Researchers at the University of California, Davis have developed a modular CRISPR activation platform that enables precise upregulation of the haploinsufficient gene FOXG1 to address neurodevelopmental disorders without DNA cleavage.

The aim of this work is to target the production of age-specific production of hyperactive platelets as a therapeutic platform to control clot formation that causes thrombosis, stroke, heart attacks, and other cardiovascular disease, as well as platelet overproduction disorders such as essential thrombocytosis. In particular, this effort specifically targets cells that have progressed down an age-specific differentiation pathway. These age specific platelets are hyperactive relative to platelets from younger progenitor cells. These older platelet progenitor cells have been characterized molecularly and functionally characterization and can be targeted using pharmacological, antibody-based, cell based or gene therapy based strategies to control clot formation and platelet activity and numbers.

RNA-guided systems mediate diverse functions ranging from mobile genetic element propagation to adaptive immunity. These systems comprise proteins that use guide RNAs bearing sequence complementarity to nucleic acid substrates, facilitating programmable recognition of different substrates by the same protein or enzyme. In RNA-guided systems known to date, one or two continuous segments in the guideRNA determines target specificity and can be altered to direct the system to a new target, including genomic DNA in eukaryotic cells. However, there are constraints to such systems, e.g., protein size and the need for a protospacer adjacent motif (PAM) in target DNA. However, there is a need for nucleic acid guided systems that overcome constraints of known systems, such as protein size or protospacer adjacent motif.UC Berkeley researchers have developed a programmable RNA-guided nucleic acid targeting platform termed the Viral Interference Programmable Repeat (VIPR) system. The system employs a repeat-based guide RNA architecture and an associated targeting protein to direct sequence-specific recognition of nucleic acid substrates. Target specificity is programmable through modification of selected guide regions, enabling adaptable targeting of DNA or RNA substrates across different biological contexts, including cellular and viral genetic material.

The central hurdle in the clinical translation of mRNA-based medicine is the inherent toxicity of the delivery vehicle. Standard Lipid Nanoparticles (LNPs) rely on cationic ionizable lipids that carry a positive charge at a pH of approximately 7.4, triggering aggressive pro-inflammatory responses and complement activation.  UC Berkeley researchers have developed a novel class of lipids engineered to resolve the "charge-toxicity" trade-off in nucleic acid delivery. Unlike conventional ionizable lipids that maintain a problematic positive charge density at physiological levels, these quaternized ionizable lipids are specifically tuned to remain neutral or negatively charged at a pH of approximately 7.4. They only transition to a positively charged state in acidic environments, such as the endosome, ensuring that the payload is released exactly where it is needed without alerting the immune system during systemic circulation. 

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A highly precise and efficient gene-editing tool designed to correct single-nucleotide DNA mutations responsible for genetic diseases.

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When a delivered plasmid lacks exclusion genes during bacterial conjugation is a phenomenon known as lethal zygosis. The effect of this lethal zygosis is a severe bottleneck for genetic engineering. UC researchers have developed materials and methods that improve bacterial conjugation.  This replication incompetent vectors that include a nucleic acid sequence that can encode an exclusion polypeptide in a donor bacterial cell can protect a recipient bacterial cell from lethal zygosis.

Researchers at the University of California, Davis have developed a technology that introduces an approach to creating semi-living, non-replicating cellular systems for advanced therapeutic applications.

Progressive Multifocal Leukoencephalopathy (PML) is a devastating and often fatal demyelinating disease of the central nervous system caused by the reactivation of the JC virus (JCV). In immunocompromised patients, the absence of effective T cell surveillance allows the virus to infect and lyse oligodendrocytes, leading to irreversible neurological damage. UC Berkeley researchers have developed a method for discovering and engineering antigen-specific T cell receptors (TCRs) that specifically target JCV.

Researchers at the University of California, Davis have developed novel antisense oligonucleotide (ASO) therapies that enhance ADNP protein expression to address haploinsufficiency in ADNP syndrome.

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.

Parkinson’s disease and related synucleinopathies currently lack disease-modifying cures, as existing treatments only manage symptoms associated with alpha-synuclein (aSyn) aggregation. To address this, UC Berkeley researchers have developed a suite of non-viral, CRISPR-mediated strategies designed for the permanent downregulation of the endogenous SNCA gene and the LRRK2 risk allele. By utilizing precise base editing of regulatory regions, genomic excision of non-coding sequences, and splicing modulation, this platform provides a durable, single-administration alternative to transient RNA-targeting therapies. The invention further enables allele-selective knockout of the LRRK2 G2019S mutation, employing a specialized CRISPR-Cas9 variant to discriminate between mutant and wild-type genes, thereby offering a highly specific and permanent therapeutic intervention for neurodegenerative disorders.

Achieving precise and tunable control over endogenous gene expression in eukaryotic cells remains a significant challenge, particularly for therapeutic applications or detailed biological studies where fine-tuning is required rather than complete on/off switching. This innovation, developed by UC Berkeley researchers, addresses this by providing a novel, programmable method for transcriptional tuning. The innovation is a two-domain fusion protein comprising the transcriptional repression domain (TRD) of the methyl-CpG-binding domain (MBD) protein MeCP2 linked to a dead Cas9 (dCas9) domain. When combined with a single guide RNA (sgRNA) that targets a specific endogenous gene, this fusion protein partially inhibits, or "tunes," the expression of that gene. Unlike traditional methods like RNAi or full CRISPR interference (CRISPRi), which often aim for complete knockdown, this system offers a highly specific and titratable way to dial down gene expression, providing a distinct advantage in studies requiring subtle modulation of gene dosage or for developing dose-dependent therapeutic strategies.

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.

Tissue targeting and cargo packaging limitations are two of the most challenging barriers to in-vivo therapeutic delivery. Overcoming both of these issues, UC Berkeley researchers have developed engineered immune cells that produce enveloped delivery vehicles (EDVs) capable of encapsulating protein and/or RNA therapeutics that can be delivered to a target cell with a predetermined trigger. Triggers can either be the presence of a small molecule, or recognition of a specific antigen on the target cell. The researchers showed that delivery can be achieved in a co-cultured system using various strategies and that the system is compatible with multiple cargo proteins of interest including Cre recombinase and RNA-complexed Cas proteins. This technology opens possibilities for broader and safer in-vivo therapeutic delivery.

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