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Decorating Chromatin for Precise Genome Editing Using CRISPR

A novel fusion construct that fuses Cas9 to a truncated version of human PRDM9 with the purpose of improving precise genome editing via homologous direceted repair (HDR). PRDM9 is a protein that deposits histone marks H3K4me3 and H3K36me3 simultaneously during meiosis to mark recombination hot spots where crossover occurs and is resolved by homologous recombination. H3K36me3 has also been demonstrated to be required upstream of homologous recombination repair after double stranded breaks (DSBs) and during V(D)J recombination for adaptive immunity. Recent evidence suggests PRDM9 acts as a pioneer factor opening closed chromatin. The newly engineered PRDM9C-Cas9 fusion construct shows increased HDR and decreased non-homologous end joining mediated insertions and deletions (indels).

Small Cas9 Protein Inhibitor

A new protein that is able to inhibit the Cas9 protein from Streptococcus iniae (SinCas9). SinCas9 is capable of robust DNA cleavage and offers an immune orthogonal Cas9 for use in gene editing in human cells. The inhibitor is a small protein from a phage and is capable of inhibiting SinCas9 activity in vitro and in human cell genome editing experiments.

Novel Phage CRISPR-Cas Effectors and Uses Thereof

UC Berkeley researchers have discovered a novel family of proteins denoted Cas12L within the Type V CRISPR Cas superfamily distantly related to CasX, CasY and other published type V sequences.  These Cas12L proteins utilize a guide RNA to perform RNA-directed cleavage of DNA.

Single Conjugative Vector for Genome Editing by RNA-guided Transposition

The inventors have constructed conjugative plasmids for intra- and inter-species delivery and expression of RNA-guided CRISPR-Cas transposases for organism- and site-specific genome editing by targeted transposon insertion. This invention enables integration of large, customizable DNA segments (encoded within a transposon) into prokaryotic genomes at specific locations and with low rates of off-target integration.

Adenylyl Cyclase Catalytic Domain Gene Transfer for Heart Failure

Heart failure (HF) is a disease of epidemic portions in the United States affecting over 6 million patients with heart failure in the US, with 400,000 new cases per year. It is the most common cause of non-elective admission to the hospital in subjects 65 yrs and older. The introduction of new drugs over the last 30 years that target pathways critical to progression of HF, along with implantable cardiac defibrillators and resynchronization devices have shown some successes, however, both the morbidity and mortality associated with heart failure remains at unacceptable levels, with as many as 30-40% of affected individuals dying within 5 years of diagnosis. Recently, preclinical and clinical trials have tested gene transfer to increase left ventricular (LV) function, especially in heart failure with reduced ejection fraction.

Use of Gene Therapy to Treat Joint Disease and Synovial Tumors

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

Improvement To Retroviral Vectors Containing The Human Ubiquitin C Promoter

UCLA researchers in the Department of Molecular Biology have developed a lentiviral vector, “pCCLc-roUBC”, containing the cellular promoter from the human ubiquitin C gene (UBC), to improve transgene expression in retroviral vectors.

Augmentations to Lentiviral Vectors to Increase Expression

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

Optimized Lentiviral Vector for Stem Cell Gene Therapy of Hemoglobinopathies

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

Generation Of Minimal Enhancer Elements Using Massively Parallel Reporter Assays

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

Improved Cas12a Proteins for Accurate and Efficient Genome Editing

Mutated versions of Cas12a that remove its non-specific ssDNA cleavage activity without affecting site-specific double-stranded DNA cutting activity. These mutant proteins, in which a short amino acid sequence is deleted or changed, provide improved genome editing tools that will avoid potential off-target editing due to random ssDNA nicking.

A Method to Prevent the Myelin Abnormalities Associated with Arginase Deficiency

UCLA researchers in the Department of Surgery have developed a gene therapy to prevent dysmyelination (and other CNS abnormalities) as a result of arginase deficiency.

Treatment for Restoring Ureagenesis in Carbamoyl Phosphate Synthetase 1 Deficiency

UCLA researchers in the Department of Surgery have developed a gene therapy to treat carbamoyl phosphate synthetase 1 deficiency.

Method To Implement A Crispr-Cas9 Copycat Gene Drive In Rodents

Currently, alleles at multiple loci in the mouse genome must be combined by Mendelian genetics in crosses of animals to one another to produce a desired compound mutant genotype. For example, to combine homozygous mutations at two loci, animals that are heterozygous for each gene must be produced by breeding, and these are subsequently crossed to one another. Since the frequency of homozygosity for each allele is 1:4 the frequency of homozygosity for both genes is 1:16. Since the average litter of mice is approximately 10 pups, and the generation time from conception to reproductive age is about 3 months, this requires a substantial number of animals and time. With the addition of each new locus (three, four, etc), the cost measured in animals, time, and money increases exponentially. These factors increase substantially more if two or more loci are genetically linked, which requires rare recombination events to combine engineered alleles on the same chromosome. The CRISPR-Cas9 gene drive system stands to revolutionize rodent breeding. If each desired allele is encoded as a gene drive element that contains an sgRNA designed to target the same genomic location in the wild type homologous chromosome, each locus will be “driven” to homozygosity in the presence of Cas9. Therefore, in order to combine three alleles, for example, a mouse with one gene drive element (A) would be crossed to a mouse that encodes Cas9. Offspring of this cross would then be crossed to mice carrying gene drive element B, and these offspring would be crossed to mice carrying gene drive element C. In the presence of Cas9 at each generation, these gene drive elements at three distinct loci will be converted to homozygosity such that 50% of offspring, those that inherit Cas9, will be triple homozygous after three generations, even if they are genetically linked loci. A CRISPR-Cas9 mediated gene drive leverages the native cellular mechanism of homology directed repair to copy a desired allele from one chromosome to another. This process can convert a heterozygous genotype to homozygosity in a single generation. While CRISPR-Cas9 gene drives have been implemented in two species of insects, flies and mosquitos, it has not been reported in any non-insect animal species. 

Biodegradable Polymeric Vectors For Delivery Of Various RNAs

Current methods for ribonucleic acid (RNA) delivery are inefficient and toxic. UCI researchers have synthesized a new delivery system that is not only efficient and non-toxic but also allows the delivery of RNAs of multiple shapes and sizes.

Biotinylated Ligand-Directed Targeting Lentiviral Vectors

UCLA researchers in the Department of Medicine have developed a novel method to conjugate targeting ligands on lentiviral vectors.  The method allows for selective transduction of mammalian cells types avoiding non-target organs.

Transcription Factor Treatment for Schizophrenia and Bipolar Disorder

Current time to diagnosis for Schizophrenia and Bipolar Disorder is extremely lengthy (~6 months), and a delay in treatment greatly increases risk for suicidal thoughts. Once diagnosis has occurred, therapeutic options for both mental illnesses are greatly varied and have numerous side effects. To address both issues, UCI researchers have developed a novel way to diagnose and treat Schizophrenia and Bipolar Disorder by targeting specific transcription factors.

Novel CRISPR Gene Therapy for Haploinsufficiency

This technology presents a way to treat human genetic disease caused by haploinsufficiency and reduced protein production. The method employs the use of adeno-associated viral (AAV) vectors for the in vivo delivery of a CRISPR-based gene expression activator (CRISPRa) that boosts transcription from the existing functional copy of the affected gene.

Targeting Lentiviral Vectors To Specific Cells And Tissues

Researchers in the UCLA Departments of Medicine and Microbiology, Immunology and Molecular Genetics have developed retroviral vectors pseudotyped with a modified Sinbus virus envelope that exhibit reduced tropism and can be used for the targeted transduction of heterologous genes into cells.

Human-Derived Reporter Gene for Positron Emission Tomography Imaging

UCLA researchers from the Department of Microbiology, Immunology, & Molecular Genetics have developed a novel reporter gene for positron emission tomography imaging of transplanted cells.

Lateral Cavity Acoustic Transducer (LCAT) for Shear-Induced Cell Transfection

Inventors at UC Irvine have developed a new technique for inserting materials, such as genes, into cells that uses a lateral cavity acoustic transducer (LCAT).  This technology is efficient, does not result in lasting damage to cells, and the device is portable.

Ocular Therapeutics Using Stem Cell Microvesicles

Researchers in the UCLA Department of Ophthalmology have invented a method of using human embryonic stem cell microvesicles (hESMVs) to induce the regenerative capacity of several tissues, in particular, the ability to induce reconstruction of diseased retinas.

Novel Tau Aggregation Inhibitor Peptide

UCLA researchers from the Department of Chemistry and Biochemistry have developed a novel approach to inhibit the aggregation of tau proteins in the brain, which is linked to over 20 dementias including Alzheimer’s Disease and Chronic Traumatic Encephalopathy.

Method to Direct the Reciprocal Interactions Between the Ureteric Bud and the Metanephric Mesenchyme

Researchers at UCLA have developed an approach to construct an embryonic kidney in vitro for the treatment of end stage renal disease.

Gene Repair For Hemophilia A

Researchers at UCLA from the Departments of Medicine and Urology have developed a treatment for hemophilia A that utilizes non-viral gene editing technologies for ex vivo repair of the mutation in the gene F8.

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