Nonablative neonatal marrow transplantation attenuates functional and physical defects of β-glucuronidase deficiency

Abstract

The toxicity of preparative regimens render neonatal bone marrow transplantation (BMT) for progressive childhood diseases a controversial treatment. Ablative BMT in neonatal mice with or without the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII) show high morbidity and developmental disruption of both brain and bone structure. In this investigation, BMT was performed with a high dose of congenic, normal bone marrow into nonablated newborn mice. Recipients had lifelong, multilineage, peripheral blood chimerism with the donor ␤-glucuronidase-positive (GUS ؉ ) cells that was both well tolerated and therapeutic. Three daily injections of normal adult marrow increased the average life span by at least 6 months and corrected the functional breeding deficits typical of the MPS VII mice. Twelve months after injection, several structural features of femurs were more like that of normal mice than of untreated MPS VII mice. Periosteal circumference and bone cortical thickness were significantly improved in males and cortical density did not differ significantly from values in normal females. Signifi- IntroductionA growing number of genetic disorders respond therapeutically to bone marrow transplantation (BMT). 1,2 BMT can restore immune function 3 and stabilize multiple forms of anemia and hemoglobinopathies. 4 For some metabolic diseases, myeloablative transplantation with normal hematopoietic tissues delivers cells carrying protein that, by cross-correction, stabilize cellular biochemistry and alleviate disease in surrounding tissues. A significant proportion of diseases that respond to BMT, such as the lysosomal storage diseases, 5 are highly progressive in nature and show improved response when BMT is performed early in development. [6][7][8][9] When treatment occurs in the first few years of life, BMT halts progressive neuropsychological retardation 10 and can reverse the hepatosplenomegaly and corneal clouding 1 commonly observed in the lysosomal storage diseases. Currently, most transplantation protocols use chemical ablative preparatory regimens to obtain high levels of engraftment. These techniques are highly toxic in the neonatal period and can cause developmental malformations as well as increased mortality. 8,11 Optimization of the transplantation regimen as well as donor cell type (both ontologically and phenotypically) are clearly paramount to the successful treatment of young children with life-threatening genetic disorders.The homing and engraftment of donor hematopoietic stem cells (HSCs) in the rapidly expanding and developing neonatal environment is not well understood. Early experiments in murine adult BMT led to the hypothesis that HSC reside in marrow "niches" that require "opening" with irradiation or cytoreductive reagents. 12 This idea was supported by experiments performed without marrow ablation that showed poor engraftment of donor cells. [13][14][15] The concept of the HSC "niche" was put into question when Brecher and colleagues 16 successfully engrafted male donor cells i...

Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

“…When engraftment of oc/oc mice was compared with control mice, there was no significant difference, indicating that there is no homing or engraftment advantage for normal cells in the osteopetrotic marrow compared to WT marrow. Our engraftment data are highly compatible with those observed in a study of successful nonablative transplantation of neonatal mice with mucopolysaccharidosis VII (MPS VII or Sly disease in humans), (24) as well as with those seen in two murine models of SCID (25) (see below).…”

Therapies for the bone in mucopolysaccharidoses

“…Early HSCT treatment provided a higher score than late HSCT. [32,33]. Newborn mice with MPS VII receiving ablative BMT lived longer than untreated mice.…”

“…A retrospective analysis demonstrated superior long-term clinical outcome for patients with MPS I when HSCT was performed early in life [27]. HSCT shows some benefits in physical activity and bone mineral density of treated mice, and early interventions provides more benefits [32][33][34]. ERT and HSCT provide a comparable impact on growth in patients with MPS II [35].…”

Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

“…Even these measures are not without dangers to infants because pretransplantation treatment usually includes toxic preparative regimens. We have developed a completely nonablative technology for neonatal transplantation (32) and have used it successfully (33) in the MPSVII mouse model of Sly syndrome (34). The advantages include: early treatment; dissemination of donor GUSBϩ macrophage progeny to bone, BM, visceral organs, and brain; provision of sufficient enzyme to alleviate lysosomal storage by crosscorrecting host cells; 3-fold increase in the average lifespan; alleviation of functional defects; and lack of immune response to the GUSB that is provided by donor cells (35).…”