In this issue of Blood, Pievani et al have identified a potential solution to the remaining barrier to the success of hematopoietic stem cell transplantation (HSCT) in children with severe phenotype Hurler syndrome (mucopolysaccharidosis type I [MPS I]).1
The benefit of hematopoietic stem cell transplantation (HSCT) for children with severe phenotype Hurler syndrome was established as a life-saving therapy over 3 decades ago. The presumed mechanism of action was cellular enzyme replacement by healthy donor cells, which cross-corrected defective host cells. As a result, disease progression stabilized, life was extended, and cognitive and cardiac function was preserved. However, as a longtime transplanter of children with Hurler syndrome, I have learned that prolonging life and treating the brain and heart is not good enough. Having followed patients for 1 to 2 decades, I have seen that transplantation, performed in children with Hurler syndrome at 1 to 2 years of age, does not correct the disease in bone and cartilage and, as a result, these children continue to suffer from debilitating orthopedic problems. Specifically, within the first decade of life, most children develop progressive kyphosis, hip subluxation, carpal tunnel disease, and deformities of the ribcage, fingers, wrists, knees, and tibia, all interfering with activities of daily life. I have seen children with Hurler syndrome undergo multiple “corrective” surgeries over their first 2 decades of life, but despite these interventions, they remain functionally challenged with, for example, difficulties walking and running and the inability to perform fine motor functions like simple handwriting using their hands. In the second decade of life, cervical or lumbar stenosis causing spinal cord compression has also been seen. One of my patients, now 15 years old, recently created a YouTube video to raise money for toys for children undergoing HSCT for Hurler syndrome. In the video, she proudly reported that after the transplant that saved her life, she had undergone 16 additional surgical procedures to help her bone disease. This patient walks with a walker and types her homework because she is handwriting challenged.
Pievani et al1 describe how neonatal bone marrow transplantation prevents musculoskeletal and bone pathology in a mouse model of MPS I. The authors tested this approach because they hypothesized that most of the bone disease in Hurler patients develops postnatally, inferring that there is in utero protection preserving musculoskeletal development before birth. They created an elegant model in which a single dose of intraperitoneal busulfan provided enough immunosuppression to enable the development of durable donor chimerism. This approach also eliminated confounding comorbidities caused by alterations of bone development due to early total body irradiation. They also developed histologic and radiographic (including microcomputed tomography) methods of assessment and used the model to test their hypothesis that neonatal transplantation would enable normal bone formation in mice with MPS I. They contrast neonatal transplantation with transplantation later in life and clearly demonstrate that timing is critical. Their model recapitulates the human experience, in that HSCT later in life does not correct musculoskeletal disease. They further examine the role of donor chimerism on bone pathology, organ infiltration, and glycosaminoglycan levels and showed that sustained donor chimerism >50% yields better results on all accounts.
The observations by these authors have huge implications for the clinic. First, it compels pediatricians to develop algorithms to diagnosis MPS disease either prenatally or in the neonatal period so that these patients can be referred for transplantation in the first month of life. The inclusion of MPS I in newborn screening panels in the United States is not common practice today. However, as evidence such as the data presented in this report accrues to support the notion that earlier transplantation is better, inclusion of MPS I in these panels should become mandatory. As noted by the authors, umbilical cord blood transplantation is an ideal choice for transplantation of newborns with Hurler syndrome. Previous reports by our group at Duke University Medical Center2 ,3 and others4,5 have shown that outcomes of HSCT in patients with Hurler syndrome are best when cord blood is used as the source of donor cells. Banked cord blood is readily available, HLA typed and cytomegalovirus negative. Full HLA matching is not required. The vast majority of patients (>95%) can identify a donor matching at ≥4 of 6 loci. In small children, high cell doses can easily be achieved with a single unit. In addition, conditioning and donor selection strategies targeted to yield the highest donor chimerism are likely to yield the best clinical results. The report by Boelens and colleagues4 showed that cord blood donors and myeloablative chemotherapy conditioning yields the highest engraftment and donor chimerism rates.
Although correction of musculoskeletal disease is a huge advance for patients with Hurler syndrome, loss of vision from corneal clouding or retinal disease is a remaining challenge for these patients. HSCT does not deliver adequate levels of enzyme to the eye, which then escapes the beneficial effects of this therapy. Thus, researchers and clinicians should be inspired by the work of these authors to create similar approaches to model and treat eye disease in patients with MPS I. Perhaps then, the disease would be fully conquered.
Conflict-of-interest disclosure: The author declares no competing financial interests.