Intrabody therapy for SPG4 hereditary spastic paraplegia
Introducing a novel intrabody therapy for SPG4 hereditary spastic paraplegia, targeting the degradation of mutant M1 spastin protein. This approach aims to mitigate neurodegenerative symptoms by employing antibodies to direct degradation of toxic protein aggregates.
Overview
Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disorder characterized by lower limb weakness and spasticity, primarily due to mutations in the SPAST gene. The most common variant, SPG4, is attributed to the toxic effects of the mutant M1 spastin protein. Traditional gene therapies face challenges in removing accumulated mutant proteins. This proposal introduces an innovative intrabody therapy designed to degrade the mutant M1 protein, thus potentially alleviating disease symptoms.
Technical specifications
Our approach involves the development of recombinant monoclonal antibodies incorporated into intrabody vectors that remain within the cell. These intrabodies target the toxic domain of the M1 spastin protein, facilitating its degradation via ubiquitination. The therapy will be tested in mouse models and patient-derived organoids. The intrabodies' efficacy will be evaluated by their ability to mitigate cellular pathologies such as mitochondrial and Golgi mis-localization, and lysosome transport issues in cultured neurons.
Technology readiness level
Currently at Technology Readiness Level 2, this therapy is in the experimental phase. Validation steps include confirming intrabody binding to M1 in cell models and assessing therapeutic effects in both neonatal and adult symptomatic animal models.
About Drexel University
Drexel University is a comprehensive private research university in Philadelphia, recognized for an urban, industry‑embedded model anchored by a longstanding cooperative education program. Year‑round co‑ops create a ready talent pipeline and align sponsored research with real‑world needs. The campus sits within an innovation district with co‑located labs and incubators, enabling companies to collaborate on prototyping with faculty. Through the university’s medical college and clinical partners, industry teams can access clinical expertise and translational pathways. Research is supported by competitive federal funding from agencies such as NIH, NSF, DOE, and DoD. A dedicated technology transfer office manages IP, licensing, corporate research agreements, and startup formation.
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