CMN Weekly (18 November 2022) - Your Weekly CRISPR Medicine News

Top picks

• Groundbreaking CRISPR treatment for blindness only works for subset of patients. This writeup in Science covers the latest clinical data released by Editas Medicine, which announced yesterday that its Phase 1/2 CRISPR trial for the most common form of hereditary blindness, Leber congenital amaurosis 10, led to clinically meaningful vision improvements in just three of the 14 patients enroled.
• Perfection is too high a bar for CRISPR treatments, says STAT Biomedical Innovation Award winner David Liu. Base- and prime-editing pioneer David Liu speaks to STAT following receipt of STAT’s 2022 Biomedical Innovation Award earlier this week.

Research

• A team across various institutions in the U.S and Korea has identified BRD7586, a cell-permeable small-molecule inhibitor of SpCas9, through a high-throughput discovery pipeline consisting of a fluorescence resonance energy transfer-based assay that is generalisable to contemporary and emerging nucleases, operates at low nuclease concentrations and targets all catalytic steps. The findings, which were published yesterday in Nature Cell Biology, address the currently unmet demand for inhibitory anti-CRISPR molecules to control the activity and fidelity of CRISPR-associated nucleases.
• In an article published earlier this week in Science Reports, a team of scientists in the UK, Poland and the U.S. report using ABE8e, a recently evolved adenine base editor (ABE), to correct primary fibroblasts isolated from patients with recessive dystrophic epidermolysis bullosa (RDEB), a rare genetic blistering skin disease. The team sought to correct the recurrent RDEB nonsense mutation c.5047 C > T (p.Arg1683Ter) in exon 54 of COL7A1, using electroporation to deliver ABE8e. Analysis of post-treatment outcomes confirmed correction of the disease-causing allele in 94.6% of cells, restoration of COL7A1 mRNA expression, as well as confirmation of C7 protein expression by western blot and in 3D skin constructs. The authors propose that this work lays a foundation for developing therapies for RDEB patients using ex vivo or in vivo base editing.
• A team of researchers in Switzerland and Spain report the development of a proof-of-concept therapeutic base-editing strategy to address two of the most prevalent FANCA mutations in patient haematopoietic stem and progenitor cells. Fanconi Anemia (FA) is a debilitating genetic disorder that arises through mutations in FANCA, which is marked by a broad range of severe symptoms including bone marrow failure and predisposition to cancer. The team found that optimising adenine base editor construct, vector type, guide RNA format, and delivery conditions led to very effective genetic modification in multiple FA patient backgrounds, including restoration of FANCA expression, molecular function of the FA pathway, and phenotypic resistance to crosslinking agents. The findings were published in Nature Communications earlier this week.
• A team in Hungary has found that although SuperFi-Cas9 - a recently developed increased-fidelity version of SpCas9 - exhibits remarkable fidelity but severely reduced nuclease activity, it works effectively with the adenine base editor ABE8e. Upon combining SuperFi-Cas9 with ABE8e in editing experiments in mammalian cells, the team observed DNA editing with high activity as well as high specificity reducing both bystander and SpCas9-dependent off-target base editing. The findings were published in Nature Communications earlier this week.

Industry

• Editas Medicine shared clinical data from the Phase 1/2 BRILLIANCE trial of EDIT-101 in Leber congenital amaurosis 10 yesterday. The data demonstrates a favourable safety profile across all dose cohorts, proof-of-concept for EDIT-101, and identified a responder population. However, meaningful improvements in vision were only observed in three of the 14 trial participants, which has prompted the company to pause enrolment in the trial and seek to identify a collaboration partner to continue development of EDIT-101. Read more about EDIT-101 in our previous clinical trial update here.
• Beam Therapeutics has enroled the first patient in the BEACON clinical trial of BEAM-101, a base-editing therapeutic candidate for the treatment of sickle cell disease (SCD). BEAM-101 is designed as a one-time treatment aimed to cure SCD through reactivation of foetal haemoglobin expression, and the BEACON trial is the first clinical trial for a base editor to be initiated in the U.S. Learn more about how the therapeutic strategy behind BEAM-101 in a previous clinical update here.
• Intellia Therapeutics has presented new intermin data from its first-in-human clinical study of NTLA-2002 for the treatment of hereditary angioedema (HAE) at the American College of Allergy, Asthma & Immunology 2022 Annual Scientific Meeting. The data presented were from 10 adult patients with HAE in the Phase 1, dose-escalation portion of the trial, with a data cut-off date of September 28th, 2022, with robust reductions in plasma kallikrein levels (which drives inflammation in HEA) and HAE attack rates observed at all doses tested. Read a full summary of the latest data here.
• ERS Genomics Limited has announced ATLATL Innovation Centre as its non-exclusive agent for licensing ERS' intellectual property for commercial and/or research use in China. Under the terms of the agreement, ATLATL will now provide access to the CRISPR-Cas9 intellectual property held by Dr. Emmanuelle Charpentier to companies and researchers in China. Read more here.
• Pre-clinical data from the combination of Imugene’s onCARlytics technology with Celularity’s CRISPR-Cas9-edited placental-derived off-the-shelf allogeneic CYCART-19 T cells was presented at the Annual Meeting of the Society for Immunotherapy (SITC) in Boston last week. The findings were presented in a poster, and demonstrated that the experimental combination therapy has the potential to target (de novo) CD19-expressing tumours.
• Ionis has annouced a partnership with Metagenomi to add gene-editing to its broad technology platform. The new partnership will leverage Ionis’ extensive expertise in RNA-targeted therapies with Metagenomi’s versatile next-generation gene-editing systems to pursue a mixture of validated and novel genetic targets with the potential to expand therapeutic options for patients.
• SeQure Dx emerges from stealth mode, vowing to fulfill the promise of on-target gene-editing therapies for biopharma partners, physicians, and patients. The company, which is founded upon Dr. J. Keith Joung’s (Massachusetts General Hospital and Harvard Medical School) ONE-seq platform, has already developed a portfolio of assays and data solutions to find, assess, and manage off-target risks from discovery to clinical development to patient impact.
• Century Therapeutics has presented pre-clinical data and provided pipeline updates at the recent SITC annual meeting in Boston. The pre-clinical data support Century's next-generation platform for iPSC-derived natural killer cells with multiple gene edits to improve persistence and anti-tumour efficacy.
• ProQR Therapeutics will present its Axiomer® RNA base-editing technology at the Oligonucleotide and Peptide Therapeutics Conference (TIDES Europe) 2022, which is being held this weekend in Austria. Axiomer technology uses a cell’s own base-editing machinery called ADAR (adenosine deaminase acting on RNA) to make specific single nucleotide edits in RNA to reverse a mutation, modulate protein expression or change a protein, and could potentially yield a new class of medicines for diverse types of diseases.

Reviews

• Prime editing: a search and replace tool with versatile base changes. In this review, scientists in China aim to systematically describe the development, characteristics, optimisation, application and security of prime editing and discuss its potential future applications within gene therapy and agriculture.
• PCSK9 Base Editing Therapeutics and Ischemic Stroke. Individuals with genetic gain-of-function variation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are at an increased risk of cardiovascular disease, including ischemic stroke. In this article, authors based at National Institutes of Health, U.S., discuss ongoing work into PCSK9 base editing and highlight future directions relevant to cardiovascular disease and ischemic stroke.

News from CRISPR Medicine News

• This week's clinical update brought news from PACT Pharma, which shared results last week from the first clinical trial using CRISPR to direct patients’ immune cells to treat solid tumours. The findings, which were published in an unedited manuscript in Nature, provide early proof-of-concept that patient immune cells can be reprogrammed to attack their own cancer. Read the update here.