2026-06-21 | Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study.

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.

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2026-05-25 | RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H.

Gene therapy and hematopoietic stem cell transplantation (HSCT) have transformed outcomes for severe mucopolysaccharidosis type I (MPS I-H), yet a critical unmet need remains. Children with MPS I-H frequently experience progressive skeletal, cardiac, and other complications despite timely HSCT, largely because enzyme activity cannot be safely and precisely titrated over time. Irreversible genetic modification via integrating vectors offers supra-physiological enzyme levels but carries long-term safety and re-dosing liabilities in patients treated early in life. We investigated RNA activation (RNAa) as a precision dosing strategy to enhance endogenous IDUA expression without permanent genome alteration. Using MTL-CEBPA, a small activating RNA that upregulates CEBPA transcription factor, we characterized CEBPA-IDUA relationships in vitro, in vivo, and in legacy clinical samples from cancer patients. CCAAT enhancer binding protein alpha activation consistently increased IDUA mRNA across A549, IMR90, and mesenchymal stem cells. In wild-type mice, two intravenous MTL-CEBPA doses produced a ∼2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow-transplanted MPS I-H mice, repeated dosing with MTL-CEBPA led to an approximately 2-fold increase in circulating IDUA activity compared with controls over the 3-weeks treatment period. The largest apparent separation from controls was observed in the homozygous cohort, although these genotype-specific differences should be interpreted cautiously given the limited subgroup sizes. In cancer patient-derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R2 = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment. These translational data demonstrate that MTL-CEBPA delivers controlled, reversible enhancement of IDUA in the context of HSCT, providing robust pharmacodynamic proof-of-concept rather than definitive evidence of durable efficacy. By enabling titratable enzyme elevation without integrating vectors, RNAa therapeutics address a key unmet need in Hurler syndrome: safe fine-tuning of residual enzyme activity over a patient's lifetime. With scalable, cost-effective oligonucleotide manufacturing, MTL-CEBPA and related RNAa therapeutics represent a clinically relevant adjuvant strategy for HSCT-treated MPS I-H, with potential for other enzyme deficiency disorders.

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2026-05-01 | B61-12 Progression of Obstructive Sleep Apnea in Hurler Syndrome: A Case Highlighting the Critical Need for Definitive Airway Management and Continuous Follow Up

Abstract Introduction Hurler syndrome, also known as Mucopolysaccharidosis type I (MPS I), is a rare autosomal recessive disorder caused by a deficiency in the enzyme alpha-L-iduronidase. This leads to the accumulation of glycosaminoglycans (GAGs) in multiple systems. OSA is a common yet under-recognized complication of Hurlers syndrome, often arising from the progressive accumulation of GAG in upper airway structures, specifically the tonsils, adenoids, macroglossia, and other soft tissue structures; often leading to challenges in anesthesia and failure of conservative treatment. Adenotonsillectomy (T&A) has limited efficacy and CPAP has challenges with compliance. Case report We present a case of a 5-year-old boy with Hurler syndrome, multisuture craniosynostosis, who presented with snoring, witnessed apneas, restless sleep and daytime somnolence. Born full term, with no significant family history, he had bilateral proptosis, severe macroglossia, high arched palate with crowding, tonsil size 2+, Mallampati 4, kyphosis, with developmental delay. PSG demonstrated severe OSA, AHI 67.9/hour, O2 desaturation nadir of 60%, ETCO2 >50mmHg of 36% and an abnormal sleep architecture. An urgent ENT, cardiology and anesthesia evaluation recommended T&A with perioperative considerations for high-risk anesthesia, difficult airway, and cervical spine instability. At that time, parents declined T&A, thus BiPAP therapy was initiated following titration study that demonstrated AHI 11.6 /hour on 10/6 cm H2O. BiPAP intolerable by the patient despite a trial for few months. The patient lost follow up for 3 years and returned with deterioration of symptoms and BiPAP non-adherence. Upon return at age 8, repeat PSG revealed interval worsening AHI 73.1 /hr, lowest O2 saturation of 52%, ETCO2 >50mmHg of 45% The patient underwent tracheostomy with resolution of sleep apnea and significant improvement in quality of life. This case highlights the importance of early OSA screening in MPS I and discusses the complexities of airway management with delay in management. Discussion OSA affects 70-90% of Hurler syndrome patients and represents a significant cause of morbidity and mortality. This case provides important insights into the natural history of progressive airway obstruction in Hurler syndrome, the limitations of conservative management approaches, and the potentially catastrophic consequences when patients with complex medical needs lose access to specialized multidisciplinary care. Tracheostomy remains the most definitive and reliable intervention for severe OSA in Hurler syndrome. While it represents a significant burden for patients and families, including risks of infection, and impact on speech development, it is often life-saving and substantially improves quality of life in appropriately selected patients. This abstract is funded by: None

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