VH14*PEST

VH14*PEST is a **bifunctional, fully human single-domain nanobody (intrabody)** targeting the non-amyloid component (NAC) region of **α-synuclein**. It is engineered by fusing the VH14 nanobody to a **PEST degron** motif derived from ornithine decarboxylase (murine or human), which directs bound α-synuclein toward proteasome-mediated degradation. This construct is designed to lower levels of intracellular α-synuclein, reduce its aggregation, and limit related proteopathic and neurotoxic stress. The primary development focus is on **Parkinson's disease** and related synucleinopathies, employing both in vitro (neuronal cell lines, iPSC-derived organoids) and in vivo (viral gene therapy in rodent models) approaches. VH14*PEST has shown efficacy in reducing α-synuclein toxicity, aggregopathy, and preserving dopaminergic neuron function in experimental models. The modality allows programmable antigen degradation and long-term titration of intracellular α-synuclein, representing a targeted intracellular immunotherapy platform.