Aberrant splicing contributes to the etiology of many inherited diseases. Pathogenic variants impact pre-mRNA splicing through a variety of mechanisms. Most notably, variants remodel the cis-regulatory landscape of pre-mRNAs by ablation or creation of splice sites, and auxiliary splicing regulatory sequences such as exonic or intronic splicing enhancers (ESE and ISE, respectively) and splicing silencers (ESS and ISS, respectively). Splicing-sensitive variants cripple the integrity of the gene, resulting in the production of a faulty message that is either unstable or encodes an internally deleted protein. Antisense oligonucleotides (ASOs) are a promising therapeutic modality for rescuing pathogenic aberrant splicing patterns as their direct base pairing abilities make them highly customizable and specific to targets. Although challenges such as toxicity, delivery and stability represent barriers to the clinical translation of ASOs, solutions to these challenges exist, as exemplified by the recent FDA approval of multiple ASO drugs.Generally, ASO's that target splicing mutations are limited to mutations in and around splicing enhancers and exonic mutations are commonly not targeted because of the idea that the mutation causes a significant change in protein function. 

Manganese (Mn) is an essential metal that must be maintained at levels within a narrow physiological range in cells and organisms to avoid deficiency or toxicity. Humans can be exposed to elevated manganese levels from occupational sources (e.g., welding) or environmental sources (e.g., drinking water). Elevated manganese levels cause manganese to accumulate in the brain, inducing neurotoxicity that can manifest as parkinsonism. Thus, manganese toxicity is a public health concern and developing ways to treat it is crucial. Based on elucidative manganese homeostasis studies, a UC Santa Cruz researcher, in collaboration with researchers at University of Texas at Austin, has developed methods for treating manganese toxicity.

Researchers at the University of California, Davis have developed a method of treating or mitigating seizure, treating epilepsy, as well as a method of reducing the frequency of seizures, using cannabigerol or dihydrocannabigerol and analogs thereof.

Researchers at the University of California, Davis have developed a targeted epigenetic approach for the prevention and treatment CDKL5 deficiency disorder.

The CRY1:CLOCK:BMAL1 sits at the core of the integrated transcription-translation feedback loop that regulates the expression of proteins that are dependent upon circadian rhythms. Disruption of circadian rhythms has been linked to altered cell homeostasis and diseases. 

The inventors have developed a genome editing therapy for bone marrow failure (BMF) in people living with dyskeratosis (DC). This technology includes two novel endogenous, isogenic models to study TINF2-DC mutations.Human embryonic stem cells (hESCs) engineered to carry the TIN2-DC T284R mutation recapitulated the short telomere phenotype observed in DC patients. Yet, telomeres in TINF2-DC hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. The inventors also established in vitro and in vivo human hematopoietic stem cell (hHSC) models to assess the changes in telomere length and proliferative capacity upon the introduction of TERT and TINF2 editing. In addition, the inventors demonstrated that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSCs. These experiments nominate TINF2 as a target for: CRISPR/CAS9 to elongate telomeres in patient with TINF2 mutations,CRISPR/CAS9 to elongate telomeres with other mutations causing TBD, and chemical interventions to elongate telomeres in general.BACKGROUNDBMF is a major cause of morbidity and mortality in DC and other telomere biology disorders (TBDs). Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for bone marrow failure.   

Resent strategies aimed to target and manipulate RNA in living cells mainly rely on the use of antisense oligonucleotides (ASO) or engineered RNA binding proteins (RBP). Although ASO therapies have been shown great promise in eliminating pathogenic transcripts or modulating RBP binding, they are synthetic in construction and thus cannot be encoded within DNA. This complicates potential gene therapy strategies, which would rely on regular administration of ASOs throughout the lifetime of the patient. Furthermore, they are incapable of modulating the genetic sequence of RNA. Although engineered RBPs such as PUF proteins can be designed to recognize target transcripts and fused to RNA modifying effectors to allow for specific recognition and manipulation, these constructs require extensive protein engineering for each target and may prove to be laborious and costly. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

Present strategies aimed to target and manipulate RNA in living cells mainly rely on the use of antisense oligonucleotides (ASO) or engineered RNA binding proteins (RBP). Although ASO therapies have been shown great promise in eliminating pathogenic transcripts or modulating RBP binding, they are synthetic in construction and thus cannot be encoded within DNA. This complicates potential gene therapy strategies, which would rely on regular administration of ASOs throughout the lifetime of the patient. Furthermore, they are incapable of modulating the genetic sequence of RNA. Although engineered RBPs such as PUF proteins can be designed to recognize target transcripts and fused to RNA modifying effectors to allow for specific recognition and manipulation, these constructs require extensive protein engineering for each target and may prove to be laborious and costly. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

Miller–Dieker syndrome (MDS), or 17p13.3 deletion syndrome results in human neuronal migration disorders characterized by type 1 lissencephaly sequence (ILS), severe mental retardation and reduced life expectancy. The understanding of these syndromes is often incomplete and is the subject of active research. Researchers have demonstrated that the gene encoding 14-3-3ε (YWHAE), one of a family of ubiquitous phosphoserine/threonine–binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1.  Gene specific transcriptional activation or repression is regulated by a complex network of transcription factors designated the Myc/Max/Mad network. MNT (max binding protein) binds DNA and a heterodimer with MAX and represses transcription and acts as an antagonist of Myc-dependent transcriptional activation and cell growth. Described below are two mice strains that may be useful in studies of Miller-Dieker Lissencephaly Syndrome generated by the same researcher.

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.

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.

The neuronal ceroid lipofuscinoses (NCLs), commonly grouped together as Batten disease, are the most common neurodegenerative lysosomal storage diseases of the pediatric population. No cure for NCL has yet been realized. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives disease progression is unknown, several small molecules have been identified with diverse mechanisms of action that provide promise for the treatment of this devastating disease. On this point, several researchers have reported the use of potential drugs for NCL patient lymphoblasts and fibroblasts, along with neurons derived from animal models of NCL disease. Unfortunately, most of these studies were inconclusive or clinical trials or follow-up results were not available. High concentrations employed and toxicity of the small molecules are clear disadvantages to the use of some of the corresponding derivatives as potential drugs. To circumvent these effects, development of nontoxic alkyl cysteines would be useful for the non-enzymatic and chemo-selective depalmitoylation of S-palmitoyl proteins, which hold good promise as an effective treatment for neuronal ceroid lipofuscinoses.

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.

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.

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

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.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with prenatal and early postnatal biological onset. Genetic factors contribute to the predisposition and development of ASD with estimated heritability rates of 50-83%. Large-scale genetic studies have implicated several hundred risk (rASD) genes that appear to be associated with many different pathways, cell processes, and neurodevelopmental stages. This highly heterogeneous genetic landscape has raised challenges in elucidating the biological mechanisms involved in the disorder. While rigorous proof remains lacking, current evidence suggests that rASD genes fall into networks and biological processes that modulate one or more critical stages of prenatal and early postnatal brain development, including neuronal proliferation, migration, neurite growth, synapse formation and function. However, these insights are mostly gained from focused studies on single rASD genes or based on transcriptome data of non-ASD brains, leaving an incomplete picture of rASD-induced molecular changes at the individual level and relationships with early-age clinical heterogeneity.

UCLA researchers from the Department of Chemistry and Biochemistry have developed a novel process to inhibit amyloid aggregation of Transthyretin, which is associated with three debilitating disorders including senile systemic amyloidosis (SSA), Familial Amyloidotic Polyneuropathies (FAP), and Familial Amyloidotic Cardiomyopathies (FAC).

UCLA researchers in the Departments of Neurology and Molecular Therapy & Medical Genetics have developed a novel approach toward broad inhibition of lipofuscin aggregation.

In general, the risk of having a child with autism spectrum disorder (ASD) is about 1 in 68, or 1.5%. But the risk goes up for families who already have a child with ASD. If a family has one child with ASD, the chance of the next child having ASD is about 20%. If the next child is a boy, the risk is 26%, whereas if it’s a girl the risk is 10%. About 47% of families had more than one child with autism. Currently if a child has a birth defect or autism, the emerging trend is to perform whole exome sequencing to identify genetic mutations. These mutations overwhelmingly come from the father, because sperm cells but not egg cells continue to divide through the life of adults. Once the mutation is identified, the diagnosis can be made in the child, but the parents are left wondering if this genetic event could recur in future children. Currently there is no genetic assessment of sperm available commercially, and no publications on the application of using sperm as a way to assess risk of childhood disease, nor is there a risk assessment available for couples that have had a child with a genetic disease due to de novo genetic mutation.

UCLA researchers have designed, synthesized, and validated a polyrotaxane nanocarrier for targeted delivery of large plasmids for gene therapy applications for treatment of Duchenne muscular dystrophy and cancer.

UCLA researchers in the Departments of Pediatrics and Chemistry & Biochemistry have developed a microfluidic device for delivery of biomolecules into living cells using mechanical deformation, without the fouling issues in current systems.

UCLA researchers in the Departments of Medicine and Cardiology have identified a novel gene and pathway in the regulation of insulin sensitivity and discovered an inhibitor of this gene useful for treating AGPAT5-related diseases.

The Mikkola group at UCLA has discovered a novel regulator of hematopoietic stem cell self-renewal. The overexpression of this regulator increases the yield of ex vivo stem cell expansion and could thereby improve the efficiency of stem cell therapies. 

Researchers at the University of California, Davis have developed a treatment for mitochondrial disease through a repurposing approach whereby a library of FDA-approved drugs was screened for previously unknown therapeutic effectiveness in these diseases.