Enzyme Replacement Therapy—An Experiment of Nature in a Chimeric Mannosidosis Calf

Extract: This paper describes an experiment of nature involving a chimeric calf with mannosidosis which had obtained a natural transplant of lymphocytes from its normal twin during fetal development as a result of fusion of the placentas. Karyotyping of 200 peripheral blood lymphocytes showed that 77% were 60,xx and 23% 60,xy. The a-mannosidase pH dependence activity profiles obtained for the chimera were similar to those for a mannosidosis calf in brain, liver, kidney, and plasma but for peripheral lymphocytes and lymph node extracts enzyme activities approaching those of the normal control calf were measured at pH 4.0–4.3. In the chimera, vacuolation of macrophages and fixed reticuloendothelial cells in lymph nodes and of pancreatic exocrine cells was considerably less than was observed in any of the 35 other calves with mannosidosis. There were considerably fewer oligosaccharides in the brain, lymph node, and liver of the chimera calf than in any of the five mannosidosis control calves. There is little doubt that the a-mannosidase produced by the population of normal cells influenced the pathology of the disease, but failure to significantly prevent the eventual clinical course even under these favorable transplant conditions is indicative that tissue or organ transplants are unlikely to be a successful cure for diseases with severe neurologic manifestations. If this disease had been purely visceral then it is postulated that the transplant would have been reasonably effective.Speculation: Although acidic a-mannosidase supplied by a natural transplant of lymphocytes, and perhaps other cells, was unable to cure or prevent all clinical manifestations of mannosidosis, the therapeutic effect noted in visceral organs indicates that transplants may be an effective means of treating some inborn errors of lysosomal catabolism that occur without severe neurologic involvement. The reduction of storage material within the brain of the chimera suggests that larger amounts of exogenous enzyme supplied over a prolonged period might be more effective in storage diseases with neurologic manifestations. If it can be established that a concentration gradient for storage material exists between certain tissues and tissue fluids then it may not be essential to actively deliver enzyme to the central nervous system.