Delivery of an Adeno-Associated Virus Vector into Cerebrospinal Fluid Attenuates Central Nervous System Disease in Mucopolysaccharidosis Type II Mice

Abstract

Mucopolysaccharidosis type II (MPS II) is a rare X-linked genetic disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), leading to impaired catabolism of ubiquitous polysaccharides and abnormal accumulation of these undegraded substrates in the lysosome. Like many lysosomal storage diseases, MPS II is characterized by both somatic and central nervous system (CNS) involvement. Intravenous enzyme replacement therapy can improve somatic manifestations of MPS II, but systemic IDS does not cross the blood-brain barrier and therefore cannot address CNS disease. In this study, an adeno-associated virus serotype 9 vector carrying the IDS gene was injected into the cerebrospinal fluid (CSF) of IDS deficient mice, a model of MPS II. Treated mice exhibited dose-dependent IDS expression and resolution of brain storage lesions, as well as improvement in long-term memory in a novel object recognition test. These findings suggest that delivery of adeno-associated virus vectors into CSF could serve as a platform for efficient, long-term enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II and many related lysosomal enzyme deficiencies.

Targeting Root Cause by Systemic scAAV9-hIDS Gene Delivery: Functional Correction and Reversal of Severe MPS II in Mice

“…The more recent demonstration of rAAV9 trans-BBB neurotropism has offered an effective solution for CNS gene delivery,21, 22 leading to successes in developing approaches for the treatment of neurological diseases, including MPS II, in animal models via systemic23, 24, 25, 26, 27, 28, 29, 30 or IT delivery 27, 31, 32, 33, 34, 35, 36, 37, 38. These studies have led to ongoing clinical trials of systemic rAAV9 gene delivery in patients with spinal muscular atrophy (SMA) (ClinicalTrials.gov: NCT02122952), MPS IIIA (ClinicalTrials.gov: NCT02716246), and MPS IIIB (ClinicalTrials.gov: NCT03315182), and IT gene delivery for giant axonal neuropathy (NCT02362438), MPS I (RGX-111, RegenxBio), and MPS II (RGX121, RegenxBio).…”

Gene therapy for Mucopolysaccharidoses

“…Hinderer et al showed that ICV administration of an AAV9 vector carrying the human IDS gene improved the CNS pathology in 2 to 3-month-old MPS II mice [88]. After vector infusion, it was shown that the enzyme activity in brain lesions increased in a dose-dependent manner.…”

Current Approaches to the Treatment of Hunter Syndrome

“…Наилучшие результаты продемонстрированы при начале лечения в неонатальном периоде [45,46]. В другом исследовании после введения в цереброспинальную жидкость больным мышам генной конструкции, созданной на базе такого вектора, как аденовирус AAV-9, были выявлены дозозависимая коррекция повреждений головного мозга и снижение содержания гликозаминогликанов во внутренних органах [47]. Мышей в этом исследовании лечили по достижении возраста 2-3 мес, когда клиническая картина заболевания уже была развернутой.…”