CMN Weekly (15 October 2021)

Top picks

• With a little help from CRISPR, lizards can now grow replicate tails much more like the original one. When a lost tail grows back, a molecular signal only produced in adults inhibits the development of skeletal and nerve tissue, so the tail is composed of just cartilage. Researchers from the University of Southern California used CRISPR to knock out the Smo gene in neural stem cells, so they became unresponsive to the signal. When edited stem cells were grafted into adult animals with lost tails, they developed new tails with cartilage, skeletal and nervous tissues.
• In an interview for Nature by Asher Mullard, CRISPR-veteran Feng Zhang from the Massachusetts Institute of Technology discusses the need for a bigger CRISPR toolbox. Among other topics, Feng Zhang talks about his recent discovery of the IscB programmable, RNA-guided DNA nucleases and the PEG10 delivery system.

Research

• Researchers in China have characterised the critical factors determining the efficacy and durability of AAV/CRISPR-mediated gene editing in dealing with complicated hepatic monogenic disorders. Among those factors are inherent hepatocytic heterogeneity and pre-eminent hepatic presence of hematopoietic cells.
• Danish and American researchers describe a novel anti-CRISPR protein, AcrIIA22, that does not bind strongly to SpyCas9 but nonetheless potently inhibits its activity. Furthermore, x-ray crystal structure and other analyses indicated that AcrIIA22 is a DNA nickase that relieves torsional stress. The findings suggest that modifying DNA topology may provide an additional route to CRISPR-Cas resistance in phages and mobile genetic elements.
• Researchers in Japan have used ssDNA-based knock-in to replace an unmethylated promoter with an almost 100% methylated promoter of the cancer-associated gene SP3 in HEK293 cells. The method provides a promising framework for artificial epigenetic modifications to further the understanding of transcriptional regulation.
• CRISPR-mediated deletion of Lyn kinase is shown to enhance the differentiation and function of iPSC-derived megakaryocytes. Thus, adopting this system during the generation of in vitro-derived platelets may contribute to their production efficiency and ability to support hemostasis.

Industry

• Sarepta Therapeutics has offered 6,172,840 shares of its common stock with an option to purchase up to an additional 925,926 shares. At $81.00 per share, the deal amounts to $500 million. Sarepta is working in precision genetic medicine for rare diseases, like Duchenne muscular dystrophy and limb-girdle muscular dystrophies.
• Intellia Therapeutics and SparingVision have announced a collaboration where Intellia will grant SparingVision exclusive rights to its in vivo CRISPR/Cas9 technology to develop ocular therapies. In return, Intellia will receive an equity stake in SparingVision and certain rights.
• Poseida Therapeutics and Takeda Pharmaceutical Company have announced a research collaboration to develop non-viral in vivo gene therapy programs. In the deal, Takeda will have an exclusive license to use Poseida's piggyBac, Cas-CLOVER nanoparticle delivery technology and other proprietary genetic engineering platforms for up to eight gene therapies.
• Hunterian Medicine has acquired a non-exclusive license to use Inscripta's MAD7 nuclease for gene-editing programs to develop human therapeutics. MAD7 is an engineered nuclease of the Cas12a/Cpf1 family that targets TTTN PAMs.
• Precision BioSciences has made a statement declaring that its allogeneic CAR T and in vivo gene editing therapies are safe and precise and that it does not include editing of CD52 in the CAR T cells. The statement comes in the vague of last week's announcement that FDA ordered Allogene to hold its clinical trial of ALLO-501A CAR T cells.
• Allogene's troubles have also affected its primary rival, CRISPR Therapeutics. Still, analysts have been split as they compare the outlook for the two companies: shares of Allogene went up while CRISPR Therapeutics tumbled. Read two analyses of the situation in BioPharma Dive and Investor's Business Daily.
• Want to know more about the FDA hold-back that recently hit Allogene's allogeneic CAR-T therapy CTX110? And how it has affected the other players in the market? Then read this piece in Evaluate Vantage by Jacob Plieth.

Clinical News

• Intellia Therapeutics will present new preclinical data on its allogeneic T cell therapy platform and the utilisation of lipid nanoparticle-based delivery. Moreover, data from gene editing in non-human primates (NHPs) for the treatment of alpha-1 antitrypsin deficiency will be presented. Presentations will occur at the ESGCT meeting on October 19-21.
• CRISPR Therapeutics has presented positive results from its ongoing Phase 1 CARBON trial evaluating the safety and efficacy of CTX110, its wholly-owned allogeneic CAR-T cell therapy targeting CD19+ B-cell malignancies. CTX110 was well tolerated, and clinical data demonstrate the potential for CTX110 to produce durable remissions.

COVID-19

• A novel smartphone-read CRISPR-Cas12a powered visual biosensor for detecting the SARS-CoV-2 N gene has been described by Chinese researchers. So far, the biosensor has only been tested in vitro with a detection limit of 1 copy/μL with no cross-reactivity and 100% positive and 100% negative agreement with qPCR results.
• A handheld device that uses detection simultaneously by Cas12a and Cas13a in a single tube is described by Chinese researchers. As a proof-of-concept, reliable dual-gene detection of SARS-CoV-2 and African Swine fever virus (ASFV) was demonstrated, exhibiting 100% sensitivity and specificity for clinical samples.

Reviews

• In a short review, researchers from Australia evaluate the clinical promises of RNAi and CRISPR technology targeting HPV cancers. Among the promising approaches mentioned are microRNAs, long non-coding RNAs and mRNA vaccines.

Opinion

• Future Medicine brings an interview with Geoff MacKay, who talks about new gene therapies for rare diseases. MacKay is the CEO of AVROBIO, a clinical-stage lentiviral gene therapy company that treats lysosomal disorders, and a board member of Talaris Therapeutics and Satellos Bioscience.