Prevention of Neurocognitive Deficiency in Mucopolysaccharidosis Type II Mice by Central Nervous System–Directed, AAV9-Mediated Iduronate Sulfatase Gene Transfer

Laoharawee, Kanut; Podetz-Pedersen, Kelly M.; Nguyen, Tam T. T. N.; Evenstar, Laura B; Kitto, Kelley F.; Nan, Zhenhong; Fairbanks, Carolyn A.; Low, Walter C.; Kozarsky, Karen; McIvor, R. Scott

doi:10.1089/hum.2016.184

Cited by 42 publications

(53 citation statements)

References 37 publications

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“…An AAV9 viral vector carrying the IDS gene has been administered to CSF through intracisternal injections in MPS II mice producing, 4 months after treatment, a significant increase in IDS activity throughout the encephalon with a reversal of CNS pathology [166]. The same results were obtained by two subsequent studies [167,168], using a similar strategy, but via intracerebroventricular injections. Laoharawee et al observed supraphysiological levels of IDS in the circulation (160-fold higher than wild-type) for at least 28 weeks post-injection and in most peripheral organs (up to 270-fold) at 10 months post-injection, but only low levels (7% to 40% of wild-type) in all areas of the brain.…”

Section: Adeno-associated Viral Vectorsmentioning

confidence: 62%

“…Laoharawee et al observed supraphysiological levels of IDS in the circulation (160-fold higher than wild-type) for at least 28 weeks post-injection and in most peripheral organs (up to 270-fold) at 10 months post-injection, but only low levels (7% to 40% of wild-type) in all areas of the brain. Nevertheless, this was enough to prevent brain pathology and neurocognitive impairment [168].…”

Section: Adeno-associated Viral Vectorsmentioning

confidence: 99%

“…This treatment reduced GAG storage, and DS and HS levels in visceral organs and the brain. The treatment also prevented the neurocognitive deficits observed in untreated mice [168]. These positive results led to the development of a phase I/II clinical trial, with the first patient being treated with in vivo gene editing therapy (ClinicalTrials.gov identifier: NCT03041324) [175].…”

Section: Genome Editingmentioning

confidence: 99%

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Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

D’Avanzo

Rigon

Zanetti

et al. 2020

IJMS

145

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Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment.

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Section: Adeno-associated Viral Vectorsmentioning

confidence: 62%

Section: Adeno-associated Viral Vectorsmentioning

confidence: 99%

Section: Genome Editingmentioning

confidence: 99%

See 1 more Smart Citation

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

D’Avanzo

Rigon

Zanetti

et al. 2020

IJMS

145

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“…In clinics, only the intrathecal delivery of IDS has been investigated [9], while several therapeutic approaches have been tested in the mouse model. These preclinical evaluations include: high systemic dosage of ERT [10], direct administration of IDS to the brain compartment by intracerebroventricular or intrathecal injections [11,12,13], gene therapy mediated by adeno-associated or lentiviral vectors encoding human IDS [14,15,16], substrate reduction therapy [17], and conjugation with brain-targeting ligands [18,19]. In many of these studies, various limitations related to safety or efficacy aspects have been highlighted, while some of them have shown to be more promising and deserving of a deeper analysis.…”

Section: Introductionmentioning

confidence: 99%

Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles

Rigon

Salvalaio

Pederzoli

et al. 2019

IJMS

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Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.

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“…GAG accumulation in the liver was also reduced, providing further evidence that gene therapy applied directly to the nervous system can cross-correct deficiencies in somatic tissues. Laoharawee et al also evaluated the effectiveness of AAV9 encoding human IDS after intracerebroventricular injection in a MPS II mouse model [89]. Low level of IDS activity in CNS lesions (7–40% of wild-type) was observed; however, GAG accumulation was reduced in brain, and neurologic deficits were improved in treated mice.…”

Section: Pre-clinical Study Of Gene Therapy For Mpsmentioning

confidence: 99%

Gene therapy for Mucopolysaccharidoses

Sawamoto

Chen

Alméciga-Díaz

et al. 2018

Molecular Genetics and Metabolism

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Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency. Preclinical studies of gene therapy for MPS have been developed over the past three decades. Currently, clinical trials of gene therapy for some types of MPS are ongoing in the United States, some European countries, and Australia. Here, in this review, we summarize the development of gene therapy for MPS in preclinical and clinical trials.

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Prevention of Neurocognitive Deficiency in Mucopolysaccharidosis Type II Mice by Central Nervous System–Directed, AAV9-Mediated Iduronate Sulfatase Gene Transfer

Cited by 42 publications

References 37 publications

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles

Gene therapy for Mucopolysaccharidoses

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