Machado-Joseph Disease (MJD)
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the ATXN3 gene. Protheragen boasts a talented team of researchers and scientists with extensive expertise in MJD. They are deeply committed to pioneering the development of cutting-edge therapies for MJD, aiming to address unmet therapeutic needs and advance targeted therapeutics in the field.
Introduction to Machado-Joseph Disease (MJD)
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most prevalent autosomal dominant neurodegenerative ataxia worldwide. It is characterized by progressive cerebellar dysfunction, pyramidal and extrapyramidal signs, peripheral neuropathy, and bulbar symptoms, leading to severe disability. The disease exhibits genetic anticipation, where successive generations experience earlier onset and more severe symptoms due to CAG repeat expansion instability.
Fig.1 Pathological mechanism of Machado-Joseph disease (MJD). (Paulson H., 2012)
Pathogenesis of Machado-Joseph Disease (MJD)
The pathogenesis of Machado-Joseph disease (MJD) is driven by a CAG trinucleotide repeat expansion in the ATXN3 gene, resulting in a toxic polyglutamine-expanded ataxin-3 protein that misfolds and forms insoluble aggregates in neurons. These aggregates disrupt proteostasis by impairing the ubiquitin-proteasome system and autophagy, leading to the accumulation of damaged proteins. Additionally, mutant ataxin-3 interferes with transcriptional regulation, induces mitochondrial dysfunction, and causes excitotoxicity through calcium dysregulation.
Fig.2 Overview of the molecular pathogenesis of Machado-Joseph disease (MJD). (Da Silva J D, et al., 2019)
Therapeutic Development for Machado-Joseph Disease (MJD)
| Drug Names | Mechanism of Action | Targets | NCT Number | Research Phase |
| Lithium Carbonate | Enhances autophagy, reduces mutant ataxin-3 aggregation, and exhibits neuroprotective effects | mTOR pathway | NCT01096082 | Phase II/III |
| VO659 | Antisense oligonucleotide (ASO) designed to selectively suppress mutant ATXN3 mRNA expression | ATXN3 gene | NCT05822908 | Phase I/IIa |
| Sodium Phenylbutyrate | Histone deacetylase (HDAC) inhibitor, improves protein clearance, reduces toxic aggregates | HDACs | NCT01096095 | Phase II |
| BIIB132 | Small molecule modulating kinase pathways to reduce neurodegeneration and improve motor function | Undisclosed (likely kinases involved in proteostasis) | NCT05160558 | Phase I |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
To advance the effective management of Machado-Joseph disease (MJD), Protheragen offers comprehensive diagnostic and therapeutic development services. With a focus on the diverse molecular mechanisms driving MJD, we are dedicated to developing innovative and targeted therapies that address the significant unmet medical needs. Our team excels in creating highly accurate disease models, enabling rigorous evaluation of the safety, efficacy, and mechanism of action of potential therapeutics.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- MJD84.2 Transgenic Model
- Homozygous Q71C Model
- Ataxin-3-Q79HA Model
- PrP/MJD77-het/hom Model
- HDProm-MJD148 Model
- Other Models
Focusing on preclinical research, Protheragen offers comprehensive pharmacodynamic (PD), pharmacokinetic (PK), and toxicology study services to support the development and regulatory approval of potential therapies. If you are interested in our services, please feel free to contact usfor more details and quotation information of related services.
References
- Paulson H. Machado–Joseph disease/spinocerebellar ataxia type 3[J]. Handbook of clinical neurology, 2012, 103: 437-449.
- Da Silva J D, Teixeira-Castro A, Maciel P. From pathogenesis to novel therapeutics for spinocerebellar ataxia type 3: evading potholes on the way to translation[J]. Neurotherapeutics, 2019, 16(4): 1009-1031.