녹아웃(KO) 마우스 | Cyagen Korea

In recent years, gene therapy has offered many patients the hope of recovery, or even a cure. It has shown strong application potential in the fields of rare diseases, ophthalmic diseases, metabolic diseases, cardiovascular diseases and neurological diseases. One of the main reasons for the vigorous development of gene therapy is the increasingly mature application of Adeno-Associated Virus (AAV) vector technology in the field . Read on for a detailed  introduction to the application of AAV-mediated gene therapy in metabolic diseases.

The application of recombinant Adeno-Associated Virus (rAAV) drugs in clinical trials of metabolic diseases around the world is mainly concentrated among the following indications, also listed in Table 1. In addition to research institutes, there are also many companies doing product research and development in this area (Table 1).






Phenylketonuria (PKU)








BMN 307




PTC Therapeutics



Homology Medicines




Pompe Disease









Mucopolysaccharidosis II (MPS II)




Mucopolysaccharidosis I (MPS I)




Wilson's disease




Crigler-Najjar syndrome









Ornithine transcarbamylase (OTC) deficiency


DTX 301


Fabry disease





4D Molecular





 Phenylketonuria (PKU)

Phenylketonuria (commonly known as PKU) is an autosomal recessive disorder that increases the levels of a substance called phenylalanine in the blood. The main symptom of PKU is abnormal metabolism of amino acids, relatively common in hereditary metabolic diseases, which is specifically caused by a defect of the gene Phenylalanine Hydroxylase (PHA). The PHA gene defect prevents phenylalanine from being converted to tyrosine, thus, phenylalanine and its keto acids accumulate and are excreted in the urine, resulting in a pungent odor. In newborns, the accumulation of phenylalanine in the blood can damage the brain and cause neurodevelopmental delays.

At present, many companies and research institutes around the world are trying to use rAAV vectors to intervene in pathogenic genes to treat the disease. Among them, Biomarin, a listed company in the United States, is in a leading position to address PKU with such a gene therapy approach. The BMN 307 AAV-mediated gene therapy drug for the treatment of phenylketonuria is currently in Phase I/II clinical trials.

Glycogen Storage Disease (GSD)

Glycogen storage disease (GSD) is a congenital hereditary disease caused by an enzyme defect in glycogen metabolism, characterized by excessive deposition of glycogen in various organs and tissues of the body, mainly affecting the liver and muscle, GSD Type I is caused by a defect in the glucose-6-phosphatase (G6Pase) system. GSD Type Ia is caused by a mutation in the G6PC gene encoding glucose-6-phosphatase. GSD Type Ib is also known as glucose-6-phosphate transfer defect, caused by mutations in the SLC37A4 gene and encoded transport enzyme. GSD Type II, commonly known as Pompe disease, is caused by mutations in the Acid α-glucosidase (GAA) gene.

Among metabolic diseases, the number of rAAV-mediated clinical trials for glycogen storage diseases is the largest. There are ten clinical trials for glycogen storage diseases in the world, which are due to its clear pathogenic genes and high mortality and disability rate.

Mucopolysaccharidoses (MPS)

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the body. There are 7 types of MPS, of which MPS II (i.e. Hunter syndrome) is common and accounts for more than half of the patients. MPS II symptoms include recurrent otitis media, hepatosplenomegaly, and mental retardation.

Mucopolysaccharidosis type II (MPS II)

MPS II is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulfatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. 

There are nine clinical trials of rAAV-mediated gene therapy for MPS in the world, this number is second only to GSD.

Wilson's Disease

Wilson's disease, also known as hepatolenticular degeneration and progressive lenticular degeneration, is an autosomal recessive genetic disorder. Mutations of a gene called ATP7B causes Wilson disease; these gene mutations prevent the body from removing extra copper. The main symptoms are liver cirrhosis and brain degeneration dominated by basal ganglia damage.

Globally, there are currently three clinical trials using rAAV for the treatment of Wilson’s disease. On August 12, 2021, Vivet Therapeutics and Pfizer Inc announced the U.S. Food and Drug Administration (FDA) granted Fast Track designation to VTX-801, Vivet’s clinical-stage gene therapy for the treatment of Wilson Disease. VTX-801 will determine the safety, tolerability, and pharmacological activity of a single intravenous infusion in adult patients with Wilson Disease.  


Crigler-Najjar Syndrome

Crigler-Najjar syndrome is a rare autosomal recessive inherited disorder characterized by the absence or decreased activity of UDP-glucuronosyltransferase, an enzyme required for glucuronidation of unconjugated bilirubin in the liver. The unconjugated bilirubin collects in the child’s liver and spleen, enters circulation, and then builds up in other tissues such as the eyes and skin. This buildup causes jaundice and eventually nerve and brain damage.

Currently, there are two clinical trials for Krigler-Najjar syndrome, GNT-0003 from Généthon and AT342 from Audentes.

Ornithine Transcarbamylase (OTC) Deficiency

Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the breakdown and removal of nitrogen the body, in a process known as the urea cycle. The mutation of ornithine transcarbamylase gene causes the enzyme activity to decrease or disappear altogether, blocking the generation of citrulline from ornithine and carbamoyl phosphate, and ultimately resulting in abnormal ammonia concentration in the blood. The mortality rate is high in children, with symptoms including mental illness and liver damage.

Currently, there are four clinical trials worldwide investigating the use of rAAV to treat ornithine transcarbamylase (OTC) deficiency.

Fabry disease

Fabry disease, also known as Anderson-Fabry syndrome, is a rare X-linked recessive genetic disorder. The cause of Fabry disease is a mutation in the GLA gene, which causes alpha-galactosidase A (alpha-GalA) deficiency. Partial or complete loss of the activity of α-GalA will lead to the cascaded accumulation of globotriaosylceramide (GL-3 or Gb3), the metabolic substrates of this enzyme, and related glycosphingolipids in various organs and tissues of the human body, thereby causing a series of organ diseases.

Currently, there are five clinical trials using rAAV for the treatment of Fabry disease worldwide. Sangamo Therapeutics, a US-listed company, has a clinical trial for the disease in Phase I/II clinical trials.


There are numerous other metabolic genetic diseases that are undergoing clinical trials using rAAV-mediated gene therapy, including Sanfilippo B syndrome, a lethal disorder caused by the deletion of a protein called NaGlu in children. uniQure's clinical trial for the disease has successfully entered Phase III.

Furthermore, since most native AAVs have a high affinity for the liver, rAAVs provide a powerful liver-targeting platform that offers the potential for the treatment of various diseases. Hereditary hemochromatosis (HH) is a common inherited disorder of iron overload syndromes that are characterized by the accumulation of iron in various organs of the body such as the liver, heart and pancreas. It has been reported that after intravenous injection, the vector rAAV5 or rAAV8 carrying the target gene FIX can enter the liver through the portal vein to play an effective role in the treatment of Hereditary hemochromatosis (HH) B.

It is clear that gene therapy using rAAV virus as a delivery system has multiple advantages and exerts a curative effect in metabolic diseases. It is believed that there will be additional gene therapy products approved for the market in the near future, with more every year to come as the technology is established.



1. Junge N, Mingozzi F, Ott M, Baumann U. Adeno-associated virus vector-based gene therapy for monogenetic metabolic diseases of the liver. J Pediatr Gastroenterol Nutr. 2015 Apr;60(4):433-40. doi: 10.1097/MPG.0000000000000703. PMID: 25594875.

2. Grisch-Chan HM, Schwank G, Harding CO, Thöny B. State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Hum Gene Ther. 2019 Oct;30(10):1274-1283. doi: 10.1089/hum.2019.111. Epub 2019 Sep 9. PMID: 31364419; PMCID: PMC6763965.

3. Kattenhorn LM, Tipper CH, Stoica L, Geraghty DS, Wright TL, Clark KR, Wadsworth SC. Adeno-Associated Virus Gene Therapy for Liver Disease. Hum Gene Ther. 2016 Dec;27(12):947-961. doi: 10.1089/hum.2016.160. PMID: 27897038; PMCID: PMC5177998.


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