Umbilical Cord Blood Transplantation to Treat Pelizaeus-Merzbacher Disease in 2 Young Boys

Abstract

Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longerterm follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.

Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking

“…Whereas they may well prove beneficial in accelerating recovery from acute conditions exacerbated by central inflammation, such as stroke and relapsing multiple sclerosis - in each of which they are already under clinical assessment (Cohen, 2013; Hess et al, 2014; Rosado-de-Castro et al, 2013; Vu et al, 2014) – their efficacy in preserving threatened neurons and glia after acute injury, or improving the ultimate extent of functional recovery, remains unproven. In that regard, the more recent use of MSCs and related umbilical cord stem cells in largely non-inflammatory and structural conditions such as cerebral palsy (Englander et al, 2015), and in the genetic non-metabolic disorders of myelin such as Pelizaeus-Merzbacher disease (Wishnew et al, 2014), while difficult to logicize or indeed even justify, again reinforces the point that cell therapeutics should being deployed only for those conditions in which their proposed mechanism of action is both well-founded and target-appropriate.…”

Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions

“…Transplantation of children with rarer LSD, including Pelizaeus-Merzbacher disease, Batten disease, Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease and I-cell disease, with UCB has also been performed in small numbers of patients with reasonable short-term outcomes [22,52,61]. However, lack of follow-up of functional outcomes in these patients leaves a gap in knowledge about the true benefit of this approach.…”

Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher Disease

“…Using diffusion tensor imaging, radial and axial diffusivity fell, while fractional anisotropy rose, suggesting diminished freedom of water movement in the plane of axonal fascicles. This result is suggestive of and consistent with myelin ensheathment of axons, but it is not in itself definitive; the patients' lack of clinical deterioration during this period and mild increase in MRI‐assessed myelination were well within the range of the natural development of PMD children , the clinical variability among whom is significant. As such, the donor‐derivation of any new myelin in these subjects, and hence the myelination competence of NSC allografts in humans, remains to be established ‐ ultimately via post‐mortem histological analysis.…”