Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Abstract

ObjectiveThe lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.MethodsHere, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.ResultsChronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.InterpretationOur data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

“…Storage material was prepared for mass spectrometry analysis as previously described ( Damme et al, 2015 ). Briefly urine samples and water extracts of TLC-isolated compounds were centrifuged at 14,000 g for 20 min, and 10 µl of extract were mixed with 10 µl of a 0.01 nmol/µl maltotriose internal standard.…”

Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis

“…As a next step, we studied the uptake and processing of rhCTSD in CTSD-deficient mice (ctsd -/-). For this purpose, a range of enzyme concentrations was firstly tested taking into account previous studies with other recombinant lysosomal enzymes (not shown) [18][19][20]. Based on these preliminary tests, we decided to give postnatal day 20 (P20) ctsd -/animals a dose of 25 mg/kg of rhCTSD by intravenous (i.v.)…”

“…ERT aims to replace the defective hydrolase by a recombinantly produced enzyme, typically administered by intravenous injection and delivered to the lysosomes via receptor-mediated endocytosis. We have previously developed an ERT strategy to treat αmannosidosis, a LSD caused by the deficiency of the lysosomal acid hydrolase MAN/α-mannosidase [18][19][20]. The treatment of patients with the engineered human MAN/α-mannosidase (velmanase alfa) has been recently approved in Europe [21].…”

Alpha-Mannosidosis: Therapeutic Strategies

“…High doses are probably necessary because the injected enzyme is quickly captured by visceral organs and thus the bioavailability of the enzyme is rapidly reduced. Recently, to overcome the immunological problems associated with ERT in alpha-mannosidosis mice, an immune-tolerant mouse model of alpha-mannosidosis was generated [ 66 ]. This mouse model allowed for an evaluation of the effect of high-dose long-term ERT on CSF pathology using rhLAMAN.…”