Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study

Abstract

Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), administered via weekly intravenous infusions. ERT is of limited efficacy owing to its inability to reach critical tissues such as the brain and bone. To address these limitations, this study explores a novel method to improve drug delivery to target organs and simplify administration: oral administration of enzyme encapsulated within nanostructured lipid carriers (NLC). Encapsulation of ERT within NLC enabled effective oral administration. In vitro analysis showed that our NLC formulation was as effective as intravenous ERT in correcting enzyme activity and reducing glycosaminoglycan (GAG) accumulation in fibroblasts from MPS-I patients, when administered periodically. Permeability studies confirmed passage across the intestinal barrier. Proteomic analyses demonstrated normalization of protein expression in energetic pathways related to hexose metabolism, and significant improvements in protein dysregulation in the cytoskeleton, cellular trafficking, lysosomal function, GAG biosynthesis and degradation, and the extracellular matrix. Furthermore, in vivo studies in MPS-I knockout (KO) mice demonstrated biodistribution of NLC-encapsulated enzymes to all tissues affected by the disease, including passage across the blood-brain barrier and access to poorly vascularized bone. These findings suggest that oral administration of ERT via NLC encapsulation represents a significant advancement in MPS-I treatment, enabling drug delivery to previously inaccessible areas. This study opens important avenues of research for future therapeutic strategies targeting LSDs.

Background

Mucopolysaccharidosis type I (MPS-I) (OMIM # 607014-6) is a rare, autosomal recessive lysosomal storage disease (LSD) characterized by a deficiency in alpha-L-iduronidase (EC 3.2.1.76), resulting from mutations in the IDUA gene that encodes this enzyme. This deficiency leads to the accumulation of glycosaminoglycans (GAGs), specifically dermatan sulfate (DS) and heparan sulfate (HS), in multiple tissues, causing progressive, multisystemic symptoms. MPS-I has a broad spectrum of disease severity, ranging from severe (Hurler syndrome; OMIM # 607014) to intermediate (Hurler-Scheie syndrome; OMIM # 607015) and attenuated (Scheie syndrome; OMIM # 607016) phenotypes [1]. Clinical features typically manifest within the first year of life, and include musculoskeletal abnormalities such as short stature, dysostosis multiplex, and thoracic-lumbar kyphosis, as well as facial coarsening, hearing loss, enlarged tonsils and adenoids, cardiomyopathy, and valvular abnormalities. Other common manifestations include organomegaly, hernias, and hirsutism [2,3,4,5,6,7]. Developmental delay, particularly in speech and cognitive function, is often observed between 12 and 24 months of age. Hydrocephaly can develop after 2 years of age, while diffuse corneal clouding becomes detectable from approximately 3 years of age [8, 9]. Current treatments for MPS-I include hematopoietic stem cell transplantation (HSCT) [10] and enzyme replacement therapy (ERT) [11,12,13,14,15]. Both approaches rely on “cross-correction”, the transfer of functional protein from healthy to deficient cells. In HSCT, donor-derived myeloid cells differentiate into tissue macrophages that cross-correct neighboring defective cells via mannose-6-phosphate (M6P) receptors: macrophages migrating to the central nervous system differentiate into glial cells, enabling neuronal correction [16]. While HSCT can halt neurocognitive decline, its use is dependent on donor availability and is limited due to transplant-associated morbidity and mortality, such as graft-versus-host disease and immunosuppression. Furthermore, long-term outcomes are often suboptimal, with progressive worsening of pre-HSCT manifestations such as hip dysplasia, kyphosis, valvular heart disease, hearing impairment, and corneal clouding [10, 17,18,19].

The approved ERT for MPS-I is laronidase (Aldurazyme®), a recombinant form of human alpha-L-iduronidase produced in Chinese hamster ovary cells, administered via weekly intravenous infusions. ERT is typically used for patients with attenuated MPS-I phenotypes [11], such as Hurler-Scheie and Scheie syndromes, and as a complementary therapy for Hurler syndrome in the peri-transplant period and beyond [19, 20]. Although generally well-tolerated, ERT requires weekly infusions of several hours, contributing to the burden for patients and their families [12]. A significant limitation of ERT is its inability to cross the blood-brain barrier and inefficient delivery to avascular tissues [11], resulting in limited improvements in cognitive function, skeletal deformities, and visual acuity. Moreover, most patients develop IgG antibodies to laronidase, potentially interfering with enzyme activity and uptake [21, 22]. Consequently, alternative therapies, such as gene therapies using viral vectors [23, 24] and nanoparticle-based approaches [25], are under development. Each therapeutic approach (HSCT, ERT, gene therapy) presents distinct advantages and disadvantages. HSCT is associated with a high rejection rate if administered after 2 years of age. Conversely, early gene therapy can result in the loss of genetic information due to cell growth in the target tissue. Moreover, comprehensive data supporting the efficacy of these treatments is yet to be gathered. Finally, while administration of ERT at early ages can stabilize disease, its effect is limited to tissues directly exposed to the enzyme [26].

To overcome the limitations of current MPS-I therapies, this study explores a novel approach: encapsulating laronidase within lipid nanoparticles to enhance enzyme delivery to target tissues [25, 27, 28]. Several national and international groups are working on developing encapsulated enzyme therapies for various lysosomal diseases. Dr. Ibane Abasolo’s group (Vall d’Hebron Hospital, Spain) is researching extracellular vesicles as alternative treatments for Fabry disease [29]. Dr. Rosella Tomanin’s group at the University of Padua, Italy, has extensive experience studying the use of nanoparticle-encapsulated enzymes [30] and gene therapies [31], to treat Hunter syndrome. Similarly, Dr. Helder Texera’s group in Brazil has explored alternative Hurler syndrome treatments, including nanoemulsion-encapsulated plasmids expressing the IDUA protein, which is deficient in this disease [32]. Working groups including those of JCR Pharmaceuticals are incorporating ligands into transferrin enzymes to facilitate access to previously inaccessible areas [33]. Despite their potential, nanoparticle-based approaches, particularly those involving oral administration, remain underexplored, highlighting the importance of further research. This strategy aims to improve drug administration and distribution compared to weekly intravenous infusions [34, 35] by utilizing a non-viral vector to protect the enzyme from gastric degradation and facilitate oral administration.

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Materials

Laronidase (Aldurazyme®) was provided by Sanofi Aventis (Ridgefield, NJ, USA). The following materials were obtained from the indicated suppliers: glyceril dibehenate (Compritol 888 ATO) from Gatefossé (Lyon, France); trimyristin (Dynasan 114) and triestearin (Dynasan 118) from IOI Oleo GmbH (Hamburg, Germany); cholesterol lanolin from Fluka (Munich, Germany); caprylic/capric triglyceride (Miglyol 812 N), olive oil, and soy lecithin from Acofarma (Barcelona, Spain); block copolymers (Kolliphor® P407 and Kolliphor P188) and d-α-tocopherol polyethylene glycol succinate 1000 from Sigma Aldrich (St. Louis, MO, USA); methyl methacrylate-methacrylic acid copolymer (EUDRAGIT® L100-55) from Evonik (Essen, Germany); and phosphate-buffered saline (PBS) buffer, pH 7.2 (Ref.: 21–040-CV) from Corning (MA, USA).

Álvarez, JV., Lis-Lopez, L., Rodrigues, D. et al. Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study. Drug Deliv. and Transl. Res. (2026). https://doi.org/10.1007/s13346-026-02130-9