New Paradigms in Management of Central Nervous System Damage in Patients with Hunter Syndrome

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a progressive lysosomal storage disease with X-linked recessive inheritance. This disease is caused by pathogenic or probably pathogenic variants in the IDS gene encoding iduronate 2-sulfatase. This enzyme insufficiency leads to glycosaminoglycans accumulation in cells of various organs and tissues, which underlies the multisystem lesion. There is neuropathic form of MPS II with progressive central nervous system (CNS) damage and behavioral disorders, and milder form without any intellectual disorders. There are methods of effective pathogenetic therapy for this disease, however, they do not affect CNS manifestations. Thus, there is topical issue in management of neuropathic MPS II forms on transporting enzyme-replacement medications through the blood-brain barrier (BBB). Development of pabinafusp alfa (JR-141), innovative drug penetrating the BBB via transcytosis mediated by the transferrin receptor, became one of the approaches to solve this problem. This publication provides the literature review on the pabinafusp alfa administration for management of neuropathic MPS II forms focusing its efficacy and safety.

1. Mukopolisakharidoz tip II: Clinical guidelines. 2025. (In Russ).]

2. Mao SJ, Chen QQ, Dai YL, et al. The diagnosis and management of mucopolysaccharidosis type II. Ital J Pediatr. 2024;50(1):207. doi: https://doi.org/10.1186/s13052-024-01769-9

3. Semyachkina AN, Voskoboeva EY, Zakharova EY, et al. Case report: a rare case of Hunter syndrome (type II mucopolysaccharidosis) in a girl. BMC Med Genet. 2019;20(1):66. doi: https://doi.org/10.1186/s12881-019-0807-x

4. Vashakmadze ND, Zhurkova NV, Namazova-Baranova LS, et al. Non-Neuropathic Form of Mucopolysaccharidosis Type II: Clinical Cases. Voprosy sovremennoi pediatrii — Current Pediatrics. 2021;20(1):72–80. (In Russ). doi: https://doi.org/10.15690/vsp.v20i1.2238)

5. Bigger BW, Begley DJ, Virgintino D, Pshezhetsky AV. Anatomical changes and pathophysiology of the brain in mucopolysaccharidosis disorders. Mol Genet Metab. 2018;125(4):322–331. doi: https://doi.org/10.1016/j.ymgme.2018.08.003

6. Burton BK, Jego V, Mikl J, Jones SA. Survival in idursulfasetreated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis. 2017; 40(6):867–874. doi: https://doi.org/10.1007/s10545-017-0075-x

7. Fukatsu T, Morio H, Furihata T, Sonoda H. Transferrin receptor-targeting property of pabinafusp alfa facilitates its uptake by various types of human brain-derived cells in vitro. Front Drug Deliv. 2023;3:1082672. doi: https://doi.org/10.3389/fddev.2023.1082672

8. Sato Y, Okuyama T. Novel enzyme replacement therapies for neuropathic mucopolysaccharidosis. Int J Mol Sci. 2020;21(2):400. doi: https://doi.org/10.3390/ijms21020400

9. Seo JH, Kosuga M, Hamazaki T, et al. Impact of intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II. Mol Ther Methods Clin Dev. 2021;21:67–75. doi: https://doi.org/10.1016/j.omtm.2021.02.018

10. Sonoda H, Morimoto H, Yoden E, et al. A blood-brain-barrierpenetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Mol Ther. 2018;26(5):1366–1374. doi: https://doi.org/10.1016/j.ymthe.2018.02.032

11. Boado RJ, Ka-Wai Hui E, Zhiqiang Lu J, Pardridge WM. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: Pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol Bioeng. 2014;111(11):2317–2325. doi: https://doi.org/10.1002/bit.25289

12. Okuyama T, Eto Y, Sakai N, et al. Iduronate-2-sulfatase with anti-human transferrin receptor antibody for neuropathic mucopolysaccharidosis II: a phase 1/2 trial. Mol Ther. 2019;27(2): 456–464. doi: https://doi.org/10.1016/j.ymthe.2018.12.005

13. Tanaka N, Kida S, Kinoshita M, et al. Evaluation of cerebrospinal fluid heparan sulfate as a biomarker of neuropathology in a murine model of mucopolysaccharidosis type II using high-sensitivity LC/MS/MS. Mol Genet Metab. 2018;125(1-2):53–58. doi: https://doi.org/10.1016/j.ymgme.2018.07.013

14. Couch JA, Yu YJ, Zhang Y, et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci Transl Med. 2013;5(183):183ra57, 1–12. doi: https://doi.org/10.1126/scitranslmed.3005338

15. Giugliani R, Martins AM, Okuyama T, et al. Enzyme replacement therapy with pabinafusp alfa for neuronopathic mucopolysaccharidosis II: an integrated analysis of preclinical and clinical data. Int J Mol Sci. 2021;22(20):10938. doi: https://doi.org/10.3390/ijms222010938

16. Okuyama T, Eto Y, Sakai N, et al. 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(2): 671–679. doi: https://doi.org/10.1016/j.ymthe.2020.09.039

17. Giugliani R, Martins AM, So S, et al. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Mol Ther. 2021;29(7):2378–2386. doi: https://doi.org/10.1016/j.ymthe.2021.03.019

18. Tomita K, Okamoto S, Seto T, et al. Divergent developmental trajectories in two siblings with neuropathic mucopolysaccharidosis type II (Hunter syndrome) receiving conventional and novel enzyme replacement therapies: A case report. JIMD Rep. 2021;62(1):9–14. doi: https://doi.org/10.1002/jmd2.12239

19. Hamazaki Т. Neurocognitive developments in siblings with neuronopathic MPS II receiving conventional and novel enzyme replacement therapies: an update. PO-256. Presented at the SSIEM Annual Symposium 2024, 3–6 September 2024, Porto, Portugal.