Genetics and Gene Therapy in Hunter Disease

Abstract

Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder.

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

“…This type of MPS, also known as Hunter syndrome, results from a recessive X-linked LoF mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase (IDS; Sestito et al, 2018). Pre-clinical models of MPS II have shown success with regard to improvement of neurological symptoms using gene replacement ex vivo after transplantation of HSPCs modified to synthesize IDS via a lentivector or in vivo using intracerebral administration of an AAV-IDS vector (Gleitz et al, 2018;Sestito et al, 2018). Two phase 1/2 open-label multicenter in vivo gene replacement trials (AAV9-IDS; RGX-121) are currently recruiting patients.…”

CRISPR-Cas Systems: Prospects for Use in Medicine

“…Current successful applications of genome editing in humans include the use of TALEN in the treatment of CD19+ acute lymphoblastic leukemia in an 11-month-old infant, and ZFNs for the treatment of type II mucopolysaccharidosis (Hunter's syndrome) [83,84].…”

Structure-Function Relationship of Heart Valves in Health and Disease

“…A number of congenital enzyme deficiencies have been linked to GAG metabolic disorders (mucopolysaccharidoses) [13]. Among mucopolysaccharidoses, the Hurler [56][57][58][59] and Hunter [60][61][62] syndromes are the most widely studied. Mucopolysaccharidoses are associated with mutations in the gene encoding lysosomal hydrolases, including endoglycosidases and exoglycosidases, which are enzymes involved in GAG degradation [56,57,62].…”

“…Mucopolysaccharidoses are associated with mutations in the gene encoding lysosomal hydrolases, including endoglycosidases and exoglycosidases, which are enzymes involved in GAG degradation [56,57,62]. Absence or malfunctioning of lysosomal hydrolases lead to GAG accumulation in various tissues, including liver, spleen, bone, skin, and central nervous system [1,60,61]. Moreover, severe congenital deficiency in dermatan sulfate synthesis leads to a short stature, prematurely aged appearance, and generalized defects in the skin, joints, muscles, and bones of individuals [13].…”