CMN Weekly (28 June 2024) - Your Weekly CRISPR Medicine News

Some of the best links we picked up around the internet

By: Gorm Palmgren - Jun. 28, 2024

Top picks

Researchers in the USA have developed a compact epigenetic editor, CHARM, to silence prion protein expression in the brain, offering a potential treatment for prion diseases. When delivered into the mouse brain via adeno-associated virus (AAV), CHARM recruits endogenous DNA methyltransferases, achieving up to 80% reduction in prion protein. This enzyme-free approach avoids cytotoxicity and off-target effects. CHARM’s small size enables precise, durable gene silencing, promising advancements for neurodegenerative disease therapies and broader epigenetic interventions.
Using in vivo AAV-SB-CRISPR screens and single-cell transcriptomics in mouse models, researchers have identified CALHM2 as a key regulator of natural killer (NK) cell cytotoxicity, tumour infiltration, and cytokine production. CALHM2-KO CAR-NK cells showed strong antitumor effects in resistant solid tumour models. This reveals genetic checkpoints limiting NK cell function and demonstrates CALHM2 KO’s potential for improved NK cell-based immunotherapies. The discovery is also mentioned in a Nature Biotechnology research briefing.

Research

Korean researchers have developed an efficient CRISPR activator (CRISPRa) system based on the small CRISPR-Cas effector Candidatus Woesearchaeota Cas12f (CWCas12f) to control gene expression without DNA damage. The new eCWCas12f-VPR system is optimised with activation domains, linkers, and nuclear localisation signals and thus enhances target-specific gene regulation.
A new CRISPR-based precision-guided sterile insect technique (pgSIT) targets Anopheles gambiae mosquitoes to control malaria. The binary CRISPR approach creates strains that, when crossed, disrupt male fertility and female-essential genes, achieving >99.5% male sterility and >99.9% female lethality. These genetically sterilised males exhibit good longevity and induce population suppression in trials.
American researchers have developed a selective CRISPR-Cas9 strategy to target somatic mutations that generate protospacer adjacent motifs (PAMs) in pancreatic cancer cells. By designing sgRNAs to target these novel PAMs, CRISPR-Cas9 can selectively introduce double-strand breaks in cancer cells, leading to their destruction while sparing normal cells.
Leveraging on IS110 insertion sequences - a family of mobile genetic elements expressing a structured non-coding RNA that binds their recombinase, enabling genomic rearrangements - American researchers have developed a programmable system for sequence-specific recombination between DNA molecules. The IS110 bridge RNA system allows DNA insertion, excision, and inversion, expanding nucleic-acid-guided genome design beyond CRISPR and RNA interference. The discovery is discussed in a Nature News & Views article.
In a similar approach, Australian researchers have developed seekRNA, which is based on the IS1111 and IS110 insertion sequences and can be reprogrammed to target different sites. seekRNA contains sequences complementary to both strands of the target site, essential for transposition, and may carry cargo, such as therapeutic genes. The discovery is discussed in a Nature Technology Feature.

Industry

2seventy bio completed an asset purchase agreement with Novo Nordisk, transferring its Hemophilia A program and in vivo gene editing technology, potentially worth up to $40 million. The deal includes 2seventy bio’s megaTAL technology and relevant intellectual property. The team involved will join Novo Nordisk to further the Hemophilia A therapy, while 2seventy bio will focus on its BCMA-targeted CAR T cell therapy, Abecma, for multiple myeloma.
Chroma Medicine has entered into an exclusive license agreement with the Whitehead Institute for the novel technology CHARM (coupled histone tail for autoinhibition release of methyltransferase). CHARM uses a compact epigenetic editing effector domain to recruit and activate endogenous DNA methyltransferases to durably silence target genes, and it can utilise a self-silencing mechanism to limit its duration of expression.
SNIPR Biome has secured funding from the Bill & Melinda Gates Foundation to develop CRISPR-Cas armed phages (CAPs) targeting entero-pathogens in pregnant women from low- and middle-income countries. This intervention aims to combat environmental enteric dysfunction (EED) by reducing gut pathogen load, potentially improving nutrient absorption and pregnancy outcomes. The project will utilise SNIPR Biome’s CRISPR-armed phage cocktail, SNIPR001, targeting E. coli and Klebsiella pneumoniae.
Beam Therapeutics has treated the first patient with BEAM-302, an investigational in vivo base editing medicine designed to precisely correct the underlying cause of severe alpha-1 antitrypsin deficiency (AATD). BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to correct the PiZ mutation, which, in its homozygous state, represents the majority of patients living with severe AATD disease.
Intellia Therapeutics has presented new data demonstrating the potential for redosing with NTLA-2001, an investigational single-dose, in vivo CRISPR-Cas9 genome editing therapy for treating transthyretin amyloidosis (ATTR). Follow-on dosing with a 55 mg dose of NTLA-2001 led to a 90% median reduction in serum TTR at day 28 in three patients who previously received the lowest dose in the Phase 1 dose-escalation study.

CRISPR screens

A whole-genome CRISPR screen has identified the neddylation pathway as a regulator of neuronal ageing and Alzheimer’s disease (AD) neurodegeneration. Blocking neddylation - the process by which the ubiquitin-like protein NEDD8 is conjugated to its target proteins - increased ageing markers and Tau aggregation in neurons with the APPswe/swe mutation, reducing their viability. Similar effects were seen in Parkinson’s disease models. This study highlights neddylation as a potential therapeutic target for AD and demonstrates a method to induce age-associated disease phenotypes in stem cell models.
CRISPR knockout screens have identified proteins modulating the balance by which non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ) repair DNA double-strand breaks in the context of chromatin structure. The Dutch researchers found that BRCA2 and POLL favour NHEJ in euchromatin, while the FANC complex and ATM favour MMEJ in heterochromatin.
Using tiling CRISPR interference screens, Polish researchers have identified three IGH enhancer regions crucial for non-Hodgkin lymphoma (NHL) cell growth. These regions produce enhancer RNAs (eRNAs), and inhibiting them reduces eRNA and oncogene expression. The study highlights critical IGH enhancer regions, offering potential therapeutic targets for NHL.

Detection

The SHINE platform, a CRISPR-based RNA detection method, offers rapid, sensitive, and specific influenza diagnostics with minimal equipment. Four assays detect influenza A, B, H1N1, and H3N2 with 100% RT-PCR concordance. Duplex assays can detect two targets, including drug resistance mutations and influenza A with human RNAse P, enhancing diagnosis and surveillance outside labs.

Reviews

Methods and applications of genome-wide profiling of DNA damage and rare mutations. This review examines and compares genome-wide methods for detecting DNA damage and rare mutations at single-nucleotide resolution, highlighting their applications and future research potential.
Pharmacological targeting of the cancer epigenome. This review discusses recent developments for each epigenetic drug class and their implications for therapy, as well as highlights new insights into the role of epigenetics in cancer.
Exploring Genetic Silencing: RNAi and CRISPR-Cas Potential Against Drug Resistance in Malaria. This review examines the key genes involved in parasite resistance and proposes gene silencing techniques that offer promise in combating malaria.