Intrathecal pseudodelivery of Ab-mAb alleviates pathology in an Alzheimer’s disease model

Abstract

Background

Intrathecal pseudodelivery is a new route of drug delivery to the CNS based on an implantable device endowed with a smart system of nanoporous membranes. We have developed a miniaturized prototype of the device for rodents. Here we present preliminary results on the use of antiAbeta mAbs intrathecally pseudodelivered in the APP/PS1 mouse model of Alzheimer’s disease.

Method

28-week-old male mice, APP/PS1 and non-transgenic were used. The device was implanted subcutaneously in the back of the mouse and connected to one of the lateral ventricles via a catheter, also subcutaneous. The reservoir of the devices was filled with artificial CSF (aCSF) or with a solution of anti-amyloid beta (Ab) antibody (clone 6E10, Biolegend) in aLCR. The infusion period was three weeks, during which animal welfare aspects were assessed. After this time, the mice were sacrificed for histopathological evaluation. All procedures were performed in accordance with institutional guidelines approved by the Ethical Committee in Research of Universidad de Oviedo.

Result

Safety: The device was successfully implanted in a total of 18 mice. Three mice showed complications 3 days after surgery, including lethargy and significant weight loss. This could be due to the surgery itself or to the post-operative medication. The rest of the mice recovered perfectly and returned to normal activity 4 days after surgery.

Efficacy: Immunohistochemistry was performed to assess the size of Ab plaques, using a rabbit polyclonal anti-Ab antibody (Invitrogen). The surface area occupied by the plaques in each of the APP/PS1 mice was determined. The results show a decrease in the area occupied by Ab-positive plaques in the mice treated with the antibody. Although not statistically significant, there is a tendency for treated mice to have a smaller area occupied by plaques.

Conclusions

Our results show that:

• Intrathecal pseudodelivery of mAbs is a feasible route of drug delivery for neurodegenerative diseases.

• Intrathecal pseudodelivery of Ab-mAb alleviates pathology in an Alzheimer’s disease model.

• Albeit preliminary efficacy and safety results are promising, further studies are needed.