Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase ( MMUT ) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb , we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
Rice planthoppers are the most widespread and destructive pest of rice. Planthopper control depends greatly on the understanding of molecular players involved in resistance to planthoppers. This paper summarizes the recent progress in the understanding of some molecular players involved in resistance to planthoppers and the mechanisms involved. Recent researches showed that host‐plant resistance is the most promising sustainable approach for controlling planthoppers. Planthopper‐resistant varieties with a host‐plant resistance gene have been released for rice products. Integrated planthopper management is a proposed strategy to prolong the durability of host‐plant resistance. Bacillus spp. and their gene products or insect pathogenic fungi have great potential for application in the biological control of planthoppers. Enhancement of the activity of the natural enemies of planthoppers would be more cost‐effective and environmentally friendly. Various molecular processes regulate rice–planthopper interactions. Rice encounters planthopper attacks via transcription factors, secondary metabolites, and signaling networks in which phytohormones have central roles. Maintenance of cell wall integrity and lignification act as physical barriers. Indirect defenses of rice are regulated via chemical elicitors, honeydew‐associated elicitor, amendment with silicon and biochar, and salivary protein of BPH as elicitor or effector. Further research directions on planthopper control and rice defense against planthoppers are also put forward. © 2019 Society of Chemical Industry
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