Commentary: Lysosomal enzymes engineered to cross the blood-brain barrier are reshaping the therapeutic landscape of neuronopathic mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by deficiencies in enzymes required for glycosaminoglycan (GAG) degradation. In MPS II (Hunter syndrome), mutations in iduronate-2-sulfatase (IDS) gene result in widespread storage pathology that includes progressive neurocognitive decline in the severe phenotype. Enzyme replacement therapy has improved systemic disease but does not cross the blood–brain barrier (BBB), leaving neurological deterioration unaddressed [1]. Thus, the need for therapies that correct both somatic and central nervous system (CNS) manifestations remains urgent.

In this issue of Neurotherapeutics, Jin and colleagues report a liver-directed AAV8 therapy encoding a brain-penetrant IDS (eBT-IDS4) [2]. The study provides evidence that a single systemic administration of a viral vector expressing IDS to mice can simultaneously target both peripheral and neurological disease manifestations in MPS II. By exploiting the liver as a continuous source of secretion, eBT-IDS4 achieves durable systemic distribution, while its optimized design allows efficient penetration across the BBB. This dual effect directly addresses one of the major limitations of conventional therapies, which are effective on somatic pathology but unable to halt neurological decline. The authors demonstrate that intravenous delivery of eBT-IDS4 in adult MPS II mice resulted in restoration of CNS IDS activity to nearly physiological levels, normalization of lysosomal storage and neuroinflammation, and measurable recovery of cognitive performance. Notably, this effect was obtained without sacrificing systemic efficacy: skeletal, cardiac, and visceral manifestations were also corrected, underscoring the capacity of this approach to provide whole-body rescue.

This work sets the stage for a broader discussion of how engineered lysosomal enzymes—whether delivered as recombinant proteins or through gene therapy vectors—are reshaping the therapeutic landscape of MPS and other lysosomal storage disorders. The idea of modifying lysosomal enzymes to improve CNS uptake has been already explored across multiple lysosomal storage disorders. Early studies by Fraldi and colleagues showed that highly secreted sulphamidase constructs carrying ApoB motifs, markedly improved enzyme secretion, stability, and CNS uptake in MPS-IIIA mice, thus translating into robust neuropathological and behavioral correction [3,4]. A similar strategy based on hematopoietic stem cell gene therapy using lentiviral IDS fused to ApoEII (IDS.ApoEII) demonstrated enhanced brain correction in MPS-II mice [5]. More recently, Gritti and colleagues optimized hematopoietic stem cell gene therapy for globoid cell leukodystrophy using chimeric enzymes with enhanced enzyme secretion and BBB cross-correction, thus, achieving improved neuropathology and functional outcomes [6]. In Pompe disease, where standard therapy fails to prevent glycogen accumulation in the CNS, antibody-fused acid-alpha glucosidase (GAA) proteins restored enzyme activity and neurological phenotype [7].

All these studies used virus-corrected either liver or hematopoietic stem cells as a reservoir of the chimeric lysosomal enzymes with enhanced CNS correction capability. Interestingly, enzyme replacement therapy approaches based on the direct delivery of recombinant brain-penetrant chimeric enzymes rather than viral vectors encoding the chimeric enzyme have been largely explored in the last years for different MPS, and some of them already reached the clinical validation. Lysosomal enzymes fused to antibody against the transferrin receptor have been developed by both JCR Pharmaceuticals and Denali Therapeutics and showed therapeutic efficacy in different MPS mouse models [[8], [9], [10]]. Importantly, clinical progress has already confirmed the feasibility of these approaches in MPS-II patients leading to approval in Japan, while clinical trials are ongoing for MPS-I, MPS-IIIA and IIIB.

Compared with other strategies, the AAV8–eBT-IDS4 approach described by Jin et al. appears to offer some advantages in terms of combining BBB crossing with robust peripheral bioavailability of the therapeutic enzyme, thus, achieving simultaneous systemic and CNS correction. On the other hand, translation to humans will require overcoming immunogenicity, ensuring long-term durability, and carefully balancing safety with efficacy.

Author Contributions

NCS wrote a draft.

AF provided input on the main points of the Commentary, reviewed and finalized the commentary.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Alessandro Fraldi reports a relationship with University of Naples Federico II that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.