CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1(-/-) mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites

CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1(-/-) mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites

Dietary Oil Source and Selenium Supplementation Modulate Fads2 and Elovl5 Transcriptional Levels in Liver and Brain of Meagre (Argyrosomus regius)

The meagre (Argyrosomus regius) is taking on increasing importance in the aquaculture industry. In view of the limited supply of fish oil (FO) as a feed ingredient, the study of the capacity to biosynthesize long-chain polyunsaturated fatty acids (LC-PUFA) from alternative dietary oil sources is important. We analyzed changes in fatty acid (FA) desaturase 2 (fads2) and FA elongase 5 (elovl5) mRNA levels in livers and brains in response to FO replacement with a blend of vegetable oils (VO) and selenium (Se) supplementation. Fish were fed for 60 days with either a diet containing FO or a diet including VO, each supplemented or not with organic Se. Results showed that fads2 and elovl5 transcription was higher in liver when fish were fed VO diets. The brain mRNA levels of both genes were not affected by the dietary replacement of FO by VO. FA composition in the liver and skeletal muscle was altered by FO replacement, particularly by decreasing eicosapentaenoic acid and docosahexaenoic acid contents. The α-linolenic, linoleic, and arachidonic acid contents increased in both liver and brain of fish fed VO diets. The effect of Se supplementation on lipid metabolism was evident only in fish fed FO, showing a decrease in the transcription of hepatic fads2. Results indicate that the total replacement of FO by VO in diets modulates the expression of genes involved in LC-PUFA biosynthesis in meagre, affecting the FA profile of the fish flesh.Fil: Silva Brito, Francisca. Universidad de Porto; PortugalFil: Magnoni, Leonardo Julián. Universidad de Porto; Portugal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Fonseca, Sthelio Braga. Universidade Federal da Paraíba; Brasil. Universidade Federal de Campina Grande; BrasilFil: Peixoto, Maria João. Universidad de Porto; PortugalFil: Castro, L. Filipe C.. Universidad de Porto; PortugalFil: Cunha, Isabel. Universidad de Porto; PortugalFil: de Almeida Ozório, Rodrigo Otávio. Universidad de Porto; PortugalFil: Magalhães, Fernando Antunes. Universidad de Porto; PortugalFil: Magalhães Gonçalves, José Fernando. Universidad de Porto; Portuga

Genome-wide association study in essential tremor identifies three new loci

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor

Genome-wide association study in essential tremor identifies three new loci

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor