Skip to main content
NCBI home page
Molecular Therapy Advances logoLink to Molecular Therapy Advances
. 2026 Feb 13;34(1):201697. doi: 10.1016/j.omta.2026.201697

CSF GAG non-reducing ends in MPS IH after peripheral and brain-penetrating therapies: A model comparing IV non-targeted ERT and HCT

Troy C Lund 1,∗, John E Wagner 1, Susie Long 2, Ashish O Gupta 1, Paul J Orchard 1, Elizabeth Braunlin 3, Chester B Whitley 4, Julie B Eisengart 5
PMCID: PMC13148921  PMID: 42137289

Abstract

Mucopolysaccharidosis type IH (MPS IH) is a lysosomal disease caused by insufficient L-iduronidase (IDUA), resulting in progressive accumulation of glycosaminoglycans (GAGs) in the central nervous system (CNS). Hematopoietic cell transplantation (HCT) replaces IDUA through cellular cross-correction, stabilizing the CNS. Intravenous (i.v.) enzyme replacement therapy (ERT) is also effective at reducing GAG accumulation; however, it is thought to inefficiently cross the blood-brain barrier. To compare the effect of i.v. ERT on GAG degradation in the CNS with the effect of brain-penetrant therapy, i.e., HCT, we measured cerebrospinal fluid (CSF) GAG non-reducing ends in patients with MPS IH who were ERT-naive (n = 33), received i.v. ERT prior to HCT (n = 34), or underwent HCT (n = 26). We found that CSF GAGs (cGAGs) were 33%–65% lower in patients exposed to i.v. ERT. One year after HCT, cGAGs declined to their lowest levels. There was no difference in cGAG levels between patients treated with i.v. ERT for 52 weeks after HCT and those treated for only 8 weeks after HCT. In summary, i.v. ERT can lead to a significant decrease in cGAGs prior to HCT, indicating that i.v. ERT may affect CNS biomarkers, which reach their lowest levels with a brain-penetrant therapy.

Keywords: Hurler syndrome, biomarkers, heparan sulfate, enzyme replacement therapy, mucopolysaccharidosis, hematopoietic stem cell transplant, blood brain barrier

Graphical abstract

graphic file with name fx1.jpg

Open in a new tab

Lund and colleagues determined new biomarkers in cerebrospinal fluid for glycosaminoglycan non-reducing ends, which were measured in a large cohort of children with mucopolysaccharidosis type IH. Levels were lower after exposure to enzyme replacement therapy, with a further decline following hematopoietic stem cell transplantation.

Introduction

Mucopolysaccharidosis type IH (MPS IH), or Hurler Syndrome (OMIM #607014), is a fatal neurodegenerative childhood disorder characterized by a loss of alpha-L-iduronidase (IDUA) activity, resulting in a buildup of glycosaminoglycans (GAGs) in all body tissues, including the central nervous system (CNS). The development of treatments for MPS IH stemmed from the keen observations by Fratantoni et al. who in 1968 described that MPS IH fibroblasts (deficient in iduronidase, although this was not known at the time) cocultured with MPS II fibroblasts (Hunter syndrome, characterized by a loss of iduronate-2-sulfatase activity) did not demonstrate GAG buildup; instead, intracellular GAGs were catabolized.1 This “cross-correction” of one diseased cell type by another was a key finding and stimulated subsequent work that led to the discovery of the lysosomal enzymes responsible for GAG accumulation in each disease. Ultimately, alpha-IDUA was cloned,2,3 characterized, purified, and tested as an intravenous (i.v.) enzyme replacement therapy (ERT) in a clinical trial in children with MPS I.4 Early results indicated improvements in liver size, increased height and weight, increased range of motion, and decreased episodes of apnea in the treated children.5

Fortunately, the concept of “cross-correction” explained the success of the earliest treatment for MPS IH: the use of bone marrow transplant (BMT) or hematopoietic cell transplant (HCT), using marrow from healthy donors with replete iduronidase in children with MPS IH. Following successful engraftment, the resultant healthy donor leukocytes would migrate throughout the recipient tissues and “donate enzyme,” allowing accumulated GAG catabolism.6

While many children start i.v. ERT to replace the deficient alpha-IDUA, its benefits are largely considered to be limited to specific tissues outside the CNS (e.g., liver, spleen, and cardiopulmonary) due to the inability to sufficiently cross the blood-brain barrier (BBB) and prevent neurocognitive regression in MPS IH.7,8,9 It is well established that after HCT, donor cells of myeloid origin (often termed microglia-like) cross the BBB and engraft in the brain.10,11 These CNS-localized, IDUA-replete donor cells are thought to be responsible for neurologic disease stabilization after HCT in MPS IH.12 Currently, HCT remains the standard treatment for MPS IH, with i.v. ERT being used as a safe adjunct to HCT.13,14,15

In two pilot studies, we showed that i.v. ERT lowered CSF GAGs (cGAGs) by 43%–79% compared to those who were ERT-naive and that a relative decrease in one of the GAG components (non-reducing end I0S6) between pre-HCT to post-HCT was associated with preservation of intelligence quotient (IQ) points in some patients.16,17 To expand upon these pilot studies, we examined the relationship of i.v. ERT exposure, with and without brain-penetrant therapy (i.e., HCT), on cGAGs in cerebrospinal fluid (CSF) samples from several cohorts of patients with MPS I (Figure 1A; Table 1). Specifically, these groups were: (1) i.v. ERT-naive and pre-HCT, (2) treated with i.v. ERT with CSF sampled 1–12 weeks after ERT initiation and pre-HCT, (3) patients 1 year post-HCT who received short-course i.v. ERT (weekly for 8–14 weeks after HCT), and (4) patients 1 year post-HCT who received long-term i.v. ERT (weekly for 1 year). There was also a previously reported subgroup treated with one dose of intrathecal (IT) ERT + i.v. ERT, with CSF sampled 8–12 weeks after the IT dose and pre-HCT.17 We evaluated how these different therapy exposures differentially affected cGAGs. Here, we report findings comparing patients by age, sex, number of i.v. ERT doses, and treatment.

Figure 1.

Figure 1

Open in a new tab

Changes in CSF GAG in patients with MPS IH in response to i.v. ERT and HCT

(A) Schematic indicating the timeline of the patient cohorts. (B) Simple linear regression between CSF NRE and age for ERT naive patients. (C) Differences in CSF GAG NRE in patients with MPS IH who were ERT naive, comparing younger (<6 months) and older (>6 months) cohorts.

(D) Simple linear regression between CSF NRE and age, excluding patients who were 6 months of age or younger. (E) CSF GAG NRE species from ERT naive patients (>6 months of age), patients who received i.v. ERT and were >6 months of age, patients who received i.v. ERT and were <6 months of age, and patients 1 year after HCT (ST-ERT and LT-ERT inclusive). (F) Comparison of CSF GAG NRE between the +i.v. ERT group and the ITx1 + i.v.-ERT group. Data are shown as mean ± SD. Pairwise comparisons show p-values derived from a Student’s t test.

Table 1.

Subject demographics

Cohort in which CSF NRE were measured ERT naive (pre-HCT) +i.v. ERT (pre-HCT) ITx1, +i.v. ERT (1 dose IT) +ST-ERT, 1-year post-HCT +LT-ERT, 1-year post-HCT
# 34 33 21 15 11
# Male 13 16 10 8 5
Age at sampling in years, median (range) 0.94 (0.06–2.49) 0.98 (0.13–2.67) 1.34 (0.63–2.80) 2.21 (1.25–3.50) 2.23 (1.25–3.75)
# i.v. doses pre-HCT median (range) 0 6 (1–52) 12 (9–22) NA NA
# < 6 months of age at the time of sampling 6 6 0 NA NA
Open in a new tab

ST-ERT: receiving i.v. ERT for a short-term period after HCT, defined as 8–14 weeks. LT-ERT, receiving i.v. ERT for a long-term period after HCT, defined as 52 weeks. NA: not applicable.

Results

We measured cGAGs (NRE I0S0, I0S6, heparan sulfate [HS]) in the ERT-naive group, and initial analyses showed higher cGAGs in very young (<6 months) infants compared with older infants. Linear regression analyses between age and cGAG concentration showed p < 0.01 for each NRE species (Figure 1B). A direct comparison between the very young and older groups showed a 2.7-fold, 1.8-fold, and 2.8-fold increase in NRE in the very young group (Figure 1C, p = 0.0002, p = 0.0001, p < 0.0001 for I0S0, I0S6, and HS, respectively). Excluding infants <6 months of age and repeating the linear regression between age and cGAG concentration showed no significant relationship (Figure 1D, p > 0.2 for each NRE tested).

In the +i.v. ERT group, patients (>6 months of age) showed 66% lower I0S0 (p = 0.0001), 42% lower I0S6 (p < 0.0001), and 32% lower HS (p = 0.0008) compared to those in the ERT-naive group (who were also >6 months of age), consistent with our previously reported pilot data (Figure 1E).16

The +i.v. ERT group included a small subgroup of patients <6 months of age at initial assessment, which were analyzed separately (Table 1, n = 6). In contrast to the differences in GAG levels in aive patients <6 months versus >6 months of age, patients who had started i.v. ERT had cGAG levels that were similar in both age groups (Figure 1E, red versus purple bars; p = 0.0870, p = 0.2200, and p = 0.7407 for I0S0, I0S6, and HS, respectively).

Evaluation of cGAGs in patients with MPS IH 1 year post-HCT (receiving +ST-ERT or +LT-ERT) showed mean NRE concentrations of 7.7, 43.0, and 75.6 ng/mL for I0S0, I0S6, and HS, respectively, which were significantly lower than in the pre-HCT +i.v. ERT group (Figure 1E, p < 0.0001 for all NREs).

We previously examined the effect of IT administration of ERT on cGAGs, which had been designed to more directly reach the CNS space.17 In the current study, we were able to compare patients receiving +i.v. ERT alone with those who received one IT dose plus i.v. ERT. We found no significant differences in I0S0, I0S6, or HS (Figure 1F, p = 0.2024, p = 0.4288, and p = 0.0612 for each NRE, respectively).

Contrary to our analysis of the ERT-naive patients, which showed an age-related effect on cGAGs (Figure 1B), we did not observe any significant relationship between age and cGAGs in linear regression analyses of the +i.v. ERT group (Figure 2A, all p > 0.4). We were next interested in understanding whether there was any dose effect in the +i.v. ERT group. The number of ERT doses received prior to cGAG measurement ranged from 1 to 52, with a median of 6 doses. The median cGAG concentrations for those patients receiving i.v. ERT were 32.0, 154.0, and 196.0 ng/mL for I0S0, I0S6, and HS, respectively (Figure 2B). Interestingly, patients with as few as 1–2 doses of i.v. ERT obtained cGAG concentrations very close to the median values (Figure 2B), and while there was a negative trend between the number of i.v. ERT doses and cGAGs, it did not reach significance and was mainly driven by a single subject receiving i.v. ERT for 52 weeks (Figure 2B). The median age of i.v. ERT initiation was 12 months in the +i.v. ERT-treated group. When examining the effectiveness of i.v. ERT by age of initiation (i.e., before or after 12 months), cGAG levels tended to be lower in those who initiated i.v. ERT earlier, though the data were only significant for one NRE species (Figure 2C). Finally, separating the naive and +i.v. ERT groups by sex showed no significant differences among the cGAG levels (Figure 2D, all p > 0.4).

Figure 2.

Figure 2

Open in a new tab

Minimal effect of dose and sex on CSF GAG NRE

(A) Simple linear regression of CSF GAG NRE and age in patients receiving i.v. ERT (all pre-HCT). “Age” indicates the patient’s age at the time of CSF sampling. (B) Simple linear regression of CSF GAG NRE and number of ERT doses in patients receiving i.v. ERT (all pre-HCT). Arrows indicate the median values. (C) Patients from (A) were binned according to whether they started i.v. ERT before 12 months of age or after 12 months of age. (D) Differences in CSF GAG NRE in naive and ERT-treated groups by sex (includes patients <6 months in the +i.v. ERT group). Pink bars indicate females; blue bars indicate males. (E) Direct comparison of patients with MPS IH who were ERT naive or received +i.v. ERT; all were <6 months of age at the time of CSF sampling. (F) Individual CSF GAG NRE concentrations by age for the patients in (E), with the number of doses of i.v. ERT indicated for patients receiving +i.v. ERT. A single subject, denoted by a blue square, was determined to have attenuated MPS-I and was not included in any other analyses. Data are shown as mean ± SD. Pairwise comparisons were derived from a Student’s t test.

Infants <6 months of age in the +i.v. ERT group had 90%, 70%, and 75% lower cGAGs than infants <6 months who were ERT-naive for I0S0, I0S6, and HS, respectively (Figure 2E). The higher relative reduction in cGAGs in the very young (<6 months) group is driven by a higher starting level of cGAG accumulation compared to infants >6 months of age. Although the numbers are small, a closer examination of the +i.v. ERT infants <6 months by age and dose indicated that as few as 3 doses of i.v. ERT were associated with substantially lower cGAGs compared to a similarly aged subject in the ERT-naive group (Figure 2F).

Of note, one infant diagnosed with MPS-I as a neonate had a genotype consistent with an attenuated form of MPS-I and had lower cGAGs than infants with the severe form of the disease (blue square, Figure 2F).

Routinely, i.v. ERT is discontinued 8–12 weeks after HCT (+ST-ERT). Eleven patients, however, elected to continue weekly i.v. ERT long-term (+LT-ERT) after HCT (at least through 1 or 2 years post-HCT). +LT-ERT patients had similar cGAGs compared to the +ST-ERT group at 1 year post-HCT (Figure 3A; p > 0.1 for all NRE species). A caveat for these analyses is that several patients had measurements lower than the detection limit for I0S0 (<5 ng/mL) and HS (<50 ng/mL) and were assigned the lower limit of detection value (5 and 50 ng/mL, respectively) for statistical purposes, though in reality they may have been lower. The number of patients reaching the lower limit of detection for I0S0 was 8 of 15 in the +ST-ERT group and 7 of 11 in the +LT-ERT group. The number of patients reaching the lower limit of detection for HS was 4 of 15 and 8 of 11 in the +ST-ERT and +LT-ERT groups, respectively.

Figure 3.

Figure 3

Open in a new tab

CSF GAG NRE and urine GAG NRE in patients maintained on long-term post-HCT i.v.-ERT

(A) CSF GAG NRE species from patients 1 year after HCT who discontinued i.v. ERT early (+ST-ERT) and those who maintained weekly i.v. ERT long-term for 1 year after HCT (+LT-ERT). (B) Urine GAG NRE from patients 1 year after HCT who received +ST-ERT and +LT-ERT. The dotted line represents the age-appropriate upper limit of the normal range. (C) Urine GAG NRE from patients 2 years after HCT who received +ST-ERT and +LT-ERT (out to 2 years). (D) Intrapatient urine GAG NRE 1 and 2 years after HCT for patients receiving +ST-ERT. Data are shown as mean ± SD. Pairwise comparisons were derived from a Student’s t test.

Urine GAG (uGAG) NRE analyses were performed in many patients in our cohorts at 1 year after HCT and indicated that there was less uGAG in the +LT-ERT group (Figure 3B, p = 0.0313 and p = 0.0147 for I0S0 and I0S6, respectively) compared to the +ST-ERT group. Similarly, uGAG analyses at 2 years after HCT indicated less uGAG in the +LT-ERT group, who were still receiving i.v. ERT (Figure 3C). For some patients within the +ST-ERT group, there were year-over-year consecutive measurements of uGAGs. Figure 3D indicates that urine NRE can continue to decrease over 1–2 years of time without additional ERT (p < 0.05 for I0S0, I0S6, and HS). There were only two patients receiving i.v. ERT 1 and 2 years after HCT (+LT-ERT) with year-over-year uGAG measurements, and their values showed no significant differences (Figure S1), perhaps suggesting that a maximal benefit had been reached.

We evaluated for plasma and leukocyte IDUA activity concordance in the +ST-ERT and +LT-ERT and found no association (Figure 4A, p = 0.9308 and p = 0.9999, respectively). In addition, there was no difference in IDUA activity in plasma of patients with MPS IH receiving +ST-ERT or +LT-ERT at 1 year or 2 years post-HCT (Figure 4B). Given that patients were completely engrafted after HCT, comparable results were also obtained for leukocyte IDUA activity in the same groups, as expected (Figure 4B).

Figure 4.

Figure 4

Open in a new tab

Correlations between plasma and leukocyte IDUA activity and NRE

(A) Simple linear regression of plasma and leukocyte IDUA activity from patients 1 year after HCT who received +ST-ERT or +LT-ERT. Values from 1 to 2 years post-HCT are both included. The red shaded area indicates the 95% confidence interval.

(B) Plasma and leukocyte IDUA activity from patients 1 year and 2 years after HCT who received +ST-ERT or +LT-ERT. Patients in the 2-year post-HCT graph received a full 2 years of i.v. ERT post-HCT. (C) Heat maps showing multivariate correlations among plasma IDUA, leukocyte IDUA, and CSF GAG NRE from patients 1 year after HCT who received +ST-ERT (black dots) or +LT-ERT (red dots) (data combined). (D) Heat maps showing multivariate correlations among plasma IDUA and leukocyte IDUA from patients who received +ST-ERT after HCT. (E) Urine GAG NRE from patients 1 and 2 years after HCT who received +LT-ERT. Scales represent correlation coefficients. Correlation p-values are shown below each heat map.

Furthermore, there was no strong correlative relationship between leukocyte or plasma iduronidase activity and cGAG concentration assessed at 1 year post-HCT, irrespective of +ST-ERT or +LT-ERT (Figure 4C). There was a significant correlation between leukocyte IDUA activity and two of the uGAG NRE species in the +ST-ERT group 1 year post-HCT but not for plasma (Figure 4D). For patients on +LT-ERT, there was no correlation between leukocyte or plasma IDUA activity and uGAGs (Figure 4E).

Finally, to understand the magnitude of change in cGAGs from i.v. ERT in HCT recipients, we compared the decline in cGAGs in recipients of i.v. ERT before and after ERT treatment (Figure 5). We also compared the decline in cGAGs in transplant recipients before and after transplant (Figure 5). Using the CSF NRE concentrations at baseline pre-HCT in naive patients, we calculated a percent decrease to the mean NRE concentration in the +i.v. ERT group of 33%–65% (depending on the NRE species), and HCT led to a further 29%–44% reduction in cGAG NREs (Figure 5).

Figure 5.

Figure 5

Open in a new tab

Effect of treatment on CSF GAG according to treatment modality

The mean CSF GAG NRE concentrations from ERT naive patients (>6 months of age), pre-HCT values from patients receiving i.v. ERT, and NRE concentrations in patients maintained on ST-ERT or LT-ERT (1-year post-HCT) were used to calculate the percent decrease from the pre-HCT naive level (red dotted line). Bars and whiskers represent the median and range, respectively, for NRE species.

Discussion

These findings have an impact on the understanding of current therapies as well as the assessment of new treatments for MPS I and other MPS conditions.18,19,20,21,22 Without a clear understanding of the effect of ERT on CNS GAG degradation, it was presumed that i.v. ERT would have limited impact because of the BBB. Therefore, there was a general consensus that i.v. ERT alone would be insufficient for the elimination of GAGs in the CNS. First, we find that very young infants have the highest levels of cGAGs, which has not been previously appreciated. Second, while i.v. ERT is not typically thought to cross the BBB efficiently, our data show a significant association between receiving i.v. ERT and lowering of cGAGs in one of the largest cohorts of patients with MPS IH evaluated.7,8,23 Third, our study also found that there was seemingly no effect of IT ERT (given as a single dose pre-HCT). Fourth, consistent with efforts across the broad therapeutic landscape to develop CNS-penetrant therapies, we found that HCT, which is a brain-penetrant therapy, was associated with the largest reduction in cGAGs.16 Finally, although some patients chose to remain on i.v. ERT for 52 weeks after HCT (+LT-ERT group), there was no difference in cGAGs as a result of this prolonged i.v. ERT use.

cGAG in very young infants

Although we did find an association between elevated cGAGs and younger age (in patients with pre-HCT), this seemed to hold only for the very young infants at 1–2 months of age. This suggests that cGAG accumulation likely occurs prior to birth. We can hypothesize that after birth, there may be an increase in GAG excretion through the renal system, allowing for total body GAG reduction, but there is little data to support this thus far. Nevertheless, having very high levels of CNS HS is of concern, given that it is generally accepted that HS is the key pathogenic constituent contributing to neurologic inflammation and deterioration.24 This would argue for initiating ERT as early as possible. Like HCT, where the neurocognitive benefits have been established for patients <24 months of age,25 there is probably a “critical therapeutic window” early in life in which patients with MPS IH can gain maximal neurocognitive benefit from starting early i.v. ERT.

Interestingly, we determined that an infant with attenuated MPS I had the lowest levels of cGAGs compared to MPS IH infants of similar age. This suggests that cGAGs may correlate with disease phenotype and could be helpful in determining which patients are attenuated as opposed to truly severe (Hurler) shortly after birth, when the genotype is not predictive. The proportion of infants with an unclear genotype is likely to grow as newborn screening for MPS I is offered in many states. This idea should be tested in a large number of infants.

CNS targeting and CNS response to standard i.v. ERT therapy

We clearly show that i.v. ERT exposure results in an effect on cGAGs, which has not been previously examined in great detail. Nevertheless, various “CNS-targeting” strategies are being developed to more effectively deliver enzyme to the CNS.26,27 One of the leading candidates utilizes iduronidase fused to a humanized anti-human transferrin receptor antibody Fab (JR-171) to allow transport across the BBB via transferrin receptor engagement.26 Early data showed that enzyme levels and substrate reduction in the murine brain were both greater in JR-171-treated animals compared to iduronidase-treated animals.26 These observations led to a phase I/II clinical trial primarily designed to test the safety of JR-171 in human patients, which demonstrated excellent tolerability.28 Early efficacy data demonstrated decreased CSF HS in patients with MPS-I exposed to JR-171, but interpretation was complicated by the fact that patients had already received laronidase. In addition, a standard i.v. ERT therapy group as a comparator was not included, as is not uncommon in phase I/II trails. Future trials utilizing CSF HS as a biomarker should consider that i.v. ERT can influence CSF.

There are other examples suggesting that i.v. ERT can influence cGAGs. Ou et al. delivered high dose i.v. ERT to a mouse model of MPS IH (10.6 mg/kg per week for 4 weeks) and determined that cerebral cortex IDUA activity increased to 97% of wild-type mice, while cortex GAG was reduced by 63%. In addition, i.v. ERT-treated animals showed a reduction in their inherent learning abnormality, as tested via the water T-maze.19 In the MPS dog model, Dierenfeld et al. showed that neonatal dogs given a standard dose of i.v. ERT (0.58 mg/kg) or high-dose ERT (1.57 mg/kg) for 65–81 weeks demonstrated lower brain GAGs at the end of therapy in the higher-dose group.29 In contrast to our data, the same study showed that GAG clearance was enhanced with IT ERT therapy, although the animals received more doses of IT therapy (delivered every 3 months) compared to our cohort.29 Whether changes in our IT ERT schedule to weekly, for example, would make a greater difference in cGAGs is possible, but not known, and perhaps impractical as a treatment.

Evidence that i.v. ERT is associated with cGAG reduction has also been suggested in a small cohort of patients with mostly attenuated MPS I (n = 10, of whom eight had Hurler-Scheie) who were treated with i.v. ERT and subsequently underwent CSF sampling.30,31 Vera et al. showed a mean 43% reduction in CSF HS-derived NRE in patients with MPS I after 26 weeks of i.v. ERT (0.58 mg/kg weekly) compared to baseline levels. One patient evaluated after 52 weeks of therapy showed further attenuation of cGAG concentration.30

The most direct explanation for these findings is that a portion of the i.v.-delivered ERT crosses the BBB into the CSF space. In neonatal (2-day-old) mice, data suggest that mannose 6-phosphate (M6P)/insulin-like growth factor II (IGF-II) receptor (M6P/IGF2R) expression is higher early in life and can transport the lysosomal enzyme B-glucuronidase across the BBB, whereas older mice (7 weeks) have down-regulated receptor expression and less capable of transport.32 Although this is the same receptor responsible for iduronidase uptake, the relationship between 2-day old mice and human age and development is difficult to determine. Additionally, in a recent gene therapy study using lentiviral modification of autologous hematopoietic cells prior to HCT to treat patients with Hurler syndrome, IDUA activity was found in the CSF of patients post-HCT, although no activity was present pre-HCT, despite 7 of 8 patients having received i.v. ERT for several months.18 The lack of detection in their assay does not exclude the possibility that small amounts of IDUA could have been present in the CSF below the limit of detection, and even low levels of IDUA could have a dramatic effect on GAGs due to the catalytic nature of the enzyme. The source of enzyme post-HCT is presumed to be CNS-engrafted, gene-corrected cells overexpressing IDUA.

Metabolic filtration

An alternative explanation is that ERT could have an effect on peripheral GAGs, whereby GAG is broken down by enzyme in donor hematopoietic cell marrow and somatic cells, allowing cGAGs to move down a concentration gradient from the CNS to the periphery.33 Direct evidence for this process is lacking; in fact, there is some evidence to the contrary from the Dickson lab. In Sanfilippo B mice, which have elevated brain and cGAGs, they used adeno-associated viral vector-7 (which does not cross the BBB) to deliver α-N-acetylglucosaminidase (the missing enzyme in Sanfilippo B) fused to a transmembrane domain to prevent secretion and circulation. Remarkably, they showed no decrease in brain or cGAGs, despite a reduction in serum GAGs.34

Combined therapies

We show that HCT (the definitive BBB-targeting therapy) results in lower cGAGs overall. Maintenance of i.v. ERT for 1 year after HCT did not result in further reduction of cGAGs; whether there is any functional difference is not known, and further follow-up is required. To understand HCT’s true contribution, the appropriate control group would have been age-matched patients with MPS IH who were maintained on i.v. ERT for a similar time frame and did not undergo HCT, which is ethically not in line with early HCT being the standard of care. As further evidence for the effectiveness of HCT, one patient in the cohort was on i.v. ERT for 52 weeks pre-HCT and had relatively low pre-HCT cGAG values but demonstrated another 50% reduction in cGAGs 1 year after successful HCT (having discontinued ERT 10 weeks after HCT). Whether this reduction would have occurred without HCT is not known.

For uGAGs, we found that patients receiving long-term i.v. ERT after HCT tended to have the lowest levels of uGAG NREs, although total uGAG content was not significantly affected. This may be explained by the limited number of patients sampled in the post-HCT +LT-ERT group (n = 6) or by the presence of other GAG species in the urine that are not affected by ERT, allowing for higher total GAG levels.

The lack of an association between cGAGs and leukocyte (or plasma) IDUA is interesting, as one might assume that higher IDUA activity would lead to greater cGAG reduction. It is likely that the compartments of CSF and peripheral blood are separated by complex mechanisms that do not allow a simple correlation to exist at a pharmacodynamic level. While plasma IDUA did not correlate with any other biomarker, leukocyte IDUA showed some inverse association with uGAG. This is likely the result of circulating, fully engrafted donor cells metabolizing much of the accumulated somatic GAGs, which is then reflected in lower levels in the urine.

Is there a limit to GAG correction?

There was no significant association between time on i.v. ERT and cGAGs, although the one patient who received 52 weeks (and 52 doses) of i.v. ERT had among the lowest cGAG levels when assessed. Interestingly, patients receiving +ST-ERT continued to demonstrate decreases in uGAGs from 1 year to 2 years post-HCT, whereas patients receiving +LT-ERT from 1 to 2 years after HCT did not demonstrate significant further reduction in uGAGs. Although the numbers were small (n = 7 and n = 4, respectively), this suggests that there is a maximal benefit in terms of uGAG reduction that can be achieved on i.v. ERT. A case report of a patient with attenuated MPS I who was treated with only i.v. ERT (and no HCT) indicated that her uGAG levels remained about twice the upper limit of normal after 18 years of weekly i.v. ERT, suggesting a threshold for uGAG reduction by i.v. ERT.35

Sequential effect of early ERT followed by HCT

Overall, these data suggest that the driving force in cGAG reduction early on is i.v. ERT, with subsequent HCT having a more durable influence.

Given that GAG buildup begins prenatally, early initiation of i.v. ERT is favored.36 Supportive evidence for very early (neonatal) treatment is also evident from canine and murine studies.29,37 In humans, there may be added clinical benefits to initiating i.v. ERT early, including improvements in airway disease and cardiac function (reviewed by Muenzer).36 Case reports also suggest that skeletal outcomes can differ with very early ERT ((initiated at 3 days of life) compared to no treatment, as demonstrated between two siblings with MPS-I.38 Finally, it is clear that i.v. ERT does not adversely affect HCT outcomes by causing graft failure (through immune rejection), which was a concern early in its use.13,14

We propose that the current working hypothesis is that early i.v. ERT (pre-HCT) promotes significant cGAG reduction, and after HCT, donor-derived, CNS-engrafted myeloid cells are responsible for continued cGAG reduction and provide normal iduronidase, allowing for cross-correction of the disease pathophysiology. Demonstrating any added benefit of i.v. ERT on top of HCT in terms of cGAG response is difficult, but it could be accomplished by sampling CSF 1 year after HCT in patients who were maintained on i.v. ERT for 1 year, followed by discontinuation of i.v. ERT and repeating CSF sampling 1 year later; the reverse scenario could also be done. In this design, each patient serves as their own control. Importantly, a functional correlation needs to be formally determined to understand whether there is any meaningful clinical benefit to continuing i.v. ERT after HCT. For instance, we have previously shown a link between a relative decrease in CSF NRE and a relative increase in IQ 2 years after HCT, which should be revisited in a longer-term study.17 In addition, understanding the long-term changes in cGAGs after HCT would be useful to determine whether further decrements in GAG are possible.

Limitations

Our observations were performed in a limited cohort of patients; this is due to the rarity of the disease. International collaborations have been done, but sample collection is often not performed in the same manner or at the same time points (or at all), which complicates study design. A lack of measurement of enzyme activity in CSF, as well as the absence of clinical correlation, limits the interpretation of our results. A future goal is to measure neurocognition in this cohort of patients longitudinally and to determine whether there is a clear (or any) clinical correlation between these CSF biomarkers and cognitive function, which may allow for clear recommendations on the timing and duration of pre- and post-HCT i.v. ERT.

Materials and methods

All patients were assessed at the University of Minnesota Rare Disease Center of Excellence, as is standard at our institution, both prior to and following HCT. Patients who were <6 months of age were identified by newborn screening, followed by genetic confirmation with a genotype predictive for MPS IH, or had a family history of MPS IH. Other patients were identified by elevated urine GAGs, reduced dried blood spot IDUA activity, and physical stigmata of MPS IH, such as kyphosis, umbilical hernia, organomegaly, joint stiffness, development delay, enlarged head, and/or course facies. This study and the use of all patient samples were approved by the Institutional Review Board at the University of Minnesota, protocol code 0808M42321 (date of last approval: 8/22/2025). The protocol for patients receiving intrathecal ERT was reviewed and approved by the FDA (IND 100782), and the trial was registered at www.clinicaltrials.gov (NCT00638547), as previously reported.17

Lumbar puncture with CSF collection was performed at initial evaluation as part of the standard-of-care assessment. Eight transplanted patients required a second HCT and were retransplanted within 6 months of the first transplant; all were fully engrafted. Any samples classified as 1-year post-HCT were collected 1 year after the second HCT. CSF NREs were quantified at ARUP Laboratories (Salt Lake City, UT) as previously described39,40; total HS was estimated as the sum of the two most abundant disaccharides (D0A0+D0S0) released after enzymatic digestion.17,39,41 The overall outcomes of patients in the cohort receiving a dose of IT ERT have been previously reported.42 Plasma and leukocyte IDUA activity was measured by the Greenwood Genetic Cetner (Greenwood, SC 29646). For patients receiving i.v. ERT, cGAG, leukocyte IDUA, or plasma IDUA were drawn 5–7 days after the i.v. infusions to avoid skewing the results from the infusion.

The subject groups were as follows (Table 1).

  • 1.

    ERT naive upon first CSF sampling (ERT naive group, pre-HCT).

  • 2.

    Received i.v. ERT prior to first CSF sampling (+i.v. ERT group, pre-HCT).

  • 3.

    Received one dose of intrathecal ERT in addition to weekly (8–12 weeks) i.v. ERT (IT × 1, +i.v. ERT group, pre-HCT).

  • 4.

    Underwent HCT, were 1 year from transplant and received i.v. ERT for a short term after HCT, defined as 8–14 weeks (+ST-ERT, post-HCT).

  • 5.

    Underwent HCT, were 1 year from transplant, and received i.v. ERT for a long term after HCT, defined as 52 weeks (+LT-ERT, post-HCT).

Statistics

A Student’s t test was used to compare two groups (Prism, version 10.5.0). Simple linear regression was used to model the relationship between two continuous variables (Prism, version 10.5.0). Heat maps for multivariate determination of correlation was performed in JMP, version 18.2.2.

Data and code availability

A de-identified dataset underlying the results reported in this article may be made available upon reasonable request to academic investigators without commercial affiliations for the purpose of verifying and replicating the results.

Acknowledgments

We are grateful for funding from the Department of Pediatrics.

Author contributions

T.C.L.: Conceptualization, Investigation, Formal analysis, Data Curation, Writing - Original Draft. J.E.W.: Writing - Review & Editing. S.L.: Writing - Review & Editing. A.O.G.: Data Curation, Writing - Review & Editing. P.J.O.: Data Curation, Project administration, Funding acquisition, Writing - Review & Editing. E.B.: Writing - Review & Editing. C.B.W.: Writing - Review & Editing. J.B.E.: Writing - Review & Editing.

Declaration of interests

T.C.L. has consulted for Orchard Therapeutics and Sanofi Genzyme. A.O.G. has served as a primary investigator for Orchard Therapeutics. E.B. is a speaker for Sanofi/Genzyme and receives research support from BioMarin and Bluebird Bio. C.B.W. has received funding from JCR Pharmaceuticals Co., Lysogene, MiNA Therapeutics, Sangamo Therapeutics, Inc., Sanofi, Takeda Pharmaceuticals, and Ultragenyx. P.J.O. has received honoraria, consulting fees, and/or research support from Denali, JCR, Orchard Therapeutics, Regenxbio, and Sanofi Genzyme. J.B.E. has received honoraria, consulting fees, and/or research support from Denali, JCR, Lysogene, Novel Pharma, Orchard Therapeutics, Regenxbio, Sanofi Genzyme, Sobi, and Takeda.

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.omta.2026.201697.

Supplemental information

Document S1. Figure S1
mmc1.pdf (892.2KB, pdf)
Document S2. Article plus supplemental information
mmc2.pdf (8.5MB, pdf)

References

  • 1.Fratantoni J.C., Hall C.W., Neufeld E.F. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162:570–572. doi: 10.1126/science.162.3853.570. [DOI] [PubMed] [Google Scholar]
  • 2.Scott H.S., Anson D.S., Orsborn A.M., Nelson P.V., Clements P.R., Morris C.P., Hopwood J.J. Human alpha-L-iduronidase: cDNA isolation and expression. Proc. Natl. Acad. Sci. USA. 1991;88:9695–9699. doi: 10.1073/pnas.88.21.9695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Clarke L.A., Nasir J., Zhang H., McDonald H., Applegarth D.A., Hayden M.R., Toone J. Murine alpha-L-iduronidase: cDNA isolation and expression. Genomics. 1994;24:311–316. doi: 10.1006/geno.1994.1621. [DOI] [PubMed] [Google Scholar]
  • 4.Kakkis E.D., Muenzer J., Tiller G.E., Waber L., Belmont J., Passage M., Izykowski B., Phillips J., Doroshow R., Walot I., et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N. Engl. J. Med. 2001;344:182–188. doi: 10.1056/NEJM200101183440304. [DOI] [PubMed] [Google Scholar]
  • 5.Kakkis E.D., Schuchman E., He X., Wan Q., Kania S., Wiemelt S., Hasson C.W., O'Malley T., Weil M.A., Aguirre G.A., et al. Enzyme replacement therapy in feline mucopolysaccharidosis I. Mol. Genet. Metab. 2001;72:199–208. doi: 10.1006/mgme.2000.3140. [DOI] [PubMed] [Google Scholar]
  • 6.Hobbs J.R., Hugh-Jones K., Barrett A.J., Byrom N., Chambers D., Henry K., James D.C., Lucas C.F., Rogers T.R., Benson P.F., et al. Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet. 1981;2:709–712. doi: 10.1016/s0140-6736(81)91046-1. [DOI] [PubMed] [Google Scholar]
  • 7.Watson G., Bastacky J., Belichenko P., Buddhikot M., Jungles S., Vellard M., Mobley W.C., Kakkis E. Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Ther. 2006;13:917–925. doi: 10.1038/sj.gt.3302735. [DOI] [PubMed] [Google Scholar]
  • 8.Muenzer J., Wraith J.E., Clarke L.A., International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Treatment of Mucopolysaccharidosis, I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123:19–29. doi: 10.1542/peds.2008-0416. [DOI] [PubMed] [Google Scholar]
  • 9.Consiglieri G., Tucci F., De Pellegrin M., Guerrini B., Cattoni A., Risca G., Scarparo S., Sarzana M., Pontesilli S., Mellone R., et al. Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome. Sci. Transl. Med. 2024;16 doi: 10.1126/scitranslmed.adi8214. [DOI] [PubMed] [Google Scholar]
  • 10.Nolan E.E., Durose W., Taghizadeh L.A., King C.J., Gupta A.O., Orchard P.J., Lorentson M., Braaten K., Furcich J.W., Lund T.C. Loss of early myeloid donor cell engraftment into the central nervous system with nonmyeloablative conditioning. Blood Adv. 2023;7:7290–7294. doi: 10.1182/bloodadvances.2023010923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Loeb A.M., Pattwell S.S., Meshinchi S., Bedalov A., Loeb K.R. Donor bone marrow-derived macrophage engraftment into the central nervous system of patients following allogeneic transplantation. Blood Adv. 2023;7:5851–5859. doi: 10.1182/bloodadvances.2023010409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Krivit W., Sung J.H., Shapiro E.G., Lockman L.A. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 1995;4:385–392. doi: 10.1177/096368979500400409. [DOI] [PubMed] [Google Scholar]
  • 13.Grewal S.S., Wynn R., Abdenur J.E., Burton B.K., Gharib M., Haase C., Hayashi R.J., Shenoy S., Sillence D., Tiller G.E., et al. Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. Genet. Med. 2005;7:143–146. doi: 10.1097/01.gim.0000154299.22120.6a. [DOI] [PubMed] [Google Scholar]
  • 14.Cox-Brinkman J., Boelens J.J., Wraith J.E., O'Meara A., Veys P., Wijburg F.A., Wulffraat N., Wynn R.F. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant. 2006;38:17–21. doi: 10.1038/sj.bmt.1705401. [DOI] [PubMed] [Google Scholar]
  • 15.Tolar J., Grewal S.S., Bjoraker K.J., Whitley C.B., Shapiro E.G., Charnas L., Orchard P.J. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant. 2008;41:531–535. doi: 10.1038/sj.bmt.1705934. [DOI] [PubMed] [Google Scholar]
  • 16.Lund T.C., Braunlin E., Polgreen L.E., Gupta A.O., Orchard P.J., Eisengart J.B. Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy. Ann. Neurol. 2023;94:1182–1186. doi: 10.1002/ana.26786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Eisengart J.B., Pierpont E.I., Kaizer A.M., Rudser K.D., King K.E., Pasquali M., Polgreen L.E., Dickson P.I., Le S.Q., Miller W.P., et al. Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes. Genet. Med. 2019;21:2552–2560. doi: 10.1038/s41436-019-0522-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gentner B., Tucci F., Galimberti S., Fumagalli F., De Pellegrin M., Silvani P., Camesasca C., Pontesilli S., Darin S., Ciotti F., et al. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. N. Engl. J. Med. 2021;385:1929–1940. doi: 10.1056/NEJMoa2106596. [DOI] [PubMed] [Google Scholar]
  • 19.Ou L., Herzog T., Koniar B.L., Gunther R., Whitley C.B. High-dose enzyme replacement therapy in murine Hurler syndrome. Mol. Genet. Metab. 2014;111:116–122. doi: 10.1016/j.ymgme.2013.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Aldenhoven M., Wynn R.F., Orchard P.J., O'Meara A., Veys P., Fischer A., Valayannopoulos V., Neven B., Rovelli A., Prasad V.K., et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125:2164–2172. doi: 10.1182/blood-2014-11-608075. [DOI] [PubMed] [Google Scholar]
  • 21.Wijburg F.A., Whitley C.B., Muenzer J., Gasperini S., Del Toro M., Muschol N., Cleary M., Sevin C., Shapiro E., Bhargava P., et al. Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Mol. Genet. Metab. 2019;126:121–130. doi: 10.1016/j.ymgme.2018.10.006. [DOI] [PubMed] [Google Scholar]
  • 22.Okuyama T., Eto Y., Sakai N., Nakamura K., Yamamoto T., Yamaoka M., Ikeda T., So S., Tanizawa K., Sonoda H., Sato Y. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol. Ther. 2021;29:671–679. doi: 10.1016/j.ymthe.2020.09.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Scarpa M., Orchard P.J., Schulz A., Dickson P.I., Haskins M.E., Escolar M.L., Giugliani R. Treatment of brain disease in the mucopolysaccharidoses. Mol. Genet. Metab. 2017;122S:25–34. doi: 10.1016/j.ymgme.2017.10.007. [DOI] [PubMed] [Google Scholar]
  • 24.Simonaro C.M., Ge Y., Eliyahu E., He X., Jepsen K.J., Schuchman E.H. Involvement of the Toll-like receptor 4 pathway and use of TNF-alpha antagonists for treatment of the mucopolysaccharidoses. Proc. Natl. Acad. Sci. USA. 2010;107:222–227. doi: 10.1073/pnas.0912937107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Aldenhoven M., Jones S.A., Bonney D., Borrill R.E., Coussons M., Mercer J., Bierings M.B., Versluys B., van Hasselt P.M., Wijburg F.A., et al. Hematopoietic Cell Transplantation for Mucopolysaccharidosis Patients Is Safe and Effective: Results after Implementation of International Guidelines. Biol. Blood Marrow Transplant. 2015;21:1106–1109. doi: 10.1016/j.bbmt.2015.02.011. [DOI] [PubMed] [Google Scholar]
  • 26.Kida S., Koshimura Y., Yoden E., Yoshioka A., Morimoto H., Imakiire A., Tanaka N., Tanaka S., Mori A., Ito J., et al. Enzyme replacement with transferrin receptor-targeted alpha-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice. Mol. Ther. Methods Clin. Dev. 2023;29:439–449. doi: 10.1016/j.omtm.2023.05.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Sonoda H., Morimoto H., Yoden E., Koshimura Y., Kinoshita M., Golovina G., Takagi H., Yamamoto R., Minami K., Mizoguchi A., et al. A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. Mol. Ther. 2018;26:1366–1374. doi: 10.1016/j.ymthe.2018.02.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Harmatz P., Giugliani R., Martins A.M., Hamazaki T., Kubo T., Kira R., Minami K., Ikeda T., Moriuchi H., Kawashima S., et al. alpha-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial. Mol. Ther. 2024;32:609–618. doi: 10.1016/j.ymthe.2024.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Dierenfeld A.D., McEntee M.F., Vogler C.A., Vite C.H., Chen A.H., Passage M., Le S., Shah S., Jens J.K., Snella E.M., et al. Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. Sci. Transl. Med. 2010;2 doi: 10.1126/scitranslmed.3001380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Vera M.U., Le S.Q., Victoroff A., Passage M.B., Brown J.R., Crawford B.E., Polgreen L.E., Chen A.H., Dickson P.I. Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I. Mol. Genet. Metab. 2020;129:91–97. doi: 10.1016/j.ymgme.2019.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Zhang H., Dickson P.I., Stiles A.R., Chen A.H., Le S.Q., McCaw P., Beasley J., Millington D.S., Young S.P. Comparison of dermatan sulfate and heparan sulfate concentrations in serum, cerebrospinal fluid and urine in patients with mucopolysaccharidosis type I receiving intravenous and intrathecal enzyme replacement therapy. Clin. Chim. Acta. 2020;508:179–184. doi: 10.1016/j.cca.2020.05.035. [DOI] [PubMed] [Google Scholar]
  • 32.Urayama A., Grubb J.H., Sly W.S., Banks W.A. Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier. Proc. Natl. Acad. Sci. USA. 2004;101:12658–12663. doi: 10.1073/pnas.0405042101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Whitley C.B., Ramsay N.K., Kersey J.H., Krivit W. Bone marrow transplantation for Hurler syndrome: assessment of metabolic correction. Birth Defects Orig. Artic. Ser. 1986;22:7–24. [PubMed] [Google Scholar]
  • 34.Le S.Q., Sorensen A., Sukupolvi S., Jewhurst G., Austin G., Doray B., Cooper J.D., Dickson P.I. Reduced heparan sulfate levels in cerebrospinal fluid reflect brain neuron correction in Sanfilippo B mice. J. Clin. Investig. 2025;135 doi: 10.1172/JCI195268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Pjetraj D., Santoro L., Sgattoni C., Padella L., Zampini L., Monachesi C., Gabrielli O., Catassi C. 18-year follow-up of enzyme-replacement therapy in two siblings with attenuated mucopolysaccharidosis I. Am. J. Med. Genet. 2023;191:564–569. doi: 10.1002/ajmg.a.63029. [DOI] [PubMed] [Google Scholar]
  • 36.Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol. Genet. Metab. 2014;111:63–72. doi: 10.1016/j.ymgme.2013.11.015. [DOI] [PubMed] [Google Scholar]
  • 37.Baldo G., Mayer F.Q., Martinelli B.Z., de Carvalho T.G., Meyer F.S., de Oliveira P.G., Meurer L., Tavares A., Matte U., Giugliani R. Enzyme replacement therapy started at birth improves outcome in difficult-to-treat organs in mucopolysaccharidosis I mice. Mol. Genet. Metab. 2013;109:33–40. doi: 10.1016/j.ymgme.2013.03.005. [DOI] [PubMed] [Google Scholar]
  • 38.Gabrielli O., Clarke L.A., Bruni S., Coppa G.V. Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-up. Pediatrics. 2010;125:e183–e187. doi: 10.1542/peds.2009-1728. [DOI] [PubMed] [Google Scholar]
  • 39.Orchard P.J., Gupta A.O., Eisengart J.B., Polgreen L.E., Pollard L.M., Braunlin E., Pasquali M., Lund T.C. Hematopoietic stem cell transplant for Hurler syndrome: does using bone marrow or umbilical cord blood make a difference? Blood Adv. 2022;6:6023–6027. doi: 10.1182/bloodadvances.2022007212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Lawrence R., Brown J.R., Al-Mafraji K., Lamanna W.C., Beitel J.R., Boons G.J., Esko J.D., Crawford B.E. Disease-specific non-reducing end carbohydrate biomarkers for mucopolysaccharidoses. Nat. Chem. Biol. 2012;8:197–204. doi: 10.1038/nchembio.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Raymond G.V., Pasquali M., Polgreen L.E., Dickson P.I., Miller W.P., Orchard P.J., Lund T.C. Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H. Sci. Rep. 2016;6 doi: 10.1038/srep38305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Lund T.C., Doherty T.M., Eisengart J.B., Freese R.L., Rudser K.D., Fung E.B., Miller B.S., White K.K., Orchard P.J., Whitley C.B., Polgreen L.E. Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I. JIMD Rep. 2021;58:89–99. doi: 10.1002/jmd2.12190. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Figure S1
mmc1.pdf (892.2KB, pdf)
Document S2. Article plus supplemental information
mmc2.pdf (8.5MB, pdf)

Data Availability Statement

A de-identified dataset underlying the results reported in this article may be made available upon reasonable request to academic investigators without commercial affiliations for the purpose of verifying and replicating the results.

Articles from Molecular Therapy Advances are provided here courtesy of American Society of Gene & Cell Therapy

RESOURCES