Mucopolysaccharidoses: Treatment

INTRODUCTION — The mucopolysaccharidoses (MPS) are lysosomal diseases caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs), also known as mucopolysaccharides. These conditions are differentiated by their clinical features and age of presentation (table 1). The MPS can affect many different systems, including the respiratory, cardiovascular, skeletal, and neurologic systems. Enzyme replacement therapy (ERT) is available for some MPS. Other therapies focus on treatment of symptoms.

Treatment of the MPS is reviewed here. The clinical features and diagnosis of these disorders, as well as associated complications, are discussed separately. (See "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications".)

OVERVIEW OF MANAGEMENT — Most therapies for MPS are directed toward treatment of complications and are not specific for the underlying abnormality. Supportive or symptomatic management can improve the quality of life for patients and their families, but they cannot prevent the inevitable decline in function. However, specific therapies, such as enzyme replacement therapy (ERT), hematopoietic cell transplantation (HCT), and gene therapy, alone or in combination, may alter the natural history of these disorders [1]. The choice of therapy depends upon the type of MPS and the disease severity in the specific patient. Management of complications is discussed in detail separately. (See "Mucopolysaccharidoses: Complications".)

ENZYME REPLACEMENT THERAPY — Enzyme replacement therapy (ERT) is approved in the United States, European Union, and several other countries for patients with MPS I, MPS II, MPS IVA, MPS VI, and MPS VII (table 1) [2]. Indications vary across the MPS, but generally ERT is used in patients with moderate-to-severe disease or clinical complications. The exception is patients under two years of age with severe MPS I (Hurler), for whom hematopoietic cell transplantation (HCT) is preferred if there is a suitable donor. (See 'Hematopoietic cell transplantation' below.)

MPS I — In patients with MPS I (Hurler, Hurler-Scheie, and Scheie syndromes), treatment with recombinant human alpha-L-iduronidase (laronidase), the deficient enzyme, reduces lysosomal storage in the liver and improves some clinical manifestations while stabilizing others [3-7]. Better outcome is achieved if laronidase is initiated before serious complications occur [6,8]. The recommended dose is 0.58 mg/kg (rounded up to the nearest whole vial) given intravenously (IV) once a week.

Laronidase is approved in the United States for patients with Hurler and Hurler-Scheie forms of MPS I and for patients with the Scheie form who have moderate-to-severe symptoms. In the European Union, it is indicated to treat the nonneurologic aspects of confirmed MPS I [5].

The approval of laronidase was based on a phase III study in 45 patients with MPS I [4]. In this trial, patients were randomly assigned to weekly IV infusions of laronidase or placebo [4]. After 26 weeks of therapy, patients in the laronidase group compared with those in the placebo group had improved forced vital capacity (FVC) and walking distance and reduced hepatomegaly and urinary glycosaminoglycan (GAG) levels. In addition, laronidase improved sleep apnea and shoulder flexion among the more severely affected patients.

All 45 patients were enrolled in a 3.5-year open-label extension study, which 40 completed [9]. As in earlier trials, urinary GAG levels decreased within the first 12 weeks and liver volume within the first year. Stabilization or improvement was also noted in percent predicted FVC, six-minute walk test, sleep apnea, shoulder flexion, and activities of daily living. Corneal clouding did not change appreciably. Infusion reactions were generally mild and decreased after six months. Although 93 percent of patients developed antibodies to laronidase, 29 percent were seronegative at their last assessment.

Similar findings (including normalized liver size, further increased range of motion, increased height and weight growth, and improved airway size) were noted in a series of 10 patients at one year and in 5 of those patients at six years of follow-up [3,5,10]. The five patients had some worsening of preexisting neurologic symptoms, and carpal tunnel syndrome still required release. Patients with substantial valvular disease at baseline continued to progress, needing valve replacement, but those with mild or minimal disease may have stabilized. At the six-year follow-up, 4 of the original 10 patients had died of various causes, including two with postsurgical complications for preexisting problems.

The safety and efficacy of laronidase in children younger than five years were illustrated in a prospective, open-label, multinational study that included 16 children with Hurler syndrome and four with Hurler-Scheie [11]. Clinical improvements were noted in 94 percent of patients at week 52 (eg, improved hepatomegaly, left ventricular hypertrophy, apnea/hypopnea index). The mean urine GAG level declined by approximately 50 percent by 13 weeks and was sustained thereafter.

ERT in patients with MPS I does not appear to reverse corneal or optic disc changes [5,12]. Intrathecal ERT in a canine model of Hurler syndrome normalized GAG storage in the brain and decreased spinal meningeal storage [13]. One patient with MPS I (Hurler syndrome) and progressive cognitive decline demonstrated improved neurocognitive performance after intrathecal ERT [14]. Another patient with MPS I and spinal cord compression was treated with four monthly intrathecal infusions of ERT and was shown to have improvement in pulmonary function and the 12-minute walk test [15]. Intrathecal therapy remains experimental. One study showed that peripheral ERT was associated with significantly lower levels of all cerebrospinal fluid (CSF) biomarkers including CSF nonreducing ends (NRE) compared with ERT-naïve Hurler syndrome, indicating that a small amount of ERT is able to cross the blood-brain barrier (BBB) and has activity in the CSF space [16].

A phase I/II, nonrandomized, single-center study of eight patients undergoing hematopoietic stem- and progenitor-cell (HSPC) gene therapy for MPS I showed promising data interim results [17]. Previously undetectable levels of alpha-L-iduronidase (IDUA) in the CSF at baseline were detectable after HSPC gene therapy in all the patients. Overall, the findings suggested a rapid and profound metabolic correction in the central nervous system (CNS).

MPS II — ERT for MPS II (Hunter syndrome) with recombinant human iduronate sulfatase (idursulfase) is licensed for use in many countries worldwide [18-20]. Idursulfase (0.5 mg/kg) is administered in weekly infusions [18,21]. ERT is not predicted to cross the BBB. Improvements in physical and respiratory function and reduction in mortality have been reported [22]. Somatic improvements may occur even in the most severe patients, but cognitive benefits have not been seen [23]. Thus, ERT is typically started in newly identified patients with MPS II but not those with end-stage brain disease.

In one clinical trial, 96 male patients (ages 5 to 31 years) treated with weekly infusions of idursulfase for 53 weeks had a mean increase in the six-minute walk test and percent predicted FVC [20,24]. Treatment also decreased mean urinary GAG levels and liver and spleen volume. Growth, sleep apnea, cardiac function, quality of life, and mortality were not examined. Anaphylactoid reactions were observed in some patients during infusion. The most common infusion-related reactions included headache, fever, cutaneous reaction, and hypertension. The frequency of infusion-related reactions decreased with time.

A retrospective review of 22 patients (aged 18 months to 21 years) treated with ERT for at least two consecutive years examined improvement in somatic manifestations (skeletal disease, joint range of motion, liver/spleen size, respiratory infections, cardiac disease, diarrhea, skin/hair texture, and disease-related hospitalizations) [25]. All patients had improvement in four or more somatic signs/symptoms, with the majority showing improvement in five to six of these findings. Limited experience in children younger than five years of age suggests that early initiation of ERT may delay or prevent the development of irreversible manifestations of the disease [26,27]. A phase III clinical trial of intrathecal administration of idursulfase is ongoing.

A systemic, broad-based, published/gray-literature search and review of studies of males with confirmed MPS II treated with ERT or HCT indicated less clear benefits of improved six-minute walk tests, height, early treatment, and harms of other adverse reactions for both treatments [28].

In a phase II/III randomized, open-label, placebo-controlled trial in 49 patients with MPS II, intrathecal idursulfase reduced cerebrospinal glycosaminoglycan levels from baseline by 72 percent at week 52 but did not significantly blunt the progression of cognitive impairment compared with placebo [29].

MPS III — Intrathecal ERT for MPS IIIA (Sanfilippo A syndrome) was ineffective in clinical trials [30]. Early-phase trials for MPS IIIB (Sanfilippo B syndrome) using IV or intracerebroventricular (ICV) delivered ERT are underway [31]. A clinical trial to assess intracerebral administration of gene therapy encoding human N-sulfoglucosamine sulfohydrolase (hSGSH) that began in 2019 is on hold, and a trial of gene therapy for MPS IIIB was terminated. A consensus clinical guideline has been created by an international panel of clinical experts with extensive experience in managing patients with MPS IIIA [32].

MPS IVA — Elosulfase alfa (recombinant human N-acetylgalactosamine-6-sulfate sulfatase [rhGALNS]) is approved for the treatment of MPS IVA (Morquio A syndrome) [33]. In a randomized trial of 176 patients with MPS IVA, patients who received weekly infusions of elosulfase alfa for 24 weeks walked 22.5 meters farther in six minutes, on average, than patients who received placebo [34]. Urine keratan sulfate levels were also reduced. No further improvement in walking ability was seen in a 48-week extension trial. In premarketing clinical trials, 8 percent of patients had anaphylactic reactions during the infusions, prompting inclusion of a boxed warning for the drug. Premedication with an antihistamine, with or without an antipyretic, prior to infusion is recommended.

Adeno-associated virus (AAV) mediated gene therapy has been studied in a rat model [35].

MPS VI — Galsulfase (recombinant human N-acetylgalactosamine-4-sulfatase [rhASB]) is approved as specific therapy for MPS VI (Maroteaux-Lamy syndrome) [36]. Galsulfase (1 mg/kg/dose) is administered once weekly. ERT for MPS VI decreases urinary GAG excretion and improves patient function and survival.

In preapproval randomized clinical trials, patients with severe manifestations of MPS VI who received weekly infusions of galsulfase for 24 weeks had reduced urinary GAG excretion and improved functional status (outcomes included six-minute walk test, shoulder range of motion, and joint pain) [37,38]. In an open-label, phase II trial, patients who received weekly infusions for 48 weeks responded with improved endurance and decreased pain compared with their baseline [39].

In a phase III trial, patients in the treatment group had greater mean increases in the distance walked in 12 minutes and the number of stairs climbed in 3 minutes than those in the placebo group (a difference between groups of 92 meters [95% CI 11-172] and 5.7 stairs per minute [95% CI -0.1-11.5], respectively) [40,41]. Increased survival, in addition to improved pulmonary function and endurance, was demonstrated in a long-term study of galsulfase treatment (mean duration of ERT was 6.8 years) [42].

Intrathecal ERT for MPS VI has been studied in a cat model [43].

Liver-directed AAV-mediated gene therapy was studied in nine patients with MPS VI [44]. Levels of serum active arylsulfatase B reached 30 to 100 percent of normal in the patients who received high-dose therapy. These patients did not require reintroduction of ERT during the two years of follow-up.

In a phase IIa study with odiparcil, an orally available small molecule that results in the synthesis of odiparcil-linked GAGs, facilitating their excretion and reducing cellular and tissue GAG accumulation, odiparcil demonstrated good safety and increased total urine GAGs, chondroitin sulfate, and dermatan sulfate with potential benefits [45].

MPS VII — Vestronidase alfa (recombinant human beta-glucuronidase [rhGUS]) is approved for the treatment of MPS VII [46]. In a phase III clinical trial, 23 patients aged 5 months to 25 years with MPS VII were treated with vestronidase alfa at doses up to 4 mg/kg every two week for up to 164 weeks. Patients showed improvement in the six-minute walk test at 24 weeks (mean difference 18 meters compared with placebo) and continued to demonstrate improvement after 120 weeks. Two patients also had marked improvement in pulmonary function. The effect on CNS manifestations was not determined. The recommended dose is 4 mg/kg given IV every other week.

HEMATOPOIETIC CELL TRANSPLANTATION — Hematopoietic cell transplantation (HCT) leads to the progressive replacement of enzyme-deficient hematopoietic cells with donor-derived enzyme-competent cells in vascular and extravascular compartments of the body [47]. HCT has been used most successfully to treat Hurler syndrome (MPS IH) and is routinely offered only to patients with Hurler syndrome under approximately two years of age. In this situation, HCT is considered standard of care. The risks of the procedure are considerably reduced compared with previous years, and long-term engrafted survival rates of greater than 90 percent are expected in expert institutions. The procedure-related risk is considered acceptable compared with the disease-related risk. HCT is less commonly used in milder MPS I and II and MPS VI and VII and is not considered as standard of care in the same way it is in the younger child with Hurler syndrome (table 1) [48,49].

In the majority of patients with successful engraftment, HCT reduces hepatosplenomegaly, increases joint mobility, decreases airway obstruction, improves cardiac function, decreases cerebrospinal fluid (CSF) pressure, improves or stabilizes hearing, and, especially in younger patients, may stabilize mental regression [48,50-58]. However, long-term follow-up over three to four decades indicates that patients with MPS IH continue to have a significant disease burden, including requirement for surgical correction for hip dysplasia and thoracolumbar kyphosis, loss of mobility, suboptimal cardiopulmonary function, cognitive impairment, gross and fine motor limitations, vision and hearing deficits, and psychiatric manifestations [59]. In Hurler syndrome, HCT is more effective at preventing disease progression than reversing established disease. Clinical outcomes after transplant are most clearly related to the age at transplant (the younger the better) and to the enzyme delivered to host tissue by engrafted donor white cells. This delivered dose is better when the donor is fully rather than partially engrafted and when the donor is not a carrier of the disease [48,50-56,60]. Enzyme replacement therapy (ERT; laronidase) is used in many transplantation centers to stabilize or improve the clinical status of patients with MPS I before and a short time after HCT.

The donor cell sources for HCT include bone marrow, mobilized peripheral blood stem cells, or umbilical cord blood, and the donor may be a human leukocyte antigen (HLA) matched family donor or an HLA-matched, unrelated donor. Regardless of cell source or donor relationship, conditioning therapy (usually chemotherapy drugs) is given to the recipient to ablate the host bone marrow and host immune system. This is done so that donor hematopoietic stem cells (HSCs) are not rejected and there is a physical host marrow space into which those HSCs can engraft.

HCT has been performed in more than 600 patients with Hurler syndrome [57,60,61]. Results have improved greatly in series from both single institutions and from registry studies. In one series of 285 patients with Hurler syndrome, event-free survival at five years was 81 percent after transplantation with an HLA-matched sibling donor or a six-out-of-six matched, unrelated, cord blood donor [60]. Results were slightly lower for those who had a 5-out-of-6 matched cord blood donor or a 10-out-of-10 HLA-matched, unrelated donor (68 and 66 percent, respectively). Survival was significantly lower in those with a four-out-of-six matched, unrelated cord blood donor or an HLA-mismatched, unrelated donor (57 and 41 percent, respectively). In another series, survival when transplanted from 2004 onward was 84 and 81 percent at one and eight years, respectively [61].

Engraftment is reduced when busulfan is not used in the conditioning regimen or when busulfan is used but the drug is not pharmacokinetically monitored and adjusted in order to achieve a target level. In addition, ex vivo graft manipulation with T cell-depleting antibodies further reduces engraftment of donor cells [62]. A second transplant is indicated when engraftment fails and is usually successful. There is evidence that engraftment levels are higher after cord blood transplant compared with bone marrow transplant [60]. An additional factor in favor of cord blood as a donor cell source is that cord blood is cryopreserved and therefore immediately available, leading to a reduced interval between diagnosis and transplant.

A large, multi-institutional study examined the factors that determined the long-term outcomes of different organ systems after successful HCT [63]. Age at HCT and the intelligence quotient (IQ) at HCT were the strongest predictors of neurodevelopmental outcome. Use of radiotherapy in conditioning therapy adversely impacted subsequent neurodevelopment. A normal enzyme level after HCT was another significant predictor of superior outcome after HCT for most other organ systems including orthopedic. The course of corneal clouding is variable. Most patients have mild residual corneal clouding, but corneal transplantation is rarely required [57]. Retinal function may decline [64]. HCT has the least effect on the skeleton, presumably because of poor penetration of the skeletal tissues by the enzyme derived from the transplanted leukocytes. Orthopedic surgical procedures are often required, although those with a normal enzyme level grow better and require fewer interventions such as for cord compression [48,58,65-67].

In patients with Hurler syndrome and cardiomyopathy, ERT before HCT may be lifesaving [68-70]. In one series of 18 patients in whom laronidase was continued until donor cell engraftment, the survival and engraftment rate was 89 percent [70]. The use of laronidase was not associated with increased risk of graft-versus-host disease (GVHD) or graft failure. The use of ERT before HCT and until donor engraftment in patients with Hurler syndrome is also associated with improved cognitive outcomes [71]. (See 'MPS I' above.)

HCT has also improved the clinical outcomes of patients with milder MPS I and II and MPS VI and VII [72-76]. However, HCT has not prevented the central nervous system (CNS) decline in patients with severe MPS II in most series and has not been successful in other types of MPS [48]. MPS III A to D patients usually do not benefit and may worsen after the procedure [77,78]. HCT does not correct well the bony abnormalities in MPS IV A and IV B or MPS I. The reason for the lack of success of HCT in some types of MPS is uncertain, although it is possible that the transplanted cells do not secrete sufficient enzyme or the enzyme may not be taken up sufficiently to correct the deficiency. It is possible that outcomes in some of these populations may improve with early HCT with full donor engraftment from a noncarrier donor. This question warrants further study.

GENE THERAPY AND GENE EDITING — Human gene therapy studies have begun in MPS VI and are slated to take place in the next few years in MPS IIIA, IIIB, II, and IH [79]. (See "Overview of gene therapy, gene editing, and gene silencing".)

Rationale — The rationale for gene therapy in MPS stems from the observation in patients who have undergone hematopoietic cell transplantation (HCT) for Hurler syndrome (MPS IH) that clinical outcome is improved when engraftment is complete and a noncarrier donor was used compared with incomplete engraftment or use of a carrier donor. In addition, enzyme replacement therapy (ERT) is costly, requires lifelong infusions, and has limited efficacy on skeletal, cardiac, pulmonary, and ophthalmologic complications. Gene therapy has been associated with some benefits in murine models of MPS, and it has been shown to be more effective than conventional HCT in non-MPS lysosomal diseases including metachromatic leukodystrophy [80-82]. (See "Metachromatic leukodystrophy", section on 'Treatment'.)

Stem cell gene therapy using viral vectors — In stem cell gene therapy approaches, autologous hematopoietic stem cells (HSCs) are transduced with an adenovirus or lentivirus vector that delivers healthy gene copies with a promoter that ensures gene expression in the progeny of the corrected stem cell. In this way, all patients have a well-matched donor, and immune suppression is not required after transplant.

In a phase I/II open-label study of gene therapy for MPS VI, nine patients over four years of age were sequentially enrolled to receive one of three doses (low, intermediate, and high) of an adenovirus vector expressing arylsulfatase B (ARSB) [83]. Patients in the high-dose group had levels of serum ARSB that were 30 to 100 percent of the mean normal level and were sustained over the two-year study period. Urinary glycosaminoglycans (GAG), metabolites that accumulate in untreated MPS VI and are excreted in the urine, were only modestly increased in the high-dose group. No clinical deterioration was noted in this group, and resumption of ERT was not required. Low- and intermediate-dose gene therapy was less efficacious, with serum ARSB levels only 20 percent of the mean normal level and urinary GAG levels sufficiently high that patients were required to restart ERT. No serious adverse events attributable to therapy were reported.

Gene editing — The EMPOWERS clinical research study is enrolling adults with MPS I to test an investigational type of gene therapy called genome or gene editing (by the zinc finger nuclease) as a potentially lasting treatment. The goal of this treatment is to permanently produce enough of the missing enzyme to reduce or abrogate symptoms and prevent complications.

OTHER THERAPIES — Miglustat, an inhibitor of glucosylceramide synthase that crosses the blood-brain barrier (BBB), did not improve or stabilize behavior or decrease ganglioside levels in a randomized trial of 25 patients with MPS III [84]. Odiparcil, an orally available small molecule that can potentially decrease the lysosomal accumulation in patients with MPS VI, is under trial [45].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mucopolysaccharidoses".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – The mucopolysaccharidoses (MPS) are lysosomal diseases that are differentiated by their clinical features and age of presentation (table 1). (See "Mucopolysaccharidoses: Clinical features and diagnosis".)

●Overview of management – Most therapies for MPS are directed toward treatment of complications and are not specific for the underlying abnormality. Supportive or symptomatic management can improve the quality of life for patients and their families but cannot prevent the inevitable decline in function. (See 'Overview of management' above and "Mucopolysaccharidoses: Complications".)

●Specific therapies – Specific therapies, such as enzyme replacement or hematopoietic cell transplantation (ERT or HCT), may alter the natural history of these disorders. The choice of therapy depends upon the type of MPS and the disease severity in the specific patient. (See 'Overview of management' above.)

•Enzyme replacement therapy – Therapy to replace the defective enzyme is available for MPS I, II, IVA, VI, and VII. Indications vary across the MPS, but generally ERT is used in patients with moderate-to-severe disease or clinical complications. (See 'Enzyme replacement therapy' above.)

•Hematopoietic cell transplantation – HCT is the standard of care for patients less than two years of age with Hurler syndrome (a severe form of MPS I). It is less commonly used in milder MPS I and II and MPS VI and VII. (See 'Hematopoietic cell transplantation' above.)

•Gene therapy/editing – Gene therapy and gene editing for MPS is an active area of exploration. (See 'Gene therapy and gene editing' above.)

•Others – Substrate analogs stabilizing mutated enzyme and small molecules that can help reduce substrate and decrease the lysosomal accumulation are under study. (See 'Other therapies' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ed Wraith, MD; Emil Kakkis, MD, PhD; Robert Wynn, MD, MRCP, FRCPath; and Simon Jones, MD, who contributed to earlier versions of this topic review.