Use of Enzyme Replacement Therapy (Laronidase) before Hematopoietic Stem Cell Transplantation for Mucopolysaccharidosis I: Experience in 18 Patients

doi:10.1016/j.jpeds.2008.07.004

The Journal of Pediatrics

Volume 154, Issue 1, January 2009, Pages 135-139

https://doi.org/10.1016/j.jpeds.2008.07.004 Get rights and content

We describe the use of enzyme replacement therapy in conjunction with hematopoietic stem cell transplantation in 18 consecutive patients with severe mucopolysaccharidosis type I. The survival and engraftment rate was 89% overall and 93% for the 15 patients who received full-intensity conditioning.

Section snippets

Methods

The patient cohort comprised consecutive children under age of 2 years with MPS I Hurler who underwent HSCT at our center between February 2004 and January 2008. The diagnosis of MPS I Hurler was based on α-L iduronidase activity and mutation analysis. All patients received a weekly laronidase infusion (0.58 mg/kg) for ≥ 12 weeks before undergoing transplantation. Stem cell source and donor characteristics varied. Patients and donors were typed to allele level at class I (HLA-A, -B, and -C) and

Results

Eighteen patients age 2 years or younger with MPS I (10 males, 8 females) underwent HSCT with laronidase (Table I). The mean age at first transplantation was 12 months. Most of the patients (14/18; 78%) received an unrelated donor transplant (9 cord donors and 5 adult donors). One patient presented with severe cardiomyopathy and an ejection fraction of only 3% to 4%; after 6 months of laronidase, his ejection fraction improved to 20%, and he was able to undergo HSCT. Of note, 2 similar patients

Discussion

The excellent results for HSCT in MPS I can be attributed to the accumulated effect of full-intensity conditioning regimens, including busulfan targeting, the use of well-matched (including cord blood) donors, individualization of GVHD prophylaxis according to donor type, and good supportive care in a center well versed in alternative donor transplantation. These data suggest that short-term use of laronidase is not associated with increased risk of either GVHD or graft failure. We surmise that

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Cited by (65)

Long-term evolution of mucopolysaccharidosis type I in twins treated with enzyme replacement therapy plus hematopoietic stem cells transplantation
2021, Heliyon
Citation Excerpt :
ERT for MPS-I has been used in the United States and Europe since 2003, with a usage registry in more than 600 patients according to the international registry of MPS (The MPS I Registry). ERT improves the efficacy of HSCT when they are combined, mainly ameliorating lung and orthopedic deterioration (Kakkis et al., 2001; Valayannopoulos et al., 2010; Wynn et al., 2009; Stoop et al., 2013; Aldenhoven et al., 2008; Gassas et al., 2011). ERT does not cross the blood-brain barrier (because of its large molecular size), or reverse skeletal changes, heart anomalies or corneal opacity (Sifuentes et al., 2007), which are probably induced by inflammation and fibrosis secondary to the continuous storage of GAGs and increased cytokine activity (Laraway et al., 2013; Wraith et al., 2004; Gabrielli et al., 2010).
Mucopolysaccharidoses (MPSs) are a heterogeneous group of diseases that have in common the accumulation of glycosaminoglycans (mucopolysaccharides) within the lysosome. The diseases are caused by a deficiency of the enzyme α-L-iduronidase which is responsible for the degradation of glycosaminoglycans (GAGs or mucopolysaccharides). More than 100 mutations in the gene have been reported, resulting in marked clinical/response variability. MPSs usually present as multisystem and progressive clinical disorders which affect psychomotor and cardiovascular development, the cornea and the musculoskeletal system. Seven phenotypically distinct diseases have been described, and MPS type I (MPS-I) is divided into three clinical forms: severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome) or mild (Scheie syndrome).
For the treatment of MPS-I, Enzyme Replacement Therapy (ERT) with α-L-iduronidase and Hematopoietic Stem Cells Transplantation (HSCT), separately or in combination, have produced clinical improvement, especially with regards cardiovascular symptoms and psychomotor development. This article presents the long-term (more than seven years) follow-up of monochorionic, diamniotic twins who were diagnosed with MPS-I at an early stage, and treated with ERT (from age 10 months) plus HSCT (from age 18 months). Overall, the treatment has facilitated stable development with an overall good response and better control of symptoms associated with MPS-I.
The natural history of neurocognition in MPS disorders: A review
2021, Molecular Genetics and Metabolism
Citation Excerpt :
Cord blood instead of bone marrow as the source of donor cells also had good outcomes [29]. Finally, the use of ERT (enzyme placement therapy) combined with transplant increased survival [2,30,31] and in one report improved neurocognitive outcomes as well [32]. Recent publications on the effectiveness of ERT as the sole treatment for patients with MPS IH [33,34] have indicated that it has little impact on neurocognitive function or neurologic status in comparison with hematopoietic cell transplant but may prolong life.
MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative neuronopathic disease. Studies of the natural history of neurocognition are necessary to determine the profile of abnormality and the rates of change, which are crucial to select endpoints for clinical trials of brain treatments and to make clinical recommendations for interventions to improve patients’ quality of life. The goal of this paper is to review neurocognitive natural history studies to determine the current state of knowledge and assist in directing future research in all MPS disorders. There are seven different types of MPS diseases, each resulting from a specific enzyme deficiency and each having a separate natural history. MPS IX, will not be discussed as there are only 4 cases reported in the literature without cognitive abnormality.
For MPS IH, hematopoietic cell transplant (HCT) is standard of care and many studies have documented the relationship between age at treatment and neurocognitive outcome, and to a lesser extent, neurocognitive status at baseline. However, the mortality and morbidity associated with the transplant process and residual long-term problems after transplant, have led to renewed efforts to find better treatments. Rather than natural history, new trials will likely need to use the developmental trajectories of the patients with HCT as a comparators. The literature has extensive data regarding developmental trajectories post-HCT. For attenuated MPS I, significant neurocognitive deficits have been documented, but more longitudinal data are needed in order to support a treatment directed at their attention and executive function abnormalities.
The neuronopathic form of MPS II has been a challenge due to the variability of the trajectory of the disease with differences in timing of slowing of development and decline. Finding predictors of the course of the disease has only been partially successful, using mutation type and family history. Because of lack of systematic data and clinical trials that precede a thorough understanding of the disease, there is need for a major effort to gather natural history data on the entire spectrum of MPS II. Even in the attenuated disease, attention and executive function abnormalities need documentation.
Lengthy detailed longitudinal studies are needed to encompass the wide variability in MPS II.
In MPS IIIA, the existence of three good natural history studies allowed a quasi-meta-analysis. In patients with a rapid form of the disease, neurocognitive development slowed up until 42 to 47 months, halted up to about 54 months, then declined rapidly thereafter, with a leveling off at an extremely low age equivalent score below 22 months starting at about chronological age of 6. Those with slower or attenuated forms have been more variable and difficult to characterize. Because of the plethora of studies in IIIA, it has been recommended that data be combined from natural history studies to minimize the burden on parents and patients. Sufficient data exists to understand the natural history of cognition in MPS IIIA. MPS IIIB is quite similar to IIIA, but more attenuated patients in that phenotype have been reported. MPS IIIC and D, because they are so rare, have little documentation of natural history despite the prospects of treatments.
MPS IV and VI are the least well documented of the MPS disorders with respect to their neurocognitive natural history. Because, like attenuated MPS I and II, they do not show progression of neurocognitive abnormality and most patients function in the range of normality, their behavioral, attentional, and executive function abnormalities have been ignored to the detriment of their quality of life. A peripheral treatment for MPS VII, extremely rare even among MPS types, has recently been approved with a post-approval monitoring system to provide neurocognitive natural history data in the future.
More natural history studies in the MPS forms with milder cognitive deficits (MPS I, II, IV, and VI) are recommended with the goal of improving these patients’ quality of life with and without new brain treatments, beyond the benefits of available peripheral enzyme replacement therapy. Recommendations are offered at-a-glance with respect to what areas most urgently need attention to clarify neurocognitive function in all MPS types.
Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes
2019, Genetics in Medicine
Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.
In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.
Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.
Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future
2019, Biology of Blood and Marrow Transplantation
Citation Excerpt :
In addition, the authors found that full-donor chimerism was required for the reduced antibody response. Allogeneic HSCT corrects the immune response to ERT by replacing the patient's immune system with the donor's immune system [44]. The age at which HSCT is performed has a significant impact on its efficacy.
Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis, present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations, financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981. The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes) and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and the development of innovative regimens have significantly improved the outcomes of both engraftment failure and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors, including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.
Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I
2019, Molecular Therapy Methods and Clinical Development
Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy.
Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison
2018, Genetics in Medicine
Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age.
Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years.
Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis.
As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

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: Dr Wraith has undertaken paid and unpaid consultancy work for, and has been a principle investigator in, studies sponsored by Genzyme.

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Clinical and laboratory observationUse of Enzyme Replacement Therapy (Laronidase) before Hematopoietic Stem Cell Transplantation for Mucopolysaccharidosis I: Experience in 18 Patients

Section snippets

Methods

Results

Discussion

J Pediatr

Genet Med

The mucopolysaccharidoses

Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines

Bone Marrow Transplant

Trends in haematopoietic cell transplantation for inborn errors of metabolism

J Inherit Metab Dis

Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure

Bone Marrow Transplant

Enzyme-replacement therapy in mucopolysaccharidosis I

N Engl J Med

Clinical and laboratory observation
Use of Enzyme Replacement Therapy (Laronidase) before Hematopoietic Stem Cell Transplantation for Mucopolysaccharidosis I: Experience in 18 Patients