Lymphocyte Gene Therapy for Mild Hunter Syndrome 
Table 1 - Survival After Bone Marrow Transplantation For Mucopolysaccharidosis Diseases 
Utilizing A Closely-Matched Donor (University of Minnesota - October, 1993) 
Type of Donor Surviving Fraction Survival 
(%) 
MPS I 
MPS II 
MPS III 
MPS VI 
Total 
HLA-identical 
10/13 
1/1 
3/3 
2/2 
16/19 
84% 
Other relative 
2/5 
0/2 
2/7 
29% 
Unrelated 
6/10 
0/1 
1/1 
7/12 
59% 
Total 
18/28 
1/2 
4/6 
2/2 
25/38 
All children with MPS n, MPS m, and MPS VI who have survived with complete or partial 
donor engraftment have shown a clinical response with improvement of several biochemical and 
physiologic indicators such as urine and hepatic GAG accumulation, liver and spleen size (22, 29, 
30). All engrafted patients are free of the life-threatening obstructive airway disease, a therapeutic 
response to transplantation which has been life-saving . (22. 29, 31) 
Although height measurements, radiographic studies, and bone biopsy showed little or no 
improvement in the skeletal system during the first 1 to 3 years posttransplantation (22), more 
recent radiographic observations are showing some bony remodeling in children who have been 
engrafted for several years. Serial long bone measurements indicate that linear growth is within 
the normal range; however, early patterns of abnormal skeletal growth which have occurred 
before engraftment still persist. 
The response of central nervous system disease following bone marrow transplantation is 
significant. In engrafted patients, electroretinographic abnormalities have been attenuated (32). 
Lumbar CSF pressure and cranial imaging studies have showed resolution of hydrocephalus (29). 
Long-term intellectual progress continues to be evaluated with variable outcomes which are 
related, in part, to pretransplantation neurologic damage (29) thus indicating the need for early 
treatment. 
In the past, interpretation of the response to donor marrow engraftment has been limited 
owing to underlying genetic heterogeneity. However, recent comparison of the outcomes of 
children surviving BMT to the natural history of untreated children with identical mutations has 
provided a better evaluation of the response to transplantation (33). The outcome of patients 
undergoing BMT was studied with respect to common molecular genotypes in a blinded, 
retrospective fashion. Of 22 patients with Hurler syndrome undergoing BMT, 10 were found to 
have common alpha-L-iduronidase genotypes previously associated with severe disease (5 were 
W402X/W402X; 5 were W402X/Q70X) of which 6 were long-term survivors with donor 
engraftment. Of 2 survivors with "classic” severe genotypes, both maintained normal IQ scores 
several years after transplant (IQ 86 at 5y-llm and IQ 94 at 4y-6m, respectively) and had no 
increase in brain atrophy (volume loss by CT). Four others with developmental delay (Bayley 
MDI <80) continued to survive but with persistently low IQ. Thus, retrospective mutation 
analysis demonstrated that children with "severe" molecular genotypes may have prolonged 
survival with preservation of intellectual function, if engrafted early in the course of disease and 
prior to significant brain damage. These encouraging results provide an example of how 
knowledge of the molecular genetic basis of an MPS disease facilitates an understanding of the 
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