Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
This protocol was a prospective, Phase I study of allogeneic bone marrow transplantation
 (BMT) as the primary therapy for Osteogenesis Imperfecta Types II and III. Compatible sibling
 donors and unrelated donors were stratified and analyzed according to the type of donor. All
 patients with a sibling donor will received a chemotherapy conditioning regimen; a non-T cell
 depleted allogeneic marrow, and GVHD prophylaxis. All patients with an unrelated donor will
 receive a chemoradiotherapy conditioning regimen, a T-cell depleted allogeneic marrow, and
 GVHD prophylaxis. The primary objective of this study was to investigate the safety and
 toxicity of these BMT procedures in this particular population.
The secondary objective of the protocol assessed the engraftment of donor mesenchymal cells
 and their ability to increase the synthesis of normal type I procollagen relative to the
 synthesis of mutated type I procollagen and to assess whether BMT improves the bone structure
 and the clinical condition of these patients with OI.
Inclusion Criteria:

 -  Patient has diagnosis of OI Type II or III. Because there are no specific, defined
 clinical criteria consistently used to make this diagnosis, we provide the following
 clinical guidelines to assist in diagnosis. Any appropriate combinations of the
 following clinical findings will be acceptable.

 Diagnosis of OI Type II

 -  Antenatal ultrasonography (if performed for other indications) by established
 obstetric impressions including short femurs, a small thoracic cage and poorly
 mineralized bones. Analysis of collagen synthesized from cultured cells obtained from
 chorionic villus sampling (CVS) may establish the diagnosis; however, no CVS will be
 performed specifically for enrollment into this study.

 -  Clinical examination including prematurity, low birth weight, characteristic facies
 (blue sclera, beaked nose, extremely soft calvarium), "frog-leg" hips, small thoracic
 cavity, fractures at birth or shortly thereafter, loose skin or lax joints that cannot
 be readily explained by other factors.

 -  Radiographic evaluation demonstrating various aspects of the characteristic picture of
 telescoped femur, bowed tibias, beaded ribs, flattened vertebral bodies and virtual
 absence of calvarial mineralization.

 Diagnosis of OI Type III

 -  Antenatal ultrasonography (performed for other indications) by established obstetric
 impressions for this more moderate form of OI. Chorionic villus sampling will be
 accepted as above.

 -  Clinical examination including short stature, bony deformities, many fractures at
 birth or shortly thereafter. Blue scleras and dental abnormalities are also common.

 -  Radiographic abnormalities including thin, osteopenic bones of the limbs with evidence
 of fractures, growth plate abnormalities, and an undermineralized calvarium.

 -  Diagnosis of other diseases with possibly similar presentation to OI (e.g.
 hypophosphatasia and rickets) should be excluded by obtaining a serum calcium,
 phosphate and alkaline phosphatase. These parameters can be expected to be within
 normal limits (alkaline phosphatase may be somewhat elevated) in patients with OI.

 -  Age less than 3 years at time of transplant.

 -  Parents or legal guardians must sign an informed consent indicating that they are
 aware this is a research study and have been told of its possible benefits and toxic
 side effects, including treatment related mortality. Patients or their guardians will
 be given a copy of the consent form.

 -  Identification of a suitable bone marrow donor.

 -  Any donor must be of sufficient size so that adequate bone marrow may be harvested.

 -  HLA mismatched sibling or unrelated donor. DNA typing will be per- formed on unrelated
 donors. Donors must be a 6/6 match or a 5/6 match (with serologic mismatch at a single
 Class I allele or mismatch at a single DR1 allele).

 Exclusion Criteria:

 -  Patients who are ventilatory dependent due to primary lung parenchymal disease prior
 to BMT.

 -  Patients with evidence of basilar invagination/compression.