RARE DISEASE
Mucolipidosis
Mucolipidosis
Mucolipidosis
Drug discovery
1
drug
With orphan designation
Overview
Mucolipidosis (ML) encompasses rare autosomal recessive lysosomal storage disorders caused by defective trafficking of lysosomal enzymes due to GNPTAB, GNPTG, or MCOLN1 mutations [1][3][7]. ML types II/III (I-cell disease) involve skeletal dysplasia, developmental delay, cardiorespiratory complications, and progressive neurodegeneration, while ML IV features severe psychomotor impairment and retinal degeneration [1][7][15]. Diagnosis relies on elevated plasma lysosomal enzymes, genetic testing, and imaging showing dysostosis multiplex [1][6][12].
Therapies
Supportive care dominates: physical/occupational therapy, respiratory support, and corrective surgeries [1][9]. Bisphosphonates (e.g., alendronate) show efficacy in reducing pathologic bone resorption in ML II/III [3]. Experimental gene therapy for ML IV demonstrates improved CNS outcomes in preclinical models [13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism
Research Papers
231 drug discovery papers about Mucolipidosis, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
231 drug discovery papers about Mucolipidosis, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-20 | Zoledronic acid ameliorates multiple organ pathologies in a murine model of mucolipidosis II by partially restoring mannose-6-phosphate-mediated lysosomal hydrolase activities.
Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.
2026-06-18 | Relevance of functional studies for assessing an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis type II.
Mucolipidosis type II (ML II) is a lysosomal storage disorder caused by deficiency of N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which impairs the trafficking of lysosomal hydrolases. Of all ML II pathogenic variants, c.3503_3504del in GNPTAB exon 19 is the most prevalent, therefore constituting a compelling molecular target for the development of personalized therapeutic strategies. Here, we explored the feasibility of an innovative RNA based-therapeutic strategy using antisense oligonucleotides (ASOs) designed to induce exon 19 skipping in GNPTAB pre-mRNA. This approach was previously successfully tested at the mRNA level in fibroblasts from ML II patients, where it generated an in-frame mRNA. In the present study, our aim was to evaluate whether GNPTAB exon 19 skipping could increase GlcNAc-PT levels and consequently improve the cellular phenotype of ML II patients carrying this pathogenic variant. To address this, we designed a functional approach based on the overexpression of a GNPTAB construct carrying the exon 19 deletion enabling the indirect evaluation of the resulting protein´s functionality. Our first results demonstrated that in ML II fibroblasts, ASO treatment led to a modest increase in lysosomal hydrolase activity at 24 h and 48 h. Moreover, LAMP-1 expression remained elevated and comparable to untreated ML II cells, indicating that GlcNAc-PT activity was not restored. To further investigate the functional relevance of exon 19 skipping, overexpression studies were performed in HEK293T cells. Three constructs (pGNPTAB WT, pGNPTAB del_exon19 and pGNPTAB c.3503_3504del) were expressed. Both pGNPTAB WT and pGNPTAB del_exon19 constructs produced the α/β-precursor. However, only the WT construct generated the mature β-subunit, whereas the pGNPTAB c.3503_3504del construct showed no detectable expression. These findings indicate that exon 19 is essential for proper GlcNAc-PT processing and enzymatic activity. Although ASO treatment corrected splicing at the mRNA level, it did not restore GlcNAc-PT activity in ML II patient cells. Nonetheless, our findings clarify the functional importance of exon 19 and demonstrate that overexpression of an exon-skipped construct provides a simple and effective strategy to indirectly assess protein functionality, supporting the prioritization of this kind of approach to test an exon-skipping ASO-based approach before advancing to studies in patient-derived cells.
2026-05-03 | Peroxisome-derived ether lipids regulate lysosomal exocytosis.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
2026-06-20 | Zoledronic acid ameliorates multiple organ pathologies in a murine model of mucolipidosis II by partially restoring mannose-6-phosphate-mediated lysosomal hydrolase activities.
Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.
2026-06-18 | Relevance of functional studies for assessing an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis type II.
Mucolipidosis type II (ML II) is a lysosomal storage disorder caused by deficiency of N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which impairs the trafficking of lysosomal hydrolases. Of all ML II pathogenic variants, c.3503_3504del in GNPTAB exon 19 is the most prevalent, therefore constituting a compelling molecular target for the development of personalized therapeutic strategies. Here, we explored the feasibility of an innovative RNA based-therapeutic strategy using antisense oligonucleotides (ASOs) designed to induce exon 19 skipping in GNPTAB pre-mRNA. This approach was previously successfully tested at the mRNA level in fibroblasts from ML II patients, where it generated an in-frame mRNA. In the present study, our aim was to evaluate whether GNPTAB exon 19 skipping could increase GlcNAc-PT levels and consequently improve the cellular phenotype of ML II patients carrying this pathogenic variant. To address this, we designed a functional approach based on the overexpression of a GNPTAB construct carrying the exon 19 deletion enabling the indirect evaluation of the resulting protein´s functionality. Our first results demonstrated that in ML II fibroblasts, ASO treatment led to a modest increase in lysosomal hydrolase activity at 24 h and 48 h. Moreover, LAMP-1 expression remained elevated and comparable to untreated ML II cells, indicating that GlcNAc-PT activity was not restored. To further investigate the functional relevance of exon 19 skipping, overexpression studies were performed in HEK293T cells. Three constructs (pGNPTAB WT, pGNPTAB del_exon19 and pGNPTAB c.3503_3504del) were expressed. Both pGNPTAB WT and pGNPTAB del_exon19 constructs produced the α/β-precursor. However, only the WT construct generated the mature β-subunit, whereas the pGNPTAB c.3503_3504del construct showed no detectable expression. These findings indicate that exon 19 is essential for proper GlcNAc-PT processing and enzymatic activity. Although ASO treatment corrected splicing at the mRNA level, it did not restore GlcNAc-PT activity in ML II patient cells. Nonetheless, our findings clarify the functional importance of exon 19 and demonstrate that overexpression of an exon-skipped construct provides a simple and effective strategy to indirectly assess protein functionality, supporting the prioritization of this kind of approach to test an exon-skipping ASO-based approach before advancing to studies in patient-derived cells.
2026-05-03 | Peroxisome-derived ether lipids regulate lysosomal exocytosis.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
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Drug Discovery Landscape
1 orphan drug designation for Mucolipidosis.
1 orphan drug designation for Mucolipidosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector type 9 with S1S3 gene encoding S1S3 variant of N-acetylglucosamine-1-phosphotransferase | gene therapies | FDA | 2020-10-20 | — | M6P Therapeutics |
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