CMN Weekly (5 May 2023) - Your Weekly CRISPR Medicine News

Top pick

• Earlier this week, researchers from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC) report in PNAS that dual CRISPR-Cas9 gene-editing therapy can eliminate HIV-1 proviral DNA in humanised mice previously treated with antiretroviral drugs. The dual gene-editing therapy is designed to cut HIV-1 DNA out of the genomes of infected cells, as well as inactivate CCR5, the human co-receptor that helps the HIV virus enter cells. The approach builds upon knowledge acquired through reported cures in human HIV patients, and is the first to combine a dual gene-editing strategy with antiretroviral drugs to cure HIV-1 in animals.

Research

• A study by researchers at New York University and the New York Genome Center combines genetic association studies, massive parallel CRISPR-based gene-editing screens, and single-cell transcriptome and proteome sequencing to discover causal variants and genetic mechanisms for blood cell traits. The novel approach, called STING-seq, addresses the long-standing challenge of directly linking genetic variants with human traits and health, and can aid in the identification of novel drug targets for diseases with an underlying genetic component. The findings were published yesterday in Science.
• Gastrointestinal bacterial infections are a major problem in blood cancer patients who are undergoing immunosuppressive chemotherapy, and translocation of E. coli from the gut to the bloodstream is a frequent cause of fatal septicaemia in this group. To combat serious problems associated with antibiotic side effects and antibiotic resistance, the team behind SNIPR Biome developed SNIPR001, a cocktail of four CRISPR-Cas armed bacteriophages designed to specifically target a diverse spectrum of E. coli strains in the gut. Pre-clinical findings published yesterday in Nature Biotechnology demonstrate that SNIPR001 is well tolerated in mice and minipigs, and reduces E. coli load in the mouse gut better than each of its four constituent components separately. SNIPR001 is being evaluated in a Phase 1 clinical trial and you can read more about its development in an earlier clinical trial update here.
• In an article published this week in Genome Biology, researchers in the U.S. reporting boosting the genome-editing efficiency of novel Cas12a variants from Lachnospiraceae bacterium (LbCas12a) in human cells and plants. Following a saturation mutagenesis approach, they identified LbCas12a-RVQ (G146R/R182V/E795Q) as being the variant with the most robust editing activity in human cells. They identified another variant, LbCas12a-RRV, with improved editing efficiency in stably transformed rice and poplar plants, leading to up to 100% editing efficiency in T₀ plants of both plant species. The team observed that this high-efficiency editing occurs even at non-canonical TTV PAM sites.
• In an article published in Nature Biotechnology earlier this week, Editas Medicine presents comprehensive data from a study of its proprietary SLEEK (SeLection by Essential-gene Exon Knock-in) gene-editing technology. SLEEK employs a CRISPR nuclease that targets a site within an exon of an essential gene. A cargo template is provided to the cells during editing, so that a correct knock-in would retain essential gene function while also integrating the transgene(s) of interest. Cells with non-productive insertions and deletions would undergo negative selection. The company reports that SLEEK achieved knock-in efficiencies of more than 90% in clinically-relevant cell types without impacting long-term viability or expansion.
• A team of researchers in China has evaluated the effect of in vivo co-delivery of Cas9 mRNA and gRNAs by SM-102-based lipid nanoparticles (LNPs) on hepatitis B virus covalently closed circular DNA (HBV cccDNA) and integrated DNA in mouse and a higher species. This treatment decreased the levels of HBV antigens and cccDNA in an adeno-associated virus (AAV)-HBV1.04 transduced mouse liver by up to 64%. In HBV-infected tree shrews (a small mammal species), the treatment achieved 70% reduction of viral RNA and 35% reduction of cccDNA. The treatment was well tolerated in both mouse and tree shrew, with no elevation of liver enzymes and minimal off-target effects detected. The findings were published earlier this week in Antiviral Research.
• In an article published in Molecular Cell this week, a team in China reports the development of DddA ortholog-based and transactivator-assisted nuclear and mitochondrial cytosine base editors with expanded target compatibility. Having identified a DNA deaminase from a Roseburia intestinalis interbacterial toxin (riDddA_tox), they generated CRISPR-mediated nuclear DdCBEs (crDdCBEs) and mitochondrial CBEs (mitoCBEs) using split riDddA_tox, which catalysed C-to-T editing at both HC and GC targets in nuclear and mitochondrial genes. The new editors could stimulate disease-associated mtDNA mutations in cultured cells and in mouse embryos with conversion frequencies of up to 58% at non-TC targets.
• A team of researchers in the Netherlands has demonstrated that a small, naturally accurate, and thermostable type II-C Cas9 ortholog from Geobacillus thermodenitrificans (named ThermoCas9) with alternative target site preference is active in human cells, and that it can be used as an efficient genome-editing tool, especially for gene disruption. The team also developed a ThermoCas9-mediated base editor, called ThermoBE4, for programmable nicking and subsequent C-to-T conversions in human genomes. ThermoBE4 exhibits a three times larger window of activity compared with the corresponding SpyCas9 base editor (BE4). The findings were published earlier this week in CRISPR Journal.

Industry

• Scribe Therapeutics announced earlier this week in a press release that it will give an oral presentation at the 2023 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting. Scribe’s suite of XE genome-editing tools are comprehensively engineered from natural CRISPR-Cas enzymes to exhibit increased activity, specificity and deliverability. The company’s presentation is expected to include data demonstrating the potential of its gene-editing platform and CRISPR by Design™ approach to overcome challenges with efficacy and safety that existing technologies face.
• It was announced this week that Paragraf has acquired CRISPR-Chip developer Cardea Bio. Paragraf is the only company in the world to mass produce graphene electronics using transfer-free graphene and standard semiconductor processes, which ensures a reliable supply of CRISPR-chips for the CRISPR Analytics Platform, enabling it to meet the needs of the rapidly growing gene editing market. According to the press release announcing the aquisition, the scaled manufacturing capabilities of Paragraf, combined with Cardea's biosensor and platform expertise, will drive continued growth of CRISPR Analytics Platform globally.
• Poseida Therapeutics announces multiple presentations at the American Society of Gene and Cell Therapy 26th Annual Meeting. The six data presentations will including two oral presentations highlighting the Company's pre-clinical gene therapy programmes and platforms. See the press release for more details.

First quarter 2023 financial results and business updates from the gene-editing companies

• Vertex Pharmaceuticals reports first quarter 2023 financial results. The company reports completion of rolling Biologics License Application (BLA) submissions for its ex vivo CRISPR-edited sickle cell disease and beta thalassemia candidate exa-cel in the U.S., and expects to reach multiple additional clinical milestones in 2023.
• Intellia Therapeutics announces first quarter 2023 financial results and highlights recent company progress this week. Among the highlights are that that company has initiated dosing in the Phase 2 study of NTLA-2002 for hereditary angioedema, and based on strong interest from investigators and patients, it expects to complete enrollment in the second half of 2023.
• Editas Medicine announces first quarter 2023 results and business updates. The company is due to provide a clinical update on the EDIT-301 Phase 1/2 RUBY trial for sickle cell disease in June at the European Hematology Association Congress (EHA) and in a company-sponsored webinar, and is on track to dose a total of 20 patients by year-end in the RUBY trial. The company also announced dosing of EDIT-301 in the EDITHAL trial for transfusion-dependant beta thalassesmia, with successful neutrophil and platelet engraftment, and that it is on track to provide a clinical update on this trial by year-end.
• Allogene Therapeutics reports first quarter 2023 financial results and business updates. According to the updates, enrollment is ongoing for the potentially pivotal Phase 2 ALPHA2 trial of TALEN-edited CAR-T candidate ALLO-501A, for the treatment of relapsed or refractory large B cell lymphoma. The company also announced that it has initiated the Phase 2 EXPAND trial to support licensure of ALLO-647 as a lymphodepleting agent for ALLO-501A.
• Cellectis provides business update and reports financial results for first quarter 2023. Among the highlights are dosing of the first patient in France with Cellectis' in-house manufactured product candidate UCART22 in the BALLI-01 clinical study. UCART22 is a TALEN-edited candidate that is currently the most advanced allogeneic CAR T-cell product in development for relapsed or refractory B-cell acute lymphoblastic leukaemia.
• Fate Therapeutics reports first quarter 2023 financial results and business updates. The company announced that dose escalation is ongoing in the Phase 1 Study of FT819, a meganuclease-edited CD19-targeted 1XX CAR T-cell candidate, and that interim clinical data demonstrated a favourable safety profile and complete responses in aggressive large B-cell lymphoma.
• Precision BioSciences announced that it will report first quarter 2023 results on May 9, 2023. See company's website for more details here.

Reviews

• CRISPR‑based diagnostic approaches: Implications for rapid management of future pandemics. This review discusses the biochemical properties of Cas12 and Cas13 orthologues in viral disease detection and other applications, and expands the scope of CRISPR‑based diagnostics to detect diseases and fight viruses as anti-virals.

Conferences

• Watch this space because CRISPRMed2024 is coming! We are organising the first-ever international CRISPR Medicine Conference to be held in Copenhagen, April 2024. We already have an exciting list of speakers lined up. Keep an eye on this page for updates.
• 2023 MEETING of the Israeli Society of Gene and Cell Therapy, to be held July 3rd, 2023 at The Wohl Center, Ramat Gan (Israel). This meeting aims to facilitate the sharing of ideas and data, foster collaboration, and advance clinical translation within gene and cell therapy, including stem cell research, genome editing, T cell engineering, and more. See here for further details and sign-up info.
• 6th International Conference on CRISPR Technologies, to be held from October 17, 2023 to October 19, 2023, at The Revere Hotel Boston Common, Boston, MA, USA. This event will will focus on the latest advances in the genome-editing field, including both academia and industry. The programme will feature talks across many facets of this field, including the optimisation of safe and effective DNA, RNA, and epigenetic-editing technologies, discovery and optimisation of naturally-occurring CRISPR and non-CRISPR enzymes, the development of precision technologies capable of generating nucleotide- or kilobase-scale edits; and overcoming barriers to realising the full potential of each of these tools. See here for abstract submission and sign-up details.

News from CRISPR Medicine News

• On Wednesday, we published a clinical trial update looking at the latest clinical news from Editas Medicine and Allogene Therapeutics. You can find that update here.

Huh, heh, wow

• First university to put gene-edited livestock into human food supply. Washington State University (WSU) has received U.S. Food and Drug Administration authorisation to have gene-edited pigs enter the food chain for human consumption — in this case, as tasty, German-style sausages. Note that the FDA authorisation is investigational, and limited to to a specific group of five pigs that are gene-edited under the supervision of Professor Jon Oatley in the School of Molecular Biosciences in WSU’s College of Veterinary Medicine, but shows that gene-editing livestock to quickly produce desirable traits for improved food production is a viable strategy for helping feed the planet’s growing population.