Compounds Treating AP-4 Associated Hereditary Spastic Paraplegia
Background
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive spasticity, weakness, and gait abnormalities and affects approximately 5-10 per 100,000 individuals worldwide. Among its subtypes, Adaptor Protein Complex 4 (AP-4)-related HSP presents a rare yet prototypical form, particularly affecting children with features of both neurodevelopmental and neurodegenerative disorders. These include developmental delay, seizures, microcephaly, and progressive motor dysfunction. Few patients are known to survive into adulthood.
The existing standard of care for HSP is primarily symptomatic, involving physical therapies and medications to manage spasticity and support mobility, which leaves considerable room for improved, targeted therapies that address the underlying genetic and cellular dysfunctions, particularly those related to defective autophagy pathways. There are no known current therapies for HSP.
Technology Overview
Dr. Darius Ebrahimi- Fakhari and his lab have developed a novel small molecule compound, that modulates Autophagy Related 9 A (ATG9A) trafficking and enhance autophagic flux, offering a promising therapeutic approach for neurological diseases such as hereditary spastic paraplegia, specifically for AP-4 associated HSP. Utilizing high-throughput screening assays, these compounds have demonstrated effectiveness in correcting protein trafficking deficiencies associated with AP-4-HSP across multiple disease models, including patient-derived fibroblasts and neurons.
Proof-of-concept data indicates that these compounds successfully restore ATG9A function, thereby alleviating related pathologies and potentially reversing disease progression at the cellular level. This marks a significant improvement over current standard care by targeting the core mechanisms of disease and offering a potential disease-modifying therapy.
BCH is also the site of the Natural History Study for Early Onset Hereditary Spastic Parapeligia (https://www.childrenshospital.org/clinical-trials/nct04712812)
Applications
- Hereditary spastic paraplegia
- AP-4 deficiency-associated diseases
- Broader application to other neurodegenerative and neurodevelopmental disorders involving autophagy dysfunction
Advantages
- Direct modulation of defective molecular pathways specific to AP-4 associated HSP
- Potential to halt or reverse disease progression rather than just alleviating symptoms
- Applicable in patient-relevant models providing a targeted approach based on individual genetic and phenotypic profiles
Current Stage
Publications
