What is Mucopolysaccharidosis?
 

Mucopolysaccharidosis (MPS) is a group of rare inherited disorders belonging to the lysosomal storage diseases. These conditions are associated with deficiencies of specific enzymes responsible for degrading glycosaminoglycans (GAGs), also known as acid mucopolysaccharides. MPS affects multiple systems throughout the body, with primary symptoms including skeletal deformities, growth retardation, hepatosplenomegaly, cardiac problems, respiratory disorders, and neurological impairment, significantly impacting patients' quality of life and life expectancy. The estimated incidence of MPS is approximately 1 in 25,000.
 

MPS is classified into seven different types (MPS I to MPS IX), each caused by deficiency of a different enzyme. MPS I, the earliest discovered and reported subtype, is characterized by deficiency of the α-L-iduronidase enzyme (IDUA). MPS II is an X-linked recessive disorder affecting predominantly males, caused by mutations in the gene encoding iduronate-2-sulfatase (IDS).

(Image: PubMed)

Pathogenesis
 

MPS affects lysosomal degradation of mucopolysaccharides (glycosaminoglycans, GAGs). GAGs are major components of the extracellular matrix (ECM) that facilitate intercellular and cell-ECM adhesion. In MPS patients, deficiency of one of the lysosomal enzymes involved in the stepwise degradation of GAGs leads to accumulation of partially degraded GAGs in lysosomes and the ECM.
 

MPS I Type, also known as Hurler syndrome, is caused by deficiency of α-L-iduronidase (IDUA). This enzyme deficiency leads to accumulation of dermatan sulfate and heparan sulfate GAGs in various organs and tissues throughout the body. Common pathogenic IDUA mutations vary among different populations. In international patients, frequent mutations include p.Trp402Ter, p.Gln70Ter, and p.Pro533Arg. In Asian populations, mutations associated with more severe subtypes mainly include p.Arg89Gln and c.1190-1G>A.
 

MPS II Type, also known as Hunter syndrome, is an X-linked recessive disorder caused by mutations in the gene encoding iduronate-2-sulfatase (IDS). Loss of IDS enzyme activity results in accumulation of heparan sulfate and dermatan sulfate in tissues throughout the body, potentially leading to secondary accumulation of gangliosides and ceramides. IDS gene mutations are diverse, including small variants (82%), large deletions or duplications (9%), and complex rearrangements (9%). In China, the p.R468W/Q mutation in exon 9 is a hotspot variant associated with severe MPS II, while p.R443X and p.G374G mutations are often linked to milder MPS II.

(Image: PubMed)

Gene Therapy
 

I) MPS I Type
 

1.  Retroviral Vectors: Using retroviral vectors carrying the IDUA gene to transduce patient-derived hematopoietic stem cells (HSCs) ex vivo, followed by reinfusion into the patient.

2.  Adeno-Associated Virus (AAV) Vectors: In vivo gene therapy using AAV vectors to deliver the IDUA gene directly to patients. High-dose intravenous injection of retroviral vectors has shown symptom improvement in neonatal MPS I mouse models.

3.  Gene Editing Technology: Using gene editing techniques to integrate IDUA cDNA with lipid complexes, delivered via intravenous injection. This approach has shown efficacy in mouse models, but faces challenges including low transfer efficiency, need for higher systemic IDUA levels, and difficulties with scaling and storage.
 

II) MPS II Type
 

1.  Adeno-Associated Virus (AAV) Vectors: Intravenous injection of AAV2/8TBG-IDS viral vectors via the tail vein in MPS II mice, controlled by the liver-specific TBG promoter, successfully restored plasma and tissue IDS activity and degraded accumulated GAGs. Additionally, temporal vein injection of AAV 2/5 vectors carrying human IDS cDNA effectively transduced multiple tissues including skeletal muscle and lung, improving neurodegenerative symptoms.

2.  Ex Vivo Gene Therapy: This approach involves culturing patient cells in the laboratory, transducing them with viral vectors carrying the target gene, and reinfusing them into the patient. While still in preclinical stages, this method using retroviral and lentiviral vectors has shown potential in MPS II mouse models.

3.  Gene Editing Technology: Technologies such as zinc finger nucleases (ZFNs) have been used in MPS II gene therapy research, enabling targeted DNA cleavage combined with exogenous delivery of the target gene and the cell's inherent DNA repair system to achieve gene editing.
 

Mouse Models
 

● IDUA KO Mice: MPS I Type model showing progressive lysosomal storage (liver, spleen, bone, heart, etc.); central nervous system (CNS) neurodegeneration (cerebellar neuronal loss, neuroinflammation, gliosis); skeletal abnormalities (dysostosis multiplex); shortened lifespan.

● IDUA W392X Point Mutation Mice: Corresponding to MPS I p.Trp402Ter; severe GAG accumulation (dermatan sulfate DS and heparan sulfate HS) in multiple tissues (liver, spleen, heart, bone, joints, CNS); skeletal abnormalities (facial dysmorphism, dysostosis multiplex); neurological involvement; significantly shortened lifespan.

● IDUA P533R Point Mutation Mice: Corresponding to MPS I p.Pro533Arg; missense mutation leads to unstable enzyme protein with partial activity, resulting in slower and less severe GAG accumulation.

● IDS KO Mice: MPS II Type model showing systemic GAG accumulation (heparan sulfate and dermatan sulfate); CNS involvement (learning and memory deficits, elevated brain GAG levels); visceral organ pathology.

● IDS R468W/Q Point Mutation Mice: Corresponding to MPS II p.Arg468Trp/Gln; systemic GAG accumulation (primarily HS and DS), particularly affecting visceral organs; severe CNS involvement.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various MPS (Types I and II) mouse models according to client needs, such as IDUA KO mice, IDUA W392X point mutation mice, IDUA P533R point mutation mice, IDS KO mice, and IDS R468W/Q point mutation mice. We welcome inquiries!

 

References:

[1] Dai Yangli, Zhu Mingqiang, Zou Chaochun. Research Status and Progress of Mucopolysaccharidosis Type I. Chinese Journal of Endocrinology and Metabolism, 2021, 37(4): 306-310. DOI: 10.3760/cma.j.cn311282-20201214-00824.

[2] Yu Hanfei, Qin Qian, Wu Jie, et al. Analysis of IDS Gene Pathogenic Variants in a Mucopolysaccharidosis Type II Family. Chinese Journal of Endocrinology and Metabolism, 2023, 39(04): 345-352.

[3] Chen Guoqing, Zhang Huiwen. Gene Diagnosis and Treatment of Mucopolysaccharidosis Type II. Journal of Clinical Pediatrics, 2024, 42(3): 270-276.

[4] Fecarotta S, Tarallo A, Damiano C, Minopoli N, Parenti G. Pathogenesis of Mucopolysaccharidoses, an Update. Int J Mol Sci. 2020 Apr 4;21(7):2515. doi: 10.3390/ijms21072515. PMID: 32260444; PMCID: PMC7178160.

[5] Hampe CS, Eisengart JB, Lund TC, Orchard PJ, Swietlicka M, Wesley J, McIvor RS. Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology. Cells. 2020 Aug 5;9(8):1838. doi: 10.3390/cells9081838. PMID: 32764324; PMCID: PMC7463646.

[6] Çelik B, Tomatsu SC, Tomatsu S, Khan SA. Epidemiology of Mucopolysaccharidoses Update. Diagnostics (Basel). 2021 Feb 10;11(2):273. doi: 10.3390/diagnostics11020273. PMID: 33578874; PMCID: PMC7916572.

[7] Zhang Wen, Liu Li. Advances in Diagnosis and Treatment of Mucopolysaccharidosis Type II. International Journal of Pediatrics, 2022, 49(6): 418-422. DOI: 10.3760/cma.j.issn.1673-4408.2022.06.015.

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