Samuel H. Doppelt

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

BACKGROUND AND METHODS Gauchers disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gauchers disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. RESULTS The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. CONCLUSIONS Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gauchers disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.

Osteoarticular and intercalary allograft transplantation in the management of malignant tumors of bone.

Since 1971, the Orthopaedic Service at the Massachusetts General Hospital has treated 106 patients with malignant or aggressive bone tumors by wide resection and replacement with frozen cadaveric allograft. Sixty‐one of these patients have been followed for over two years (mean, 4.5 years), allowing a comprehensive end‐results analysis. In 45 patients, mostly with giant‐cell tumors or chondrosarcomas, the resection involved the articular end of a long bone and the replacement not only included bone, but glycerolized (to prevent freezing injury) articular cartilage. Ten of the segments were intercalary (bone alone) and six involved a combination of bone and a metallic joint prosthesis. Patients were graded as excellent, good, fair, or failure, depending principally on functional capacity. End‐results analysis in this group showed that five of the 61 patients had either a local recurrence (2) and/or distant metastases (3); in five additional patients the limb was amputated or the implant removed, primarily because of infection (total failure rate, 16.5%). Forty‐five (73.8%) had successful transplants (graded excellent or good) and were able to live essentially normal lives. Six of the patients (10%) required a brace or cane but three of these patients were able to return to preoperative work activities. Although the operations were arduous and difficult, and despite a high infection rate (13%) and occasional pathologic fractures (10%), the results compare favorably with other techniques used to restore the skeleton following massive segmental resection. In long‐term follow‐up, the data suggest that if no complications ensue in the first two years, the results are generally quite good and the grafts show no evidence of progressive deterioration with time.

Evaluation of Gaucher disease using magnetic resonance imaging.

Magnetic resonance imaging was used to study the skeletal involvement in a series of twenty-four patients with Gaucher disease. Many sites in the marrow of these patients were characterized by an abnormally low signal intensity that reflected shortened T1 and markedly shortened T2 values in the replaced marrow. The abnormality was non-homogeneous in distribution. In the lower extremity, the proximal (femoral) areas were more frequently affected than the distal (tibial) sites. The epiphyses were generally spared unless the involvement of bone was extensive. Lack of epiphyseal involvement on the magnetic resonance images generally precluded any suspicion of osteonecrosis. The extent of involvement, as suggested by the magnetic resonance data, appeared to correlate well with the occurrence of musculoskeletal complications. Magnetic resonance imaging is more sensitive than computerized tomography in demonstrating the extent of abnormalities in patients with Gaucher disease, and it may have prognostic value.

Operational and financial aspects of a hospital bone bank.

Although bone banks have existed for many years, the elements of organizing and maintaining a hospital bone bank have not been well documented. The experience with a bone bank at the Massachusetts General Hospital between 1971 and 1980 provides a model on which to base an explanation and discussion of methods of procurement, storage, and retrieval, and the costs associated with such a facility. In 1979, the procurement rate averaged one donor per month; during that year a total of ninety-one bones were stored and six different surgeons utilized more than twenty allografts from the bank. During the same year, the approximate cost of maintaining the bank was more than

Relationship of Blood Concentrations of Calcium, Phosphate, Gastrin and Calcitonin to the Onset of Feeding in the Rat

50,000. On the basis of the number of bones used, the cost averaged more than

Quantitative computed tomography for spinal density measurement. Factors affecting precision.

2000 per implant. Such a hospital facility offers the benefits of quality control of the banked bone but is expensive and may not be feasible for many hospitals.

Dose-dependent responses to macrophage-targeted glucocerebrosidase in a child with Gaucher disease

Summary Daily fluctuations in plasma calcium concentrations in rats trained to a closely regulated feeding pattern have been compared to corresponding plasma gastrin and calcitonin concentrations. The time period studied was that extending from 4 hr prior to the start of the feeding period through the first 2 hr of feeding. Both plasma calcium and phosphate levels fell prior to the start of the feeding period and remained low at least for the first 2 hr of feeding. This pattern was also observed in rats in which food was withheld for 2 hr past the regular feeding time. Plasma 45Ca and 32P concentrations (radionuclide injected at least one week prior to sampling) did not follow the pattern of their stable counterparts. Instead, these values rose or remained constant until after feeding had commenced, after which they fell precipitously. Both plasma calcitonin and gastrin levels rose rapidly after the start of the feeding period. The primary point of emphasis is that calcitonin secretion was produced in these rats by an intestinal related stimulus and not by a rise in plasma calcium concentration. The technical assistance of Dorothy B. Raneri, Blanche P. Holloway and Johnny F. Obie is acknowledged and appreciated. Thanks are expressed to Merlene Moore for clerical assistance.

1983 bone bank procedures.

Quantitative computed tomography (QCT) was performed in duplicate on 84 patients to test the short-term precision of the technique. Statistical analysis of the data revealed that precision was not a function of spinal density. It appeared to be worse in osteopenic individuals only when expressed as a percentage. Precision was slightly better in male than in female patients. There is a 90% likelihood that a duplicate measurement will fall within 20 CT units of the first determination in female patients and within ten units in male patients.

An interpretation of acute changes in plasma45Ca following parathyroid hormone administration to thyroparathyroidectomized rats

Long-term studies of a child with Gaucher disease indicated that the response to treatment with macrophage-targeted glucocerebrosidase (glucosylceramidase) is dose dependent, and that the hematologic response precedes the skeletal response.

Analysis of the lipids of normal and Gaucher bone marrow

Bone banks large enough to support an allograft program require dedicated medical personnel to manage them. A large potential donor population, extensive financial resources, and modern storage facilities are necessary. Infected donors and contamination of procured bones during storage and retrieval must be avoided at all costs. Detailed record keeping is of vital importance to clinical investigations, especially for evaluating complications. These considerations must be taken into account before embarking on an institutional bone banking program, to provide safe and satisfactory allogeneic bone for clinical use.