2. Mucopolysaccharidosis type I (MPS I) is a
rare disease in which the body is missing or does
not have enough of an enzyme needed to break
down long chains of sugar molecules.
This disorder was once divided into three separate
syndromes:
1- Hurler syndrome (MPS I-H)
2-Hurler-Scheie syndrome (MPS I-H/S)
3-Scheie syndrome (MPS I-S)
Symptoms:
A-macrocephaly
B-hydrocephalus
C- heart valve abnormalities
D- hepatosplenomegaly
E- macroglossia
F - dysostosis multiplex
G- airway become narrow and this will lead to :
1-upper respiratory infection
2- sleep apnea
A B
C D
E F
3. CAUSES:
Mutations in the IDUA gene cause MPS I.
The IDUA gene provides instructions for producing
an enzyme that is involved in the breakdown of
large sugar molecules called glycosaminoglycans
(GAGs).
Mutations in the IDUA gene reduce or completely
eliminate the function of the IDUA enzyme. The lack
of IDUA enzyme activity leads to the accumulation
of GAGs within cells, specifically inside The
lysosomes.
Conditions that cause molecules to build up inside
the lysosomes, including MPS I, are called lysosomal
storage disorders.
Children with this form of the disorder usually have
a shortened lifespan, sometimes living only into late
childhood.
4. Delivery of a-L-iduronidase may be achieved
by either the exogenous administration of a-
L-iduronidase or through the endogenous
production of a-L-iduronidase following stable
engraftment of cells producing enzyme within
the affected individual.
The first experience with hematopoietic stem
cell transplantation (HSCT) as therapy for
Hurler was reported by Hobbs, and since that
time HSCT has been accepted as the standard
of care for patients with MPS IH.
Data from our institution as well as others
indicate that there is an increased risk of
pulmonary and cardiac complications after
HSCT in patients with MPS IH.
5. NO STUDY TITLE STATUS
1 Stem Cell Transplantation for Hurler Completed
2 Stem Cell Transplant w/Laronidase for Hurler Completed
3 Laronidase (Aldurazyme TM) Enzyme
Replacement Therapy With
Hematopoietic Stem Cell Transplant
for Hurler Syndrome
Terminated
4 Gene Therapy With Modified Autologous
Hematopoietic Stem Cells for the Treatment
of Patients With Mucopolysaccharidosis Type
I, Hurler Variant
Active, not recruiting
5 Long term survival and cardiopulmonary
outcome in children with Hurler syndrome
after haematopoietic stem cell
transplantation.
Completed
6 Combination of enzyme replacement and
hematopoietic stem cell transplantation as
therapy for Hurler syndrome.
Completed
6. Hematopoietic Stem Cell Transplantation for Hurler
Syndrome, Maroteaux Lamy Syndrome (MPS VI), and
Alpha Mannosidase Deficiency (Mannosidosis)
OBJECTIVE: to determine the safety and engraftment of
donor hematopoietic cells
PATIENTS:
NO: 41
AGE: <=18 years
FEMALE : 23
MALE : 18
Region of Enrollment: United States
Patients with Mucopolysaccharidosis, type I (e.g., Hurler
syndrome)
Cardiac: ejection fraction >40%; no decompensated
congestive heart failure or uncontrolled arrhythmia
Hepatic: total bilirubin <3x Upper limits of normal
transaminases < 5.0 x Upper limits of normal
Brain MRI of a child with moderate Hunter
syndrome showing multiple patchy white
matter lesions in the periventricular and
subcortical areas. Age: 11 years.
7. Prior to transplantation, subjects will receive Busulfan
intravenously (IV) via the Hickman line four times daily
for 4 days.
Cyclophosphamide intravenously via the Hickman line
once a day for 4 days.
Anti-Thymocyte Globulin IV via the Hickman line twice
daily for three days before the transplant.
These three drugs are being given to subjects to help the
new marrow "take" and grow.
On the day of transplantation, the donor's hematopoietic
cells will be transfused via central venous catheter.
After hematopoietic cell transplant, subjects will then
receive two drugs, Cyclosporin and methylprednisolone
or MMF are given to help prevent the complication of
graft-versus-host disease and to decrease the chance
that the new donor cells will be rejected.
8. Results
Number of Patients Surviving on Study
Number of Patients Who Failed Engraftment.
Number of Patients Who Failed Engraftment.
1 patient of 41 failed engraftment
Number of Patients With Grade III-IV Acute Graft-versus-host Disease (aGVHD).
Based on variability in age, diagnosis and condition of these patients, the data on enzyme
levels and neuropsych testing is extremely difficult to report.
9. Long term survival and cardiopulmonary outcome in
children with Hurler syndrome after haematopoietic
stem cell transplantation.
Owing to few studies documenting long-term survival
of these children treated with HSCT this study has been
done.
Patients :
The diagnosis of HS was confirmed by an increase in urinary
GAG excretion, a deficiency or absence of IDUA in peripheral
blood leukocytes, and the clinical phenotype.
54 children with HS born.
Of the 39 patients alive-andengrafted after first and second
HSCT, six patients were followed-up at other centers and alive
when we contacted their centers prior to submission of the
review.
Thirty-three patients were finally included for evaluation of
disease-related cardiopulmonary burden.
10. RESULTS:
1- The outcome of the 54 children is illustrated in
Fig. 1. Of the 18 patients with graft failure, 17
received a second HSCT while one was lost to
continuing follow-up after returning to the
referring overseas center.
2- Of the 14 deaths after HCST, 13 died of
transplant related mortality and one died of
disease-related heart failure. Four children died of
graftversus-host disease and one died of EBV post-
transplant lymphoproliferative disease (PTLD).
3-all deaths occurred within the first year after
HSCT and there was no late death in our cohort.
The overall survival at 20-years was 73.7%
(95% confidence interval 60.3-83.5%).
11. Phase II Study of Combined Laronidase
(AldurazymeTM) Enzyme Replacement Therapy
(ERT) With Hematopoietic Stem
Cell Transplantation (HSCT) for Hurler
Syndrome (MPS IH)
To investigate that weekly infusions of Laronidase
ERT for 10-12 weeks prior to transplant and 8 weeks
following transplant will result in a reduction of
glycosaminoglycans (GAG) burden that is associated
with decreased complications following transplant.
Patients:
NO: 25
AGE: <=18 years
FEMALE : 11
MALE : 11
Region of Enrollment : United States, Minnesota
12. Results
Number of Patients Alive at One Year Post Transplant (one year)
Number of Patients Requiring Ventilator Support at One Year Post Transplant
Patients With Grade III-IV Acute GVHD
13. Combination of enzyme replacement and hematopoietic stem
cell transplantation as therapy for Hurler syndrome.
Objective :To determine whether enzyme replacement therapy (ERT) with iduronidase in
the peritransplant period affects outcome of hematopoietic stem cell transplantation
(HSCT) for MPS IH.
Patients :
NO: 7 with MPS IH (All patients had null mutations in IDUA gene)
Age :median age of 1.5 years
Between 2004 and 2007, seven patients received allogeneic HSCT with ERT (Table 1). Outcomes were
assessed at least 6 months after transplantation. Follow-up is reported through August 2007 (median
1.1 years).
14. For ERT, a-L-iduronidase (Laronidase;
Genzyme Corporation, Cambridge, MA,
USA) was administered weekly at a dose
of 0.58 mg/kg per dose i.v. for 11–14
weeks prior to HSCT and for additional 8
weeks after HSCT.
The goal of this dosing was to provide a
source of exogenous a-L-iduronidase from
the time of diagnosis until stable donor
chimerism was achieved.
15. Results
1- Two patients developed skin GvHD. Patient 1 had stage
3 grade C GvHD and patient 4 had stage 2 grade B GvHD.
2- we have observed that MPS IH patients with a history
of pulmonary disease including a history of pneumonia or
reactive airway disease had worse outcomes than those
who were free from pulmonary issues before HSCT
3- We reasoned that ERT before transplant could have a
potential to decrease the GAG burden in the lung and
other visceral tissues. As a result, regimen-related
morbidity and mortality of HSCT could potentially be
decreased.
4- Five out of seven MPS IH patients had two or more risk
factors a finding that we have observed to be associated
with significant morbidity and mortality in MPS IH
patients treated with HSCT alone.
16. Four pretransplant risk factors (pneumonia, abnormal sleep study with apnea, reactive airway
disease and need for supplemental oxygen) were assessed (Table 2).
•
Combination therapy results in low overall morbidity and normal a-L-iduronidase
levels.
•
suggesting an overall decrease in GAG visceral burden. a-L-iduronidase leukocyte
levels were measured following HSCT. As expected on the basis of robust donor
engraftment in all patients, enzyme levels were within the normal range after
HSCT.
17. Recommendations:
•
the effect of ERT and HSCT provides evidence that this combination
therapy is safe, and does not negatively impact on donor stem cell
engraftment and GvHD.
•
we have observed low morbidity after ERT þ HSCT combination therapy
despite significant pulmonary risk factors present before HSCT.
•
our data indicate that despite the expected formation of anti-a-L-
iduronidase antibodies, no evidence of immune-mediated graft rejection
was observed in MPS IH patients receiving pre-HSCT ERT.
•
it is possible that ERT-mediated GAG clearance in the bone marrow niche
could create a more permissive environment for donor engraftment31
when compared to patients who are recipients of HSCT alone.
•
our recommendation is to treat all severe MPS IH patients with ERT and
HSCT to improve morbidity and mortality.
•
.
18. References
•
Lum, S. H., Stepien, K. M., Ghosh, A., Broomfield, A., Church, H., Mercer, J., ... & Wynn, R. (2017). Long
term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem
cell transplantation. Journal of inherited metabolic disease, 40(3), 455-460.
•
Tolar, J., Grewal, S. S., Bjoraker, K. J., Whitley, C. B., Shapiro, E. G., Charnas, L., & Orchard, P. J. (2008).
Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler
syndrome. Bone marrow transplantation, 41(6), 531-535.
•
Boelens JJ. Trends in haematopoietic cell transplantation for inborn errors of metabolism. J Inherit Metab
Dis 2006; 29: 413–420.
•
Bijarnia S, Shaw P, Vimpani A, Smith R, Pacey V, O’Grady H, Christodoulou J, Sillence D (2009) Combined
enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome. J Paediatr Child
Health 45(7-8):469–472
•
Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas L, Orchard PJ (2008) Combination of
enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone
Marrow Transplant 41(6):531–535.
•
9 Grewal SS, Krivit W, Defor TE, Shapiro EG, Orchard PJ, Abel SL et al. Outcome of second hematopoietic
cell transplantation in Hurler syndrome. Bone Marrow Transplant 2002; 29: 491–496.
