Neonatal Bone Marrow Transplantation

Pievani A, Azario I, Antolini L, Shimada T, Patel P, Remoli C, Rambaldi B, Valsecchi MG, Riminucci M, Biondi A, Tomatsu S, Serafini M. Neonatal Bone Marrow Transplantation: An Early Treatment Option for Mucopolysaccaridosis Type I Disease. Blood 2015;125:1662-1671.

Prepared by: Rachalie Barthelemy and Peter Conaty, Advance Stem Cell Course, Fall 2015

 

LAYMAN SUMMARY

Muccopolysacchardosis type I (MPS I) is a genetic disorder which removes the body’s capability to break down certain types of sugars. When these sugars, termed glycosaminoglycans (GAGs), build up in the some of the cells, this can cause the bones and other muscular tissues, such as the heart, to become abnormally thicker than the normal tissues. These skeletal deformities can be very painful for patients with MPS I due to an early onset of carpal tunnel syndrome, arthritis, and stiffness as the bones become thick to occupy more space.

Patients with severe forms of MPS I are given bone marrow transplants (BMT) using cells from healthy donors. The purpose of this treatment is to replace the dysfunctional genes with normal functioning genes. However, BMT in these cases are given after the onset of signs and symptoms such as skeletal deformities. A similar treatment in young children (1-2 yrs) showed better outcome but the transplant does not remove some of the more painful aspects of the disorder, such as the skeletal deformities. Most children are required to undergo physical therapy and are still a high risk for cardiac problems. The children generally succumb to the disease by age of ten, mainly due to thickening of the cardiac valves.

The paper examined the effect of neonatal BMT (nBMT) in mice using the following groups: MPS I mice transplanted with bone marrow cells from Wild Type (WT) or MPS1 mice; MPS1 mice transplanted with bone marrow cells from MPS1 or WT mice. The authors evaluated the mice for the transplanted cells as the level of GAGs. The mice transplanted with cells expressing the dysfunctional gene showed a higher level of GAGs (as expected) whereas mice with WT cells showed GAGs levels similar to WT mice. Further studies evaluated the levels of enzymes needed to breakdown the GAGs. The results showed comparable levels between mice receiving the normal cells and unmanipulated WT mice. Again, as expected, the MPS I mice had a much lower level of the enzyme since they had the dysfunctional gene.

The authors also tested the length of several bones in the mice and found that those that had undergone nBMT had a significant difference in skeletal structure than the MPS I mice. The MPS I mice had thick, slightly deformed bones, especially in the facial structure. When compared, the WT nBMT and the MPS I mice, the mice transplanted with nBMT were determined to have skeletal structures similar to normal WT mice. This improved changes included a separation in the soft skeletal tissue known as the trabecular, found as bone marrow structures.

Taken together, both the decreases in GAGs in tissue and bone thickness in the WT nBMT and MPS I nBMT mice when compared to the MPS I mice showed that earlier treatment of those afflicted with MPS I showed great promise in alleviating many of the problems associated with the disorder. While there is promise in this research, it is also an early testing of a method. However, the studies are in early phases and need to be repeated for further evaluated. If the method proves to be a viable solution, it could lead to a better treatment for children diagnosed with the disorder and may lead to not only a better quality of life, but to a longer life as well.

 

SCIENTIFIC SUMMARY

Muscopolysaccaridosis type I (MPS IH) disease, also known as Hurler Syndrome, is an autosomal recessive disorder that results in an alpha-L-iduronidase (IDUA) deficiency phenotype (IDUA-/-). Due to improper functioning of lysosomal storage, IDUA-/- children fail to sufficiently breakdown materials such as glycosaminoglycans (GAGs), which cause a buildup that ultimately interrupts cellular function throughout the body. As a result, organ failure and skeletal deformations, such as a compressed spine, irregular development of the vertebrae and ribs, macrocephaly, and an overall thickening of the bones, arise.

As a method of current treatment for MPS IH patients, BMT has been partially successful in rescuing organs from failing due to the proper engraftment of donor HSCs. However, skeletal deformations have not shown any correctional improvement, proving irreversible at the time of treatment. Researchers in the article, therefore hypothesized that administering BMT to neonates diagnosed with MPS IH at a very early stage in life can prevent the development of severe bone malformations, ultimately increasing the quality of their life.

To test this theory, wild type (WT) C57BL/6 and MPS I C57BL/6 (Idua-/-) mice were studied as follows: After treating 1-2 day old mice with a busulfan-based preconditioning regimen, healthy HSCs derived from 8-12 week old mice of the same type, were administered intravenously 24 hours later. Assessing HSC engraftments levels in both the spleen and the peripheral blood, chimerism, which was determined by proper engraftment levels reaching above 50% at 4 weeks of age, noted in 13 (MPS I nBMT-hi) out of the 22 mice originally used in this study. As a result, four groups of mice were used in the following experiments: WT mice, MPS I mice, WT nBMT mice, and MPS 1 nBMT-hi mice.

IDUA, Beta-hexosaminidase, an enzyme linked to MPS IH, and GAG activity levels were assessed in the spleen, heart, liver, kidney, and lung of these mice. In MPS I mice, there was no activity of IDUA and an elevated level of Beta-hex and GAGs were seen. These levels were partially corrected in MPS I nBMT-hi mice. In regards to IDUA activity, there was a 70%, 40%, and 20% increase in the spleen, liver and kidney, and heart and lungs, of the MPS I nBMT-hi mice, respectively. The levels of GAG activity in the liver, lung, and spleen of the MPS I nBMT-hi mice practically normalized itself to that of the WT mice.

At 37 weeks of age, radiographs and an assessment of skull morphology presented cranialfacial malformations and bone deformations within the MPS I mice. MPS I mice developed short, broad faces, a blunted nose, wider skull and zygomatic arches, thicker fore- and hind-limbs that were sclerotic, and a humerus, radius/ulna, femur, and tibia that grew larger in width. In the Micro-CT evaluation of only male femurs, there was a highly dense trabecular structure present and an abnormally thick cortical structure seen in MPS I mice as compared to their MPS I nBMT-hi counterparts. To support these findings, a histopathologic evaluation was performed and showed corrective improvements in the femoral growth plates and proximal tibia of the MPS I nBMT-hi mice. Compared to the MPS I mice, MPS I nBMT-hi mice had bone malformations that were significantly reduced and practically similar to that of the WT mice. In addition, the level of correction seen in the MPS I nBMT-hi mice correlated highly with the percentage of donor HSC engraftment.

The authors concluded that BMT at an early stage could severely reduce irreversible skeletal deformations in children diagnosed with MPS IH, which would therefore increase their quality of life. Due to the production of partial levels of IDUA as a result of proper donor HSCs engraftment, the level of GAG activity decreased, ultimately allowing for the normalization of bone development. Due to the early type of these studies with regards to nBMT in MPS I mice, there is much to be considered, such as increasing the sample size. Nevertheless, early nBMT may in fact hold great promise for children diagnosed with genetic disorders, such like MPS IH.

Bone Marrow Transplant