Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Abstract

The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

“…In agreement with the current view that standard of care ERT (Elaprase TM ) does not cross the BBB and does not correct the CNS manifestations of nMPS II [ 28 ], we observed a significant, 11-fold and 30-fold elevation in HS and DS levels, respectively in nMPS II patient CSF relative to the control group ( Figure 4 A,B). In serum however, HS and DS levels were only elevated 2–3-fold over the control group, confirming that both ERT and HSCT therapies reduce peripheral GAGs in nMPS II patients ( Figure 4 C,D) while having little measurable effect in the CNS.…”

“…Current therapies for nMPS II do not adequately control many aspects of the disease, including skeletal, cardiac, and pulmonary damage. Most importantly, they do not cross the blood brain barrier (BBB) and thus do not address the CNS manifestations of nMPS II disease [ 27 , 28 ]. There is a critical unmet medical need to treat nMPS II; thus, a need remains for the development of novel IDS therapies with effective brain penetration and activity.…”

High-Throughput Liquid Chromatography–Tandem Mass Spectrometry Quantification of Glycosaminoglycans as Biomarkers of Mucopolysaccharidosis II

“…These data demonstrate that, even though these patients are on standard of care ERT (Elaprase™), there is a significant elevation of HS and DS in CSF relative to controls (Bhalla et al 2020 [ 42 ]). These results support the finding that standard of care ERT does not address the CNS manifestation of MPS II [ 43 ].…”

Hearing Loss in Mucopolysaccharidoses: Current Knowledge and Future Directions

“…ERT has been described as an effective method for changing the natural history of the MPS I attenuated form [ 51 , 52 ]. Studies have described that ERT does not improve audiological findings in patients with MPS I [ 21 , 53 ]. In a report of two case studies, a patient with conductive hearing loss experienced improved audiological findings after ERT, while a patient with mixed hearing loss did not exhibit audiological improvement [ 54 ].…”

“…Without the presence of any otolaryngologic interventions such as tympanostomy tube placement, hearing issues can progress and lead to severe or permanent hearing loss [ 97 ]. As for the ERT effects on hearing in patients with MPS VI, the results are still inconclusive [ 37 , 38 , 39 , 40 , 53 ]. Previous studies have indicated an unchanging hearing status after ERT in some patients, whereas other studies have indicated hearing improvement [ 38 , 39 , 40 ], even in the patient with sensorineural hearing loss.…”