Mucolipidosis (ML)
Mucolipidosis (ML) is a very rare genetic metabolic disorder that falls under the category of lysosomal storage diseases. It is named due to its manifestations being similar to those of mucopolysaccharidoses and sphingolipidoses. At our company, we've brought together a team of highly experienced professionals who are well-versed in addressing the complexities of drug and therapy development for Mucolipidosis.
Overview of Mucolipidosis
Mucolipidosis is a rare group of genetic metabolic disorders that are classified as lysosomal storage diseases. The estimated prevalence of mucolipidosis types II and III (ML II and ML III) is approximately 1 in 100,000 to 400,000 individuals worldwide. These disorders are inherited in an autosomal recessive manner and result from mutations in genes responsible for lysosomal enzyme transport, leading to the accumulation of various substrates within lysosomes.
Fig. 1 Qualitative representation of disease progression and stages in MLIV. (Misko, A., et al., 2021)Pathogenesis of Mucolipidosis
Mucolipidosis II and III (ML II/III) result from a deficiency in the enzyme uridine-diphosphate N-acetylglucosamine: GlcNAc-1-phosphotransferase. This enzyme's role is to attach mannose 6-phosphate (M6P) markers to lysosomal enzymes, which are essential for directing these enzymes to the lysosomes. This deficiency causes an excessive release of lysosomal enzymes from cells and a lack of these enzymes within the lysosomes. As a result, substrates such as cholesterol, phospholipids, and glycosaminoglycans accumulate within the lysosomes.
Fig. 2 Comparison of cell function between healthy control and ML II/III patients, adapted from Velhoetal. (Khan, S.A. and Tomatsu, S.C., 2020)Diagnosis Development of Mucolipidosis
Biomarker Development
Key biomarkers include elevated levels of lysosomal enzymes in the blood and decreased enzyme activity within cells. For instance, significant increases in enzymes such as arylsulfatase A, β-hexosaminidase, and α-N-acetylglucosaminidase in plasma are indicative of ML, reflecting the hypersecretion of these enzymes due to defective lysosomal transport.
Molecular Diagnosis
The diagnosis of Mucolipidosis (ML), particularly types II and III, primarily involves genetic testing to identify mutations in the GNPTAB gene, which encodes the enzyme GlcNAc-1-phosphotransferase. Molecular genetic testing, which includes sequencing of GNPTAB and GNPTG genes, is vital for confirming the diagnosis and differentiating between ML types II and III.
Therapeutics Development of Mucolipidosis
- Gene Therapy: Gene therapy holds promise for correcting the genetic defects underlying ML. Recent studies have focused on using recombinant adeno-associated viral (AAV) vectors to deliver the GNPTAB gene into mouse models of ML. These studies have shown significant improvements in bone mineral density and content, as well as a decrease in IL-6 levels in articular cartilage.
- Hematopoietic Stem Cell Transplantation (HSCT): HSCT has been explored as a treatment for ML by introducing donor-derived hematopoietic cells that generate lysosomal enzymes with M6P markers. Some studies have reported partial improvements in growth and cognitive development. However, the overall results have been inconsistent, and the procedure carries considerable risks.
Our Services
At our company, we embrace a collaborative approach, working closely with clients to develop customized and innovative therapy strategies for Mucolipidosis. Our focus on customized strategies ensures that we meet your individual needs with the highest level of support and guidance.
Platforms of Mucolipidosis Therapy Development
Animal Models of Mucolipidosis
We have considerable expertise in developing and employing animal models that accurately replicate the disease characteristics and therapeutic responses seen in Mucolipidosis. These models are instrumental in investigating the underlying mechanisms and assessing the safety and effectiveness of prospective therapies with precision.
Non-Genetically Engineering Models
They are biological systems used in research that do not involve the manipulation or alteration of an organism's genetic material.
Optional Models: High-Cholesterol Diet Model
Genetically Engineering Models
Genetically engineering models involve the manipulation of genetic material to study specific disease mechanisms and therapeutic interventions.
Optional Models: Mcoln1tm1Asoy Mice Model; Gnptabem1Cya Mice Model
Moreover, we provide a variety of detailed animal model services focused on particular signaling pathways and molecular targets.
If you are interested in our services, please don't hesitate to contact us.
References
- Misko, A., et al., "Progress in elucidating pathophysiology of mucolipidosis IV." Neurosci Lett, (2021). 755: p. 135944.
- Khan, S.A. and Tomatsu, S.C., "Mucolipidoses Overview: Past, Present, and Future." Int J Mol Sci, (2020). 21(18).
- Jezela-Stanek, A., et al., "Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV-A Review and Case Series." Int J Mol Sci, (2020). 21(12).
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.