Robert M. Shull

Long-Term Neurological Effects of Bone Marrow Transplantation in a Canine Lysosomal Storage Disease

ABSTRACT: A naturally occurring disease in Plott hound dogs, caused by deficiency of the lysosomal enzyme α-L-iduronidase, was used to study the feasibility of bone marrow transplantation therapy in a neurodegenerative storage disease. Three long-term survivors of transplantation with littermate marrow at 5 months of age (before clinical signs) had CNS enzyme activity, glycosaminoglycan storage, and light microscopic and ultrastructural changes evaluated 594, 628, and 740 days after treatment. Iduronidase activity in small amounts (1–3% of donor values) was detectable in brain tissue. Cerebrospinal fluid had higher iduronidase activity after transplantation (7–15% of donor values). Enzyme activity within the CNS resulted in significant reductions in stored glycosaminoglycans and resolution, to a large extent, of light microscopic and ultrastructural lesions observed in affected, untreated littermate control dogs.

Neurochemical Characterization of Canine α‐L‐Iduronidase Deficiency Disease (Model of Human Mucopolysaccharidosis I)

Abstract: This report presents the neurochemical findings on the first dog to die with deficiency of α‐L‐iduronidase (mucopolysaccharide α‐L‐iduronohydrolase; EC 3.2.1.76). The principal findings were (a) markedly increased glycosaminoglycan content in all neural tissues examined (from threefold in sciatic nerve to 15‐fold in brainstem), (b) a modest increase in levels of gangliosides GM2, GM3, and GD3, particularly in gray matter, (c) excessive accumulation of glycosaminoglycans in the CSF, (d) the increased glycosaminoglycans were dermatan sulfate and heparan sulfate, and (e) the molecular weights of the liver glycosaminoglycans were shifted toward smaller sizes, indicating partial degradation. The canine disorder thus resembles mucopolysaccharidosis I in all aspects.