Hereditary Spastic Ataxia (HSA)
Hereditary spastic ataxia (HSA) is characterized by the particular genetic mutations which the patient possesses and leads to the degeneration of both the spinal cord and the cerebellum. Protheragen has well-known experts in HSA which allows the company to pursue novel research angles. They are working toward developing HSA therapies to fill the gaps in therapeutic innovations and to further the scope of targeted therapeutics.
Overview of Hereditary Spastic Ataxia (HSA)
Hereditary spastic ataxia (HSA) is a rare, genetically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and ataxia due to upper motor neuron (UMN) degeneration. From a clinical viewpoint, HSA manifests with changes in gait, muscular rigidity, speech impairments, and issues with eye movement. The range of symptoms is heterogeneous, with the disease onset occurring either in childhood or adulthood based on the specific genetic alteration.
Fig.1 Pathophysiological changes in hereditary ataxia (HA) and the corresponding treatments. (Pilotto F, et al., 2024)
Pathogenesis of Hereditary Spastic Ataxia (HSA)
The hereditary spastic ataxia (HSA) involves intricate disruptions of molecular mechanisms, such as issues with axonal transport, mitochondrial processes, and protein homeostasis.
Axonal Transport Deficits and Neurodegeneration
Mutations in genes like SPAST (spastin) and KIF1C mutate microtubule dynamics and disrupt axonal transport in UMNs. Spastin is important in maintaining microtubule-integrity which is a microtubule severing protein. Loss-of-function mutations cause retrograde degeneration and axonal swellings.
Mitochondrial Dysfunction
Changes in the SPG7 gene which are associated with paraplegin, a mitochondrial protease, cause dysfunctional oxidative phosphorylation pathways and heightened production of reactive oxygen species (ROS). Mitochondrial damage contributes to energy failure in UMNs, which worsens neurodegeneration.
Protein Misfolding and Aggregation
ATXN2 mutations cause polyglutamine expansions that leads to toxic protein aggregate formations. These aggregates interfere with autophagy and proteostasis, impeding protein clearance. Such interference triggers ER stress, dysfunction of mitochondria, and eventually the degeneration of UMNs in HSA.
Glial Contributions to Neuroinflammation
Microglia activation and astrocyte dysfunction are examples of non-cell-autonomous mechanisms that heighten neurotoxicity in HSA. The presence of pro-inflammatory cytokines like TNF-α and IL-6 in elevated levels in HSA CSF also suggests that these cytokines could serve as targets for immunotherapies.
Therapeutic Development for Hereditary Spastic Ataxia (HSA)
| Drug Names | Mechanism of Action | Targets | Research Phase |
| Omaveloxolone | Activates Nrf2 pathway, reduces oxidative stress and inflammation | Nrf2-Keap1 pathway, antioxidant response elements | Approved |
| Riluzole | Modulates glutamate neurotransmission, neuroprotective effects | Glutamate receptors, voltage-gated sodium channels | Phase II/III |
| Amantadine | NMDA receptor antagonist, may improve motor symptoms | NMDA receptors, dopamine system | Phase II |
| Varenicline | Partial nicotinic acetylcholine receptor agonist, potential neuroprotection | α4β2 nicotinic acetylcholine receptors | Phase II |
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 preclinical research service provider, Protheragen is dedicated to accelerating breakthroughs in the field of hereditary spastic ataxia (HSA). We offer end-to-end solutions encompassing diagnostic development, novel therapeutic development, precise disease modeling, and rigorous preclinical validation. Our blood-brain barrier model facilitates the assessment of drug permeability and neuroprotective efficacy while mimicking the pathological disruption of BBB integrity observed in HSA.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- SPAST Knockout Model: It mimics the key features of HSA by demonstrating degeneration of the corticospinal tract and progressive motor deficits.
- ATXN2 Transgenic Model: This model mimics polyglutamine expansion-mediated neurodegeneration, showing progressive motor ataxia and Purkinje cell loss.
To advance the commercialization of novel therapies for hereditary spastic ataxia (HSA), Protheragen provides comprehensive pharmacodynamic (PD), pharmacokinetic (PK) and toxicology research services. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
- Pilotto F, Del Bondio A, Puccio H. Hereditary ataxias: from bench to clinic, where do we stand?[J]. Cells, 2024, 13(4): 319.