Bone marrow transplantation for feline mucopolysaccharidosis I

Abstract

Severe mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT. Herein we report on bone marrow transplantation to treat feline mucopolysaccharidosis I (MPS I). Five MPS I stably engrafted kittens, transplanted with unfractionated bone marrow (6.3x10(7)-1.1x10(9) nucleated bone marrow cells per kilogram) were monitored for 13-37 months post-engraftment. The tissue total glycosaminoglycan (GAG) content was reduced to normal levels in liver, spleen, kidney, heart muscle, lung, and thyroid. Aorta GAG content was between normal and affected levels. Treated cats had a significant decrease in the brain GAG levels relative to untreated MPS I cats and a paradoxical decrease relative to normal cats. The alpha-l-iduronidase (IDUA) activity in the livers and spleens of transplanted MPS I cats approached heterozygote levels. In kidney cortex, aorta, heart muscle, and cerebrum, there were decreases in GAG without significant increases in detectable IDUA activity. Treated animals had improved mobility and decreased radiographic signs of disease. However, significant pathology remained, especially in the cervical spine. Corneal clouding appeared improved in some animals. Immunohistochemical and biochemical analysis documented decreased central nervous system ganglioside storage. This large animal MPS I study will serve as a benchmark of future therapies designed to improve on BMT.

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

“…Myocardial GAG storage and valve abnormalities similar to those of MPS I patients have previously been described in MPS I cats (19,21,27). We noted complete correction of storage lesions in myocardium and aorta of the three cats with stable serum IDUA activity, and moderate improvement in the animal with reduced serum IDUA activity (Fig.…”

“…MPS I cats carry a 3-bp in-frame deletion producing the omission of a single aspartate residue from the IDUA protein, resulting in a complete loss of catalytic activity (24). These animals exhibit GAG storage in most tissues and develop substantial orthopedic, corneal, and cardiac disease within the first 6 mo of life (19)(20)(21). We treated four MPS I cats between 3 and 5 mo of age (Table 1) with an i.v.…”

“…In the present study we tested liver-directed gene therapy in the naturally occurring feline model of MPS I, which recapitulates many of the clinical and pathological features of the disease, including progressive cardiac valve involvement (19)(20)(21)(22)(23). Four animals were treated at 3-5 mo of age with an i.v.…”

Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I

“…In these studies, animals were transplanted after the neonatal period, and in some of them, engraftment levels were suboptimal. 22,[31][32][33][34] MPS VII mice treated with BMT in neonatal life showed pathological and clinical improvements by clearing lysosomal storage in bones, joints, and visceral organs, even though engraftment achieved was low (15% to 20%). 16,17 To achieve a more complete donor-derived engraftment, we decided to use a busulfan-mediated preconditioning regimen, which was previously reported to result in high levels of hematopoietic engraftment after nBMT, and a complete hepatic correction in the erythropoietic protoporphyria mouse model.…”

Lipid Composition of Whole Brain and Cerebellum in Hurler Syndrome (MPS IH) Mice

“…The life expectancy of MPS IH mice is between 12 and 17 months. Previous studies have observed accumulation of gangliosides GM3 and GM2 in Idua -/-mice, as well as in dog and cat MPS IH models, but detailed lipid analysis has not been performed in either mouse, cat, or dog [22][23][24][25][26][27][28][29][30].…”