CMN Weekly (21 June 2024) - Your Weekly CRISPR Medicine News

Top picks

• Researchers from Stanford University and the University of California, San Francisco (UCSF) have used CRISPR-Cas9-mediated gene editing in human haematopoietic stem and progenitor cells (HSPCs) to recreate a truncated form of the erythropoietin receptor. Mirroring what is seen in congenital erythrocytosis - an inherited blood disorder in which a truncated erythropoietin receptor is expressed - the team observed substantial increases in red blood cell production, without compromising HSPC functionality. The study, which was led by Kyle Kromer at USCF and Matthew Porteus at Stanford, illustrates the potential of combining human genetics with precision genome editing to develop safer and more effective genome-editing therapies for patients with severe genetic diseases, particularly those affecting red blood cells. The findings were published earlier this week in Nature Biomedical Engineering.
• The realization of CRISPR gene therapy. In this comment in Nature Chemical Biology, Yitong Ma and Lei Stanley Qi, both at Stanford University, discuss the critical role that chemical biology must play in advancing recent technological breakthroughs in base editing, prime editing and epigenetic editing towards future treatments.

Research

• In a recent article in Molecular Therapy, researchers at Rush University Medical Center in Chicago report that simultaneous Sox9 activation and RelA inhibition using a catalytically-dead Cas9 resulted in engineered mesenchymal stromal cells with enhanced cartilage-forming potential and downregulated inflammatory responses. The work was motivated by efforts to develop better mesenchymal stromal cell (MSC) preparations to treat osteoarthritis (OA), a painful and debilitating disease that affects more than 500 million people worldwide. Injection of MSCs directly into the affected joints has shown promise for the treatment for OA, but this approach is hampered by inconsistencies in the MSC cell preparations, which makes it difficult to optimise treatment and challenges the proper evaluation of clinical benefit.
• Researchers in Germany and Italy report the long-term effectiveness and safety of a CRISPR-Cas9 based approach known as homology-independent targeted integration delivered by adeno-associated viral vectors (AAV-HITI). The team, led by Alberto Auricchio at Telethon Institute of Genetics and Medicine (TIGEM, Italy) demonstrate that AAV-HITI provides prolonged transgene expression from new-born and adult mouse livers without off-target effects, and highlight its potential to treat inherited metabolic diseases in new-borns. The findings were published this week in Cell Reports Medicine.
• In an article published in the Journal of Molecular Diagnostics, researchers in the United States introduce Streamlined Highlighting of Infections to Navigate Epidemics (SHINE), a CRISPR-based RNA detection platform for influenza virus. Four SHINE assays were designed and validated for the detection and differentiation of clinically relevant influenza species (A and B) and subtypes (H1N1 and H3N2). When tested on clinical samples, the team found that the optimised assays achieved 100% concordance with quantitative RT-PCR. When duplex assays were tested for their ability to detect two targets simultaneously, the team found that they could discriminate two alleles of an oseltamivir resistance (H275Y) mutation as simultaneously detect influenza A and human RNAse P in patient samples.
• Researchers in Canada, Switzerland, Austria and Australia report in Nature Communications that SCAF1 and USP15 are drivers of pancreatic cancer. The team undertook somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, and their studies revealed USP15 and SCAF1 as pancreatic tumour suppressors. They note that mutations in USP15 and SCAF1 are observed in 31% of pancreatic cancer patients. Read the full article here.

Industry

• Ascidian Therapeutics has announced a collaboration with Roche for the discovery and development of RNA exon editing therapies for neurological diseases. As part of the agreement, Ascidian will grant Roche exclusive, target-specific rights to Ascidian’s RNA exon editing technology for undisclosed neurological targets. Ascidian will conduct discovery and certain pre-clinical activities in collaboration with Roche, and Roche will be responsible for certain pre-clinical activities, and further clinical development, manufacturing, and commercialisation. See the press release for further details. Ascidian announced earlier this year that FDA had cleared its IND application and granted fast track designation to ACDN-01, its RNA-editing candidate designed to treat Stargardt disease. Read more about that here.

Clinical Trials

• Intellia Therapeutics is scheduled to present the first clinical data from patients redosed with an investigational in vivo gene-editing therapy, NTLA-2001, at the Peripheral Nerve Society Annual Meeting next week. NTLA-2001 is a CRISPR-based therapy designed to be a single-dose treatment for transthyretin (ATTR) amyloidosis. According to a press release, the company will present data from the dose-escalation portion of the Phase 1 trial, concerning three patients who received the lowest dose of 0.1 mg/kg and subsequently received a follow-on dose of 55 mg.
• At the European Hematology Association (EHA) Annual Congress held last week, Editas Medicine reported new safety and efficacy data from the ongoing RUBY trial of reni-cel in 18 patients with sickle cell disease (SCD). Reni-cel is an autologous Cas12a-edited cell therapy candidate that works by reactivating foetal haemoglobin production, thereby compensating for the lack of functional adult haemoglobin in individuals with SCD and beta thalassemia. According to the latest clinical data, all 18 SCD patients are free of vaso-occlusive events since reni-cel infusion with follow-up ranging from 2.4 to 22.8 months. See the official press release for a full summary of the data.
• Allogene Therapeutics announced yesterday that it has initiated a pivotal Phase 2 trial investigating cemacabtagene ansegedleucel (cema-cel, formerly known as ALLO-501A), a TALEN-edited allogeneic CAR-T cell product, as part of first line treatment for patients with large B-cell lymphoma (LBCL) at risk of relapse. The trial will be the first to incorporate Foresight Diagnostics’ Investigational CLARITY^™ test to identify patients with LBCL who have minimal residual disease and are likely to relapse following standard first line treatment. Read more in the press release here, and learn more about cema-cel in our previous clinical trial update here.

Conferences

• The 3rd Copenhagen symposium on Advances in T cell therapy and Cellular engineering (CATC) will be held from 24-25 September 2024 at the Danish Technical University in Denmark. The event is dedicated to exploring recent advancements in medical science. CATC brings together scientists, clinicians, and industry professionals to discuss the latest developments in T cell therapy and cellular engineering. Read more about the symposium and register to attend here.

News from CRISPR Medicine News:

• On Monday, we published an interview with GSK’s scientific director of target discovery, Fiona Behan, PhD. She spoke about her work in oncology target discovery, what motivates her, and how her team is using machine learning to harness the power of combinatorial CRISPR screens. Read it here.
• Don't miss the next GeneHumdi X CRISPR Medicine News webinar, where Dr Paula Río from the Division of Hematopoietic Innovative Therapies at CIEMAT (Spain) will discuss CRISPR Clinical Trials: current progress and future perspectives in ex vivo approaches. The webinar airs for free on Tuesday June 25th from 15:00 – 16:00 CEST. Sign up is available here.