based assay were 98.4% (63/64) consistent with the results detected using PCR-Sanger sequencing.
• Chinese researchers have developed a polymer-based intravenous nanoparticle delivery method for targeted CRISPR gene editing of endothelial cells of the vasculatures in the lung, heart, aorta, and peripheral vessels. Endothelial cells are hard to target with viral delivery methods, so the new system could prove helpful in treating diseases caused by endothelial dysfunction. In addition, experiments with mice showed that the nanoparticles could simultaneously induce genome editing of two genes without limitation on plasmid size.

Research

• CRISPR might be helpful for new preventative treatments for Alzheimer's disease. For example, the Icelandic mutation in the APP gene (A673T) has been shown to confer protection against the onset and development of Alzheimer's by reducing the secretion of beta-amyloid peptides. Canadian researchers used CRISPR base editing or prime editing to insert the mutation in HEK293T cells and SH-SY5Y neuroblastomas and showed that this reduced secretion of the peptides.
• Researchers in China report a proton-activatable DNA-based nanosystem that enables co-delivery of Cas9/sgRNA and DNAzyme for the combined gene therapy of cancer. The system uses acid degradable polymer-coated HhaI enzymes released in the lysosomes. The nuclease then degrades ultra-long ssDNA chains nanoparticles and release the gene-editing machinery in lysosomes.
• Magnetoplexes that magnetically guide CRISPR/Cas9 systems to the heart results in efficient in vivo therapeutic gene targeting during heart failures. This was demonstrated by researchers in South Korea in mice and resulted in significantly improved cardiac repair and regeneration to facilitate improvements in cardiac function.
• Researchers in Canada have determined the three-dimensional crystal structure of AcrIIC4Hpa and elucidated the structural and mechanical interactions behind the anti-CRISPR protein. One of the findings is that AcrIIC4_Hpa inhibits DNA cleavage by the type II-C CRISPR-Cas system through an interaction with the REC2 domain.

Industry

• Cellectis has reported its business objectives for 2022, and they include pursuing recruitments into three ongoing clinical trials (BALLI-01, AMELI-01, MELANI-01) and filing an investigational new drug application (IND) for the first dual allogeneic UCART20x22. The company also reports that its two manufacturing sites in Raleigh, NC and Paris, France, are now fully operational.
• Intellia Therapeutics and Kyverna Therapeutics have announced a collaboration to develop next-generation allogeneic T-cell therapy for autoimmune diseases. Within the agreement, Intellia grants Kyverna exclusive rights to its differentiated allogeneic cell engineering platform to create KYV-201, a next-generation CD19 CAR T-cell therapy.
• Intellia Therapeutics also announced its strategic priorities and anticipated developments milestones for 2022. This includes pursuing clinical studies on therapies for cardiomyopathy, hereditary angioedema and acute myeloid leukaemia.
• Sanofi will transfer its rights and obligations related to SAR445136 to Sangamo Therapeutics. SAR445136 is a zinc finger nuclease gene-edited cell therapy candidate for the treatment of sickle cell disease, and it has been co-developed by the two companies.
• Arbor Biotechnologies and TCR2 Therapeutics will collaborate on allogeneic T-cell therapies to treat solid tumour cancers. Under the agreement, TCR2 will use Arbor’s proprietary CRISPR gene-editing technology to evaluate its allogeneic TRuC-T cell therapy candidates.
• Astellas Pharma and Modalis Therapeutics have terminated their collaboration on MDL-204 targeted at a disease in the central nervous system. The joint-research programme utilised Madalis' proprietary CRISPR-GNDM epigenetic gene modulation technology.
• ONK Therapeutics has obtained $21.5 million in Series A financing to advance its pipeline of off-the-shelf NK cell therapies for various cancers. ONK uses CRISPR gene editing to knockout checkpoint receptors in NK cells.
• SalioGen Therapeutics has raised $115 million in Series B financing to advance its proprietary Gene Coding platform. Gene Coding is an alternative to gene editing and gene therapy that can integrate new DNA sequences of any length directly into a defined location in the genome without causing double-strand breaks.

Detection

• American researchers have developed a highly sensitive CRISPR-Cas12a immuno-assay to detect CXCL9 in urine from kidney transplant patients. CXCL9 in the urine is a biomarker for acute rejection episodes, but it isn't easy to detect with traditional ELISA assays. The new immuno-CRISPR assay used anti-CXCL9 antibody-DNA barcode conjugates and amplified fluorescent signals via Cas12a-based trans-cleavage activity of FQ reporter substrates. As a result, a detection limit of 14 pg/mL of CTXL9 was achieved, equivalent to a ~7-fold increase compared to ELISA.

Reviews

• The promise and perils of CRISPR-Cas gene-editing strategies for HIV-1 elimination are discussed in a review by American researchers. Obstacles to a functional cure for HIV include precise delivery to reservoir tissue and cell sites of latent HIV-1 and assay sensitivity and specificity.
• A review by Dutch researchers highlights the diverse functions of CRISPR–Cas systems beyond adaptive immunity and discusses the implications for developing CRISPR-based applications. Among the alternative functions, some pathogenic bacteria use their Cas nuclease activity to evade the human immune system or invade the nucleus and damage the chromosomal DNA.
• The current challenges and future applications of CRISPR-based therapeutics are discussed in a review by American researchers. The review focuses on CRISPR-Cas systems that advance both conventional and emerging therapeutics.
• A review in Molecular Cell takes a closer look at the CRISPR-Cas toolbox and gene editing technologies in humans, animals and plants. The Chinese authors discuss certain limitations of current approaches and prospects for optimising CRISPR-Cas systems.
• CRISPR has potentials in dentistry, and this topic is covered in a review by Mexican researchers. The review details the understanding of the CRISPR era in oral cancer, microbiome, & diseases and points to the further studies that are needed to bridge the gap for treating oral-based diseases.
• The evolutionary plasticity and functional versatility of CRISPR systems are discussed in a review by American researchers. The authors discuss the various evolutionary mechanisms that have led to the multiple highly derived CRISPR variants of yet unknown functions that have so far been discovered.

Huh, Huh, Wow

• Japan has approved the sale of two CRISPR-edited fish: a tiger puffer and a red sea bream engineered to grow 90% and 20% bigger than their conventional counterparts. The trait has been achieved by disrupting the leptin receptor gene, which controls appetite, causing the fish to eat more and increasing the speed at which they gain weight.