Intrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type I

Nestrašil, Igor; Shapiro, Elsa; Svátková, Alena; Dickson, Patricia I.; Chen, Agnes; Wakumoto, Amy; Ahmed, Alia; Stehel, Edward; McNeil, Sarah S.; Gravance, Curtis; Maher, Elizabeth A.

doi:10.1002/ajmg.a.38073

Cited by 28 publications

(18 citation statements)

References 15 publications

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“…Another study assessed the impact of intrathecal laronidase for cognitive decline in a 23 year old male with MPS IHS [99]. The patient received monthly doses for 3 months, and then doses every 3 months for 24 months.…”

Section: Intrathecal Enzyme Replacement Therapymentioning

confidence: 99%

Mucopolysaccharidosis Type I

et al. 2020

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Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.

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Section: Intrathecal Enzyme Replacement Therapymentioning

confidence: 99%

Mucopolysaccharidosis Type I

et al. 2020

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“…Children affected with severe forms succumb to the disease by 10 years of age [9]. These patients experience multisystem dysfunction including progressive cognitive impairment, morphological brain abnormalities, skeletal deterioration, cardiopulmonary disease, hepatosplenomegaly, and sensory deficits in hearing and vision [7,10,11]. Individuals affected with attenuated forms experience similar multi-organ dysfunction; however, clinical signs are often varied and less severe, with most children surviving into adulthood.…”

Section: Introductionmentioning

confidence: 99%

“…In the dog model of MPS I, IT administration has been shown to reduce GAG levels in cerebral spinal fluid (CSF) [23] and reduce brain pathology [24]. IT therapy in humans is still undergoing clinical trials, though safety and efficacy have been reported [10,25]. A case report of an MPS I human patient treated with IT rhIDUA for spinal cord compression resulted in normal CSF GAG levels, improved stability and gait when walking, and improved ventilation [25].…”

Section: Introductionmentioning

confidence: 99%

“…A case report of an MPS I human patient treated with IT rhIDUA for spinal cord compression resulted in normal CSF GAG levels, improved stability and gait when walking, and improved ventilation [25]. A second case study of an MPS I attenuated patient treated with IT rhIDUA resulted in increased white matter, increased corpus callosum volume, and improved cognition, particularly memory [10]. Such positive benefits associated with the CNS would not be possible with IV therapy alone.…”

Section: Introductionmentioning

confidence: 99%

“…Neurological, cognitive, and behavioral signs associated with MPS I remain untreated if therapies are unable to target the CNS and therefore negatively affect quality of life. Reported cognitive impairments of MPS I human patients include low intelligence quotients (IQ), poor attention scores, and memory deficits when compared to non-affected individuals [10,26]. Cognition tests of human MPS I patients reflect impaired working memory [26] which may be due to smaller hippocampal volumes [27].…”

Section: Introductionmentioning

confidence: 99%

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Cognitive Abilities of Dogs with Mucopolysaccharidosis I: Learning and Memory

Provoost

Siracusa

Stefanovski

et al. 2020

Animals

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Mucopolysaccharidosis I (MPS I) results from a deficiency of a lysosomal enzyme, alpha-L-iduronidase (IDUA). IDUA deficiency leads to glycosaminoglycan (GAG) accumulation resulting in cellular degeneration and multi-organ dysfunction. The primary aims of this pilot study were to determine the feasibility of cognitive testing MPS I affected dogs and to determine their non-social cognitive abilities with and without gene therapy. Fourteen dogs were tested: 5 MPS I untreated, 5 MPS I treated, and 4 clinically normal. The treated group received intrathecal gene therapy as neonates to replace the IDUA gene. Cognitive tests included delayed non-match to position (DNMP), two-object visual discrimination (VD), reversal learning (RL), attention oddity (AO), and two-scent discrimination (SD). Responses were recorded as correct, incorrect, or no response, and analyzed using mixed effect logistic regression analysis. Significant differences were not observed among the three groups for DNMP, VD, RL, or AO. The MPS I untreated dogs were excluded from AO testing due to failing to pass acquisition of the task, potentially representing a learning or executive function deficit. The MPS I affected group (treated and untreated) was significantly more likely to discriminate between scents than the normal group, which may be due to an age effect. The normal group was comprised of the oldest dogs, and a mixed effect logistic model indicated that older dogs were more likely to respond incorrectly on scent discrimination. Overall, this study found that cognition testing of MPS I affected dogs to be feasible. This work provides a framework to refine future cognition studies of dogs affected with diseases, including MPS I, in order to assess therapies in a more comprehensive manner.

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