CMN Weekly (14 March 2025) - Your Weekly CRISPR Medicine News

Top picks

• In an article published this week in PNAS, researchers at Duke University and North Carolina State University report the discovery of new CRISPR-Cas systems that could add to the capabilities of the already transformational gene editing and DNA manipulation toolbox. Of the newly discovered Cas9 orthologues, one system from Streptococcus uberis that is commonly found in dairy cows shows particular promise for human health with demonstrated genome-, transcriptome-, and epigenome-editing activity. They report that S. uberis Cas9 performed competitively against benchmarks with promising repression, activation, nuclease, and base editing activity. In addition, the small size of S. uberis Cas9 offers a packaging advantage for delivery to human cells, and it can also target specific gene sequences that are inaccessible to other gene-editing nucleases.

Research

• In a recent study published in Cell Reports Medicine, researchers led by Dr. Yung-Yao Lin at Queen Mary University of London report a clinically-relevant transplantation strategy using CRISPR-corrected human myogenic cells in hydrogels that generate functional muscle tissue in a mouse model of muscular dystrophy. The study, which involved collaborators at UCL Great Ormond Street Institute of Child Health and the Blizard Institute, demonstrated that engineered 3D cell-laden hydrogel constructs successfully engrafted in dystrophin-deficient mdx nude mice without requiring pre-treatment of host muscles. The team reports that the transplanted cells produced full-length dystrophin at both 4 weeks and 5-6 months after transplantation.
• In an article published in Nature Communications earlier this week, researchers in China report new insights about the target cleavage activity of Cas9d, the smallest Cas9 family member. Using cryo-EM structures of Cas9d in target-free and target-bound states as well as biochemical assays, they found that Cas9d uses a compact architecture for target cleavage and that the sgRNA serves dual roles: adapting between Cas9d and targets while providing structural support. They also report that upon target binding, the sgRNA-REC domain module undergoes conformational changes that enable heteroduplex formation and nuclease activity, and that this hybrid functional module precisely monitors heteroduplex complementarity, resulting in a lower mismatch tolerance compared to SpyCas9. Using a structure-guided engineering approach, the researchers generated a more compact Cas9 system with preserved activity, further advancing the development of high-fidelity mini-CRISPR tools.
• Researchers at various institutes in the United States present a new CRISPR screening approach called Perturb-FISH, which is a combination of imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs. They report that Perturb-FISH recovers intracellular effects that are consistent with single-cell RNA-sequencing-based readouts of perturbation effects (Perturb-seq) in a screen of lipopolysaccharide response in cultured monocytes and uncovers intercellular and density-dependent regulation of the innate immune response. They also report that in three-dimensional xenograft models, Perturb-FISH identifies tumour-immune interactions altered by genetic knockout. Their findings were published earlier this week in Cell.
• In an article published earlier this week in Nature Communications, scientists at Metagenomi report that compact type V-K CRISPR-associated (Cas) transposases (CAST) from uncultivated microbes can be repurposed for programmable DNA integration into the genome of human cells. They show that engineering for nuclear localisation and function enables the integration of a therapeutically-relevant transgene at a safe-harbour site in multiple human cell types and that off-targets are rare events reproducibly found in specific genomic regions. The authors propose that these CAST advancements are expected to accelerate applications of genome editing to therapeutic development, biotechnology, and synthetic biology.

Clinical

• Beam Therapeutics has announced positive initial data from its Phase 1/2 clinical trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency (AATD). The results, which were shared in a press release published on Monday, demonstrate the first-ever clinical genetic correction of a disease-causing mutation through base-editing technology. Read more about that in this week's clinical trial update.
• On Tuesday, YolTech Therapeutics announced positive interim results from an investigator-initiated trial evaluating YOLT-201, an investigational in vivo CRISPR-Cas-based gene-editing therapy in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). According to the official press release, the data indicates the extremely low immunogenicity of the lipid nanoparticle formation used to deliver YOLT-201 ensure safety upon secondary administration to achieve a cumulative therapeutic effect, and that it holds the potential to reduce the pathogenic TTR protein in the blood to the lowest levels, paving the way for optimal efficacy in the future.

Industry news and 2024 financial results and business updates

• 2seventy bio announced this week that it has entered into a definitive agreement to be acquired by Bristol Myers Squibb. Under the terms of the agreement, BMS will promptly commence a tender offer to acquire all outstanding shares of 2seventy bio at a price of $5.00 per share in an all-cash transaction. 2seventy bio’s Board of Directors unanimously recommends that 2seventy bio stockholders tender their shares in the tender offer. See the official announcement for further details.
• Cellectis reported financial results for the fourth quarter and full year 2024 as well as business updates yesterday. According to its press release, the company expects to present the Phase 1 data set (from the BALLI-01 trial) and late-stage development strategy in the third quarter of 2025 for UCART22 for the treatment of r/r ALL. For UCART20x22 in relapsed or refractory non-hodgkin lymphoma, Cellectis continues to focus on the enrolment of patients and expects a clinical data readout late this year.
• Allogene Therapeutics reported financial results for the fourth quarter and full year 2024 as well as business updates yesterday. Of note, the pivotal Phase 2 ALPHA3 trial of cema-cel in patients with large B-cell lymphoma remains a central programme for the company. That trial, which was initiated in June 2024 now has 40 sites activated and continues to generate strong enthusiasm from both community cancer centres and academic institutions. You can read more about cema-cel and the ALPHA3 trial in a previous clinical trial update. See the official press release from Allogene for the full update.
• ProQR Therapeutics announced year end 2024 operating and financial results yesterday. According to its press release, the company's Axiomer™ ADAR-mediated RNA-editing pipeline is advancing across liver and central nervous system programmes, with clinical trial application expected in Q2 2025 for its lead programme AX-0810 in cholestatic diseases. The company also expects up to four clinical data readouts in 2025 and 2026 across multiple programmes, highlighted by first clinical data for AX-0810 anticipated in the last quarter of this year.
• Caribou Biosciences reported financial results for the fourth quarter and full year 2024 as well as business updates earlier this week. Among the programme highlights are that clinical data are expected in the first half of 2025 for the ongoing ANTLER Phase 1 trial of CB-010 in patients with second-line large B cell lymphoma and the CaMMouflage Phase 1 clinical trial of CB-011 in relapsed or refractory multiple myeloma. Caribou is now advancing four clinical programmes for blood cancers and autoimmune diseases leveraging its chRDNA genome-editing technology. See the official press release for further details.
• Korro Bio announced today that the US FDA has granted orphan drug designation to KRRO-110 for the treatment of alpha-1 antitrypsin deficiency (AATD). KRRO-110 is the first RNA-editing oligonucleotide product candidate from Korro’s proprietary RNA-editing platform called Oligonucleotide Promoted Editing of RNA (OPERA™). The candidate, which was cleared for a Phase 1/2 trial in Australia late last year, consists of an RNA-editing oligonucleotide encapsulated in a lipid nanoparticle that is delivered systemically to reach the liver, to correct the pathogen mutation associated with the most severe form of AATD. You can read more about KRRO-110 in a recent clinical trial update here.

Reviews and reports

• Catecholaminergic Polymorphic Ventricular Tachycardia: Advancing From Molecular Insights to Preclinical Models. The authors of this review aim to emphasise the diverse insights gained from both in vivo and in vitro studies of catecholaminergic polymorphic ventricular tachycardia, including those involving CRISPR-Cas9 technology, along with the application of these models in various research contexts.
• Efforts to Downsize Base Editors for Clinical Applications. In this review, an author at Soonchunhyang University in Republic of Korea highlights the importance of downsizing base editors (BEs) for therapeutic applications and introduces recent advances in size-reduction strategies. Additionally, they introduce the ongoing efforts to overcome other limitations of BEs, providing insights into their potential for improving in vivo gene editing.
• Polysaccharide-Based Delivery Systems for CRISPR/Cas Gene Therapy: Overcoming Challenges and Advancing Pharmaceutical Solutions. This editorial discusses how CRISPR/Cas gene-editing technology has transformed molecular biology with its precision and therapeutic potential but highlights that delivery methods remain a critical bottleneck for clinical applications. While viral vectors, lipid nanoparticles, and synthetic polymers have limitations including immunogenicity and toxicity, polysaccharide-based delivery systems offer a promising alternative due to their natural origin, biocompatibility, and versatile chemical properties, potentially advancing CRISPR/Cas gene therapy in pharmaceutical applications.
• Current and future treatments for sickle cell disease - from hematopoietic stem cell transplantation to in vivo gene therapy. The authors of this review discuss current treatments for sickle cell disease (SCD), including drug therapies, haematopoietic stem cell transplantation, ex vivo gene therapy, the development of gene therapy tools, and progress toward curative in vivo gene therapy in SCD.
• Selecting patients with sickle cell disease for gene addition or gene editing-based therapeutic approaches: Report on behalf of a joint EHA Specialized Working Group and EBMT Hemoglobinopathies Working Party consensus conference. The European Hematology Association Red Cell & Iron Specialized Working Group (EHA SWG) and the European Blood and Marrow Transplant (EBMT) group have prioritized the development of recommendations for selecting good SCD candidates for gene therapy. The findings include a set of inclusion and exclusion criteria and the panel's proposals for new indications. The panel also proposed the recommended assessments for short-, medium-, and long-term follow-up.

News from CRISPR Medicine News

• Don't miss the next GeneHumdi webinar this coming Wednesday where Maria Silvia Roman Azcona from University of Freiburg (Germany) will present her research on (Epi)genome editing in CAR T cells. Sign up to attend the free webinar here.
• This week's clinical update brought the latest news from Beam Therapeutic's ongoing trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency. Eight months after dosing the first patient with BEAM-302, the latest safety and efficacy data indicate that a base-editing approach could transform treatment for patients with alpha-1 antitrypsin deficiency. Read the full update here.