IN VIVO MTHTT PROTEIN REDUCTION IN THE CNS AND PERIPHERY BY PASSIVE IMMUNIZATION WITH THE MONOCLONAL ANTIBODY C6-17

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by changes in personality, cognition and motor control. The cardinal neuropathological hallmark of this disease is the massive atrophy of the striatum resulting from neuronal dysfunction and loss, but which extends to other areas of the brain as well as peripheral organs. The genetic mutation underlying HD originates in Exon1 of the huntingtin gene gives rise to a toxic/mutated form of the huntingtin protein (mtHTT). The mtHTT protein is ubiquitously expressed but also exhibits the ability to propagate from cell-to-cell to disseminate pathology, a property which may serve as a new therapeutic focus. We have developed a monoclonal antibody C6-17 targeting a particularly exposed region close to the aa586 Caspase 6 cleavage site of the huntingtin protein and, as recently published, mAB C6-17 is able to block cell-to-cell propagation of mutated HTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether the freely accessible and extracellular mtHTT can be targeted by an antibody. In POC experiments, using the transgenic animal model YAC128, we found that after 3 months mAB C6-17 treatment the circulating mtHTT in the peripheral as well as in the CNS tissues was reduced. Further, we could demonstrate the presence of active mAB C6-17 in PBS/heparin perfused peripheral and CNS tissues. The mAB C6-17 treated YAC128 animals showed benefits in body wight and motor behaviors and we could observe a delay in the HD disease progression. The obtained in vivo results provide the first POC data for the feasibility and efficacy of an antibody-based anti-mtHTT approach and suggest this therapeutic strategy as a potential new HD treatment possibility.