Researchers at the University of California, Davis have engineered dominant negative CD40L mutant polypeptides that inhibit CD40/CD40L-mediated signaling, offering therapeutic potential for inflammatory, immune disorders, and cancer with improved safety profiles.

Clustered regularly interspaced short palindromic repeats (CRISPR) screening is a cornerstone of functional genomics, enabling genome-wide knockout studies to identify genes involved in specific cellular processes or disease pathways. The success of CRISPR screens depends critically on the design of effective guide RNA (gRNA) libraries that maximize on-target activity while minimizing off-target effects. Current CRISPR screening lacks tools that can natively integrate next-generation sequencing (NGS) data for context-specific gRNA design, despite the wealth of genomic and transcriptomic information available from modern sequencing approaches. Traditional gRNA design tools have relied on static libraries with limited genome annotations and outdated scoring methods, lacking the flexibility to incorporate context-specific genomic information. Off-target effects are also a concern, with CRISPR-Cas9 systems tolerating up to three mismatches between single guide RNA (sgRNA) and genomic DNA, potentially leading to unintended mutations that could disrupt essential genes and compromise genomic integrity. Additionally, standard CRISPR library preparation methods can introduce bias through PCR amplification and cloning steps, resulting in non-uniform gRNA representation.

This technology represents a groundbreaking approach to treating Primary Open Angle Glaucoma by directly targeting the trabecular meshwork pathology with lipid nanoparticle-mediated delivery of gene editing tools or anti-sense oligos.

Innovative cell lines enabling precise genetic modifications to advance research in gene function, disease modeling, and potential therapeutic interventions.

A novel method for selectively targeting and modulating brain border-associated myeloid cells for the treatment of neurological disorders.

This technology represents a pioneering approach to vaccine development, focusing on encapsulated adjuvants and antigens to enhance efficacy while minimizing side effects.

A revolutionary one-shot therapy for juvenile and adult-onset glaucoma affected by MYOC mutations, offering a permanent cure for this previously untreatable disease.

IS110 family transposons encode a protein component (also referred to as the transposase) and a non coding RNA component (also referred to as the bridgeRNA or bRNA). In its naturally occurring context, a bRNA-bound transposase directs the integration of its cognate transposon (also referred to as the donor) into target DNA sites. The nucleic acid sequence and structure of the bRNA partially determines the sequence identify of the terminal ends of the mobilized donor, and the sequence identify of the target DNA molecule (also referred to as the target or target DNA). UC Berkeley researchers have developed a programmable gene editing technology based on IS110 family transposons that can be used for targeted insertions, deletions, excisions, inversions, replacements, and capture of DNA in vitro and in vivo. Additionally, this technology can be multiplexed to achieve complex assembles of multiple fragments of DNA.

Most tumors are extremely complex, having many oncogene drivers and are, therefore, not as amenable to a CRISPR-mediated therapies. Pediatric low-grade glioma (pLGG) is a type of brain cancer that arises during childhood. Some interventions exist, including surgery and inhibitor drugs, but there is no cure for pLGG. In contrast to most types of cancer (which feature a host of driver oncogenes), pLGG tumors tend to arise due to a single driver oncogene mutation. This aspect makes pLGG a potential target for a genome editing intervention. Because CRISPR enzymes can precisely discriminate between wild-type and mutant sequences in a single cell, enzymes such as Cas9 can target a mutant oncogene site without impacting the corresponding wild-type locus in a non-cancer cell. UC Berkeley researchers have developed a CRISPR-based strategies for anti-cancer genome editing.  The invention consists of a suite of genome editing strategies with the capacity to selectively inactivate the oncogene underlying tumor pathology, for example, mutations in pLGG. Deployed via a delivery strategy with the capacity for broad genome editing of brain cells, our strategy will have the capacity to halt – and potentially reverse – tumor growth.

A novel dendronized polypeptide architecture for efficient and safe mRNA delivery, suitable for anti-tumor immunotherapy.

SUMO inhibitors offer a promising new therapy for protecting against cardiac rhythm disturbances and pump failure associated with heart attacks.

Professor Giulia Palermo and colleagues from the University of California, Riverside and the University of Rochester have developed high-fidelity Cas13a variants with increased sensitivity for base pair mismatches.The activation of these Cas13a variants can be inhibited with a single mismatch between guide-RNA and target-RNA, a property that can be used for the detection of SNPs associated with diseases or specific genotypic sequences.  

Researchers from UC San Diego have engineered human zinc finger-containing fusion proteins that target and can destroy or modify human RNA transcripts that contain expanded G4C2 hexanucleotide repeats. This approach, which they have termed zinc fingerdirected RNA targeting, provides a means to, depending on the fusion protein, 1) target and degrade disease-causing RNA transcripts containing G4C2 expansions and to 2) target, label, and track the same transcripts in living cells.

Brief description not available

Programmable base editors are a class of genome editing effector proteins that can make precise, targeted changes to DNA base pairs in a narrow window of genomic sequence without reliance on double-stranded breaks in chromosomal DNA. Base editor proteins include a deaminase fused to a CRISPR-Cas effector protein (e.g., nCas9). Base editor proteins are challenging to produce in high yields via recombinant expression in E. coli. This has limited its clinical use to mRNA/gRNA delivery; this is in stark contrast to Cas9 nuclease, which has been used in multiple clinical trials in its protein-based RNP format. There is a need for base editor proteins that are highly active and can be produced with high yield. Such is provided by the compositions and methods described herein. UC Berkeley researchers have overcome the limitations associated with producing a CRISPR-Cas base editor by creating a CRISPR-Cas fusion protein with the deaminase fusion protein.  

Brief description not available

The invention is a self-selection DNA editing system for modifying microbial communities. It consists of a gene editing tool and a donor DNA with a bacteriocin unit. This unit is integrated into the target cell's genome, providing a survival advantage and ensuring that only the successfully modified cells proliferate. This allows for precise, targeted editing of microbial populations in various settings, including in vitro and in vivo environments.

Reseachers from UC San Diego demonstrated a proof of principle for a CAGEX RNA-targeting CRISPR–Cas13d system as a potential allele-sensitive therapeutic approach for HD, a strategy with broad implications for the treatment of other neurodegenerative disorders.

This invention provides a novel method for delivering epigenetic editor components into cells using virus-like particles (VLPs). The VLPs are designed to encapsulate the necessary genetic and protein components for targeted epigenetic editing without integrating into the host cell's genome. This non-integrating approach reduces the risk of off-target effects and potential for unintended genetic modifications, making it a safer and more precise delivery system for therapeutic and research applications. The VLPs can be engineered to target specific cell types, ensuring that the epigenetic editing components are delivered only where they are needed.

Brief description not available

Optimizing the editing efficiency of CRISPR-mediated enzymes is still needed.  This is especially true in therapeutic use cases, when it would be ideal to attain high rates of editing via a low, transient dose of the enzyme in the ribonucleoprotein (RNP) format used for multiple ex vivo clinical trials. Because many CRISPR enzymes are of bacterial origin, fusion to NLS motifs can greatly enhance editing efficiency. However, CRISPR protein yields can decrease – sometimes dramatically – if the construct bears toomany NLSs. UC Berkeley researchers have developed CRISPR proteins with enhanced editing efficiencies by introducing multiple nuclear localization signal (NLS) fused at rationally selected sites within the backbone of CRISPR-Cas9. These Cas9 variants showed they can improve editing efficiency in T cells compared to constructs with terminally-fused NLS sequences and can be produced with high purity and yield.  

Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. Theprogrammable nature of these minimal systems has facilitated their use as a versatile technology for genome editing.  CRISPR-Cas enzymes with reduced requirements for a protospacer-adjacent motif (PAM) sequence adjacent to the target site could improve the breadth of target sites available for genome editing.  UC Berkeley researchers have developed a novel PAM-loose 12a variants, nucleic acids encoding the variant Cas12a proteins and systems using these variants that make the Cas12a-based CRISPR technology much easier to design a DNA target for carrying out genome editing in human cells. 

TnpB protein has generated interest as a potential compact genome-editing tool, due to the short amino acid sequence (408 AAs for ISDra2 TnpB), which overlaps with the wRNA sequence in their genomes of origin. There is a need for compositions and methods that provide more efficient TnpB systems. UC Berkeley researchers have created variant TnpB proteins and variant wRNAs that increase cleavage activity and/or DNA binding activity (e.g., revealed as endonuclease activity such as on-target endonuclease activity). These variant TnpB proteins include an amino acid sequence having one or more amino acid substitutions relative to a corresponding wild type TnpB protein. Also provided are variant TnpB wRNAs that can form a complex with a TnpB protein and a second nucleotide sequence that can hybridize to a target sequence of a target nucleic acid, thereby guiding the complex to the target sequence.

The strategy employed by the invention is inspired by splicing factors, a category of RNA-binding protein that influence alternative splicing outcomes. These splicing factors are trans-acting, and act to enhance or silence exon inclusion by binding near or on the target exon and promoting or repressing the activity of splicing machinery. Scientifically, a highly programmable, minimally disruptive system to increase exon inclusion could allow for higher-throughput identification of functional roles of specific exons than have been previously shown.

Researchers at the University of California, Davis have developed a virally derived homolog to increase the inflammatory response desirable in cancer immunotherapy.