Alexander Disease
Alexander disease is still an incurable condition because any therapy that would help silencing toxic GFAP must do so without debilitating crucial astrocyte functions. At Protheragen, we focus on understanding and managing Alexander disease by developing advanced therapies and offering disease modeling services. We aim to provide comprehensive solutions spanning from research on Alexander disease therapies to their eventual commercial release.
Overview of Alexander Disease
Alexander disease is an uncommon and deadly leukodystrophy arising from dominant alterations in the GFAP gene, which results in the build-up of incorrectly folded glial fibrillary acidic protein and the production of Rosenthal fibers within astrocytes. The clinical features of this disorder include the megalencephaly, seizures, spasticity, and developmental regression in the infantile form which is the most common. There is also the bulbar symptoms, ataxia and motor deterioration which is seen in the juvenile and adult variants.
Fig.1 Summary of the pathology of Alexander disease. (Zavala E, Zimmerman T., 2025)
Pathogenesis of Alexander Disease
Alexander disease pathogenesis is driven by heterozygous gain-of-function mutations in the GFAP gene, which leads to the accumulation of misfolded glial fibrillary acidic protein as toxic Rosenthal fibers within astrocytes. These aggregates disrupt cellular homeostasis, impair important astrocytic functions like glutamate clearance and potassium buffering, initiate chronic neuroinflammation, and ultimately result in the degeneration of white matter and profound neurological impairment.
Fig.2 Interactions between the potential drug targets for Alexander disease. (Zavala E, Zimmerman T., 2025)
Therapeutic Development for Alexander Disease
| Drug Name | Mechanism of Action | Targets | Research Phase |
| Zilganersen | Antisense oligonucleotide (ASO) designed to reduce the expression of GFAP mRNA, thereby decreasing production of mutant GFAP protein and Rosenthal fiber formation. | GFAP mRNA | Phase III |
| Levetiracetam | Synaptic vesicle glycoprotein 2A (SV2A) modulator that reduces synaptic neurotransmitter release, stabilizing neuronal excitability and suppressing seizure activity. | SV2A protein | Approved |
| Valproic Acid | Histone deacetylase (HDAC) inhibitor and GABA enhancer; modulates epigenetic regulation and increases inhibitory neurotransmission to control seizures and mood instability. | HDAC enzymes, GABA transaminase | Approved |
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
As a professional service provider in preclinical research, Protheragen is committed to advancing breakthroughs in Alexander disease. We provide full service from novel therapeutic development to accurate disease modeling, as well as comprehensive preclinical validation. By using our blood-brain barrier model, we can assess the crucial drug permeability of the central nervous system (CNS) while reducing potential harm to the body, which is critical for the development of effective therapies.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- GFAP Transgenic Model: Overexpresses mutant GFAP to mimic Rosenthal fiber accumulation in astrocytes.
- GFAP Knock-in Model: Introduces mutant GFAP at the endogenous locus, recapitulating the human Alexander disease genotype and pathology.
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 us for more details and quotation information of related services.
Reference
- Zavala E, Zimmerman T. Alexander's Disease: Potential Drug Targets and Future Directions[J]. Molecular Neurobiology, 2025: 1-14.