Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.
Highlights
Mucopolysaccharidosis type II (MPS II), known as Hunter syndrome, is an X-linked recessive lysosomal storage disorder (LSD) caused by deficiency in iduronate-2-sulfatase (IDS) activity, an enzyme responsible for the catabolism of glycosaminoglycans (GAGs) [1, 2]
We further demonstrate that systemic administration of ETV:IDS is efficacious in rescuing MPS II–relevant neurobehavioral and skeletal abnormalities, highlighting the therapeutic potential of ETV:IDS to improve aspects of MPS II disease that are minimally affected by currently available enzyme replacement therapies (ERTs)
We have previously reported that ETV:IDS administered intravenously (IV) in Ids-KO TfRmu/hu mice reduced substrate accumulation and improved lysosomal function in the central nervous system (CNS) [11]
Summary
Mucopolysaccharidosis type II (MPS II), known as Hunter syndrome, is an X-linked recessive lysosomal storage disorder (LSD) caused by deficiency in iduronate-2-sulfatase (IDS) activity, an enzyme responsible for the catabolism of glycosaminoglycans (GAGs) [1, 2]. The resulting clinical presentation of MPS II typically includes coarse facial features, hepatosplenomegaly, joint and skeletal involvement, cardiopulmonary disease, hearing loss, and dysfunction in the central and peripheral nervous system [2, 5]. Available enzyme replacement therapies (ERTs) for MPS II have been successful at reducing the accumulation of GAGs in the periphery [8, 9]. These therapies do not adequately control many aspects of the disease, including skeletal, cardiac, and pulmonary involvement, and, most importantly, do not cross the blood-brain barrier (BBB) to effectively treat the neuronopathic manifestations of MPS II [8, 9]
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