Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice

Abstract

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.

Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposon‐mediated gene delivery: implications for non‐viral gene therapy of mucopolysaccharidoses

“…Using either adenoassociated virus [21] or lentiviral vector [23] to deliver therapeutic IDUA genes to newborn mice, persistent high-level IDUA expression over several months was observed in the liver, heart, lung and brain with subsequent curative impact on several of the most important parameters of the disease, including reduced storage vacuoles in a number of tissues, reduced glycosaminoglycan excretion, prevention of craniofacial abnormalities and behavioral abnormalities. Using a single injection of retroviral vector in neonates Liu et al [24] demonstrated sustained supra-normal IDUA expression in the liver throughout an 8-month experiment which resulted in prevention of major clinical manifestations of MPS I including cardiac and bone disease, hearing loss and vision abnormalities. The latter study demonstrated the effectiveness of targeting hepatocytes.…”

“…MPS I mice [19][20][21], deficient in α-L-iduronidase (IDUA; EC 3.2.1.76), are a model for one of the most common MPS diseases in humans [22][23][24][25][26]. Here we show that the SB system can mediate prolonged expression of lysosomal enzymes to treat MPS disease.…”

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

“…MPS I mice [23] were on a C57BL/6 background and normal controls were heterozygous littermates. Some MPS I mice were injected IV with 10 10 transducing unit (U) U/kg of the retroviral vector hAAT-cIDUA-WPRE at 2-3 days after birth [7]. For compliance curves, periadventitial fat was removed from ascending aortas and the outer diameters determined halfway between the sinotubular junction and the innominate artery [23].…”

“…Pathology-Ascending aortas were fixed as described [7] and a region 3 mm from the aortic valve was obtained. Six micrometer sections were stained with Verhoeff's Van Gieson (VVG) stain.…”

“…The severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome), and mild (Scheie syndrome) forms of MPS I can all result in fragmented elastin fibers in the ascending aorta and cardiac valves in humans [2,3], which can result in aortic insufficiency due to reduced structural integrity of the valve. Dog [4,5] and mouse [3,6,7] models of MPS I also have elastin fragmentation of the ascending aorta and heart valves, which can result in aortic dilatation in addition to aortic insufficiency.…”