CMN Weekly (4 August 2023) - Your Weekly CRISPR Medicine News

Top picks

• A new San Francisco-based biotechnology company emerged from stealth yesterday, pioneering multi-kilobase gene-editing platforms to reach previously undruggable diseases. Amber Bio, co-founded by Basem Al-Shayeb, Ph.D, and Jacob Borrajo, Ph.D, launched with an oversubscribed $26 million seed financing round co-led by Playground Global and Andreessen Horowitz Bio + Health. According to the official press release, the funding will be used to advance a completely novel RNA-editing platform capable of making multi-kilobase edits, allowing a single drug to treat diseases with high allelic diversity. Amber Bio is developing its own genetic medicine programmes in-house.
• Intellia fills gene editing trial outside US after FDA request for preclinical fetal data. According to a news article published in Fierce Biotech yesterday, the FDA has asked Intellia to conduct a new pre-clinical test to measure the impact of its hereditary angioedema candidate NTLA-2002 on a developing foetus. Specifically, the FDA has requested that Intellia provide additional pre-clinical data on the inclusion of female patients of child-bearing potential. While the company carries out the requested pre-clinical study in hopes of receiving FDA clearance to include U.S. patients in a Phase 3 trial, it has reportedly been possible to fill the enrolment gap caused by the delay, by using clinical sites outside of the U.S.

Research

• In an attempt to attain precise control and programmable regulation of Cas12a's trans-cleavage activity, a team of researchers in China have developed a novel and robust CRISPR-Cas12a regulation mechanism by equipping the activator with a caging crRNA. Specifically, they constructed an integrated elongation-caged activator (EL-activator) by extending the ssDNA activator on the 3'-end. They found that appending only about 8 nt that are complementary to the crRNA repeat region is sufficient to cage the crRNA spacer/repeat region, thus effectively inhibiting Cas12a trans-cleavage activity. Their findings were published this week in Analytical Chemistry.
• In an article published this week in Analytical Chemistry, a team in China reports a novel CRISPR-Cas12a-powered electrochemical/fluorescent (EC/FL) dual-mode controlled-release homogeneous biosensor for mRNA detection, and confirmed the applicability of the strategy to detect and quantify mRNAs in complex serum environments and tumour cell lysates. The authors present their strategy as a potentially new diagnostic tool for cancer.
• Researchers based at UCLA investigated the mechanism of Cas12a target recognition using a combination of site-directed spin labeling, fluorescent spectroscopy, and enzyme kinetics. With a fully matched RNA guide, their data revealed an inherent equilibrium between a DNA unwound state and a DNA-paired duplex-like state. Using experiments with off-target RNA guides and pre-nicked DNA substrates, they could identify the PAM-distal DNA unwinding equilibrium as a mismatch-sensing checkpoint prior to the first step of DNA cleavage. The authors propose that their findings shed light on the distinct targeting mechanism of Cas12a and may better inform CRISPR-based biotechnology developments. The findings were published this week in Nucleic Acids Research.
• Realising that nuclease-based genome editing would benefit from improved methods for transgene integration via homology-directed repair (HDR), a team of scientists in the U.S. and France screened six small-molecule inhibitors of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This is a protein in the alternative repair pathway of non-homologous end joining (NHEJ), which generates genomic insertions/deletions (INDELs). From their screen, they identified AZD7648 as the most potent compound, and found that it significantly increased HDR and concomitantly decreased INDELs across different genomic loci in various therapeutically-relevant primary human cell types. Their findings were published yesterday in Nature Biotechnology.

Industry

• ERS Genomics & Transomic Technologies have entered into a CRISPR-Cas9 licensing agreement. The non-exclusive agreement will see Transomic gain access to the foundational ERS CRISPR-Cas9 patent portfolio. Founded in 2012, Transomic equips life science researchers with specially-developed and proprietary gene-modulation tools that revolve around vector-based solutions.
• Precision BioSciences is scheduled to report second quarter 2023 financial results as well as business updates today. See here for details.
• Sangamo Therapeutics announced that it will provide second quarter 2023 results in a conference call and webcast scheduled for the 8th August. See here for further details.
• HuidaGene Therapeutics and Kactus have announced a strategic collaboration and license agreement to promote commercialisation of HuidaGene's hfCas12Max^®. Under the terms of the agreement, Kactus Bio will obtain an exclusive license for manufacturing and sales of hfCas12Max^® in Greater China, as well as non-exclusive license for manufacturing and sales of GMP-grade products, while HuidaGene will receive sales-based payments.

Second quarter 2023 financial updates from gene-editing companies

• Allogene Therapeutics reported second quarter 2023 financial results and a business update this week. The announcement included pipeline updates for the company's anti-CD19 AlloCAR T candidate ALLO-501A, which is currently enroling for a Phase 2 pivotal trial for relapsed or refractory large B-cell lymphoma. The company also provided updates for its anti-CD70 AlloCAR T and anti-BCMA AlloCAR T candidates ALLO-316 and ALLO-715, respectively.
• Editas Medicine's second quarter 2023 results and business updates were also published this week. Among the highlights were that the company is on track to dose 20 total patients in the EDIT-301 RUBY trial for sickle cell disease, and that parallel patient dosing has commenced in the EDIT-301 EDITHAL trial for transfusion-dependant beta thalassemia. Clinical update for both trials are expected by the end of 2023.
• In its second quarter 2023 financial results, also published this week, Vertex Pharamaceuticals provided detailed financial updates and a status on its lead CRISPR-edited therapeutic candidate exagamglogene autotemcel (exa-cel), which is currently being evaluted in Phase 3 trials for severe sickle cell disease and transfusion-dependent beta thalassemia, and for which the FDA has accepted Biologics License Applications for both indications.
• This week, Cellectis provided business updates and preliminary financial results for the second quarter of 2023. Among the updates was a summary of positive clinical & translational data on the company's BALLI-01 trial, which is evaluating UCART22 in relapsed or refractory B-cell acute lymphoblastic leukaemia. That data was presented at the recent European Hematology Association annual meeting. The company also provided brief updates on other TALEN-edited cell therapy programmes in its pipeline.
• Intellia Therapeutics also announced second quarter 2023 financial results this week, and highlighted recent company progress. The company reported that it has now completed identification of all patients for the Phase 2 study of its CRISPR-edited in vivo candidate NTLA-2002 for the treatment of hereditary angioedema, which you can read more about in a recent clinical update here. The company plans to initiate a global pivotal Phase 3 study of NTLA-2002 as early as Q3 2024, subject to regulatory feedback. The company also announced that it is on track to submit an IND application in September 2023 for a global pivotal study of another CRISPR-edited in vivo candidate, NTLA-2001, for the treatment of transthyretin amyloidosis with cardiomyopathy. This trial is anticipated to be initated by the end of 2023, subject to regulatory feedback.

Reviews

• Genome editing in the treatment of ocular diseases. In a review article published this week in Experimental & Molecular Medicine, researchers at UCI Health Gavin Herbert Eye Institute and other departments at UC Irvine propose that the unique anatomical and physiological features of the eye provide the ideal environment for the application of gene-editing technology to treat disease. The authors discuss the discovery and development of genome-editing technologies and how these have been used so far to tackle genetic and non-genetic eye diseases. They also look at limitations that must be overcome before gene-editing technologies can be translated into real-life therapies for patients with eye diseases.
• Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from β-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing. This review article focuses on the possibility to combine pharmacologically-mediated foetal haemoglobin (HbF) induction protocols with the “de novo” production of adult hemoglobin (HbA) using CRISPR-Cas9 gene editing.
• Unlocking the secrets of ABEs: the molecular mechanism behind their specificity. In this review, authors based at Arizona State University provide an overview of the molecular mechanism of adenine base editors (ABEs), with a focus on the mechanism of deoxyadenosine deamination by evolved tRNA-specific adenosine deaminase (TadA). They also discuss how mutations and adjustments introduced through directed evolution as well as rational design have improved ABE efficiency and specificity.
• A critical review on therapeutic approaches of CRISPR-Cas9 in diabetes mellitus. The authors of this review overview the various therapeutic approaches to diabetes mellitus that involve genome editing using CRISPR-Cas9. The challenges and limitations of implementing this technology to treat diabetes mellitus are also discussed.