Engineering probiotics for treating phenylketonuria

Abstract

The invention discloses engineering probiotics for treating phenylketonuria and a preparation method of the engineering probiotics, the engineering probiotics are Escherichia coli Nissel 1917 derivative bacteria, and an exogenous Lphenylalanine ammonia lyase gene, an Lphenylalanine transport protein gene and an Lamino acid deaminase gene are integrated on a genome. The engineering probiotics disclosed by the invention can be used for preparing phenylketonuria treatment medicines.

Description

technical field [0001] The invention belongs to the field of genetic engineering and medicine, and in particular relates to an engineering probiotic for treating phenylketonuria, a preparation method thereof and an application thereof in preparing a medicine for treating phenylketonuria. Background technique [0002] Phenylketonuria (PKU) is a congenital disorder of phenylalanine metabolism. In China, the incidence of PKU in newborns is about 1 / 11000. If a child with PKU is not diagnosed and treated in time, hyperphenylpropionic acidemia will occur, which will seriously affect the intellectual development of the child and cause epilepsy and movement disorders. Symptoms, accompanied by disorders of melanin synthesis. [0003] Phenylketonuria is caused by liver phenylalanine hydroxylase (phenylalanine hydroxylase, PAH) deficiency or mutations in tetrahydrobiopterin synthase and dihydrobiopterin reductase. PAH is mainly expressed in the liver and can convert phenylalanine int...

AI Technical Summary

Problems solved by technology

PAH mutations lead to metabolic disorders of phenylalanine in the liver and cannot be converted into tyrosine. Instead, phenylalanine and α-ketoglutarate accumulate in blood and tissues and are excreted into urine. , the accumulation of its metabolites in the central nervous system will produce toxicity, which will induce excitement, restlessness, hyperactivity and mental abnormalities in children.

[0004] As one of the essential amino acids, phenylalanine is mainly obtained from food. Children with PKU cannot completely avoid phenylalanine intake. Therefore, the only treatment for children with PKU is to adopt a low-phenylalanine diet. Food restriction strategy, but this strategy has great side effects on the development of adolescents and pregnant women, and because of the poor taste of this type of food, the patient's compliance is poor

In addition, there are currently some strategies for the treatment of PKU that are still in the experimental stage, for example, through in vitro recombinant expression of phenylalanine ammonia-lase (stlA), which has the ability to degrade phenylalanine, and through oral administration of protein to reduce blood Medium phenylalanine, but the disadvantage is that direct oral protein is easily decomposed by digestive enzymes in the intestine

Scientists are also trying gene therapy, placing recombinant adenovirus carrying cDNA expressing PAH gene into mice to restore PAH activity in the liver, but currently there are mainly problems of low transport efficiency and short-term curative effect

[0005] At present, the most widely used animal models of phenylketonuria in the world are mainly the Pah enu1 and Pah enu2 Two disease models. Although these two disease models can simulate the disease phenotype of phenylketonuria, the mutants of these two animal models cannot represent the vast majority of patients, so they are not clinically representative

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