Recombinant Technologies LLC — Department of Health and Human Services SBIR Phase II: NIA

Description

Abstract Alzheimer’s disease is the most common cause of dementia and fourth most common cause of death. Amyloid-beta (Aβ) plays a crucial role in initiation and progression of Alzheimer’s disease (AD). Accumulation of Aβ on the surface of neuronal cells is known to cause synaptic dysfunction and further cascade into other dysfunctions in AD. Removal of circulatory Aβ would shift the equilibrium of Aβ levels between brain and blood towards blood and thus would deplete brain amyloid levels and improve memory. Treatments that target and reduce Aβ accumulation may be beneficial to AD patients in terms of better living conditions. Recombinant Technologies [RTL] is working towards developing an extracorporeal apheresis device that would sequester blood Aβ in AD patients. RTL believes that safe and efficient removal of Aβ would offer benefit that other options may not achieve. The proposed device, namely, Amytrapper would help AD patients live better. The device is centered on our proprietary active pharmacological ingredient [API], a tetrameric retro-inverso peptide that is pegylated. The peptide has a high affinity for a specific motif on Aβ that is involved in misfolding and self- aggregation/oligomerization. Upon injection of the same API in the previous POC studies, we have demonstrated depletion from the brain of Aβ42 and cognition improvement in a clinically relevant mouse model of AD. In the preceding phase 1 research we have obtained proof of concept for this amytrapper device. We have successfully created and tested the amytrapper prototype column matrix which was composed of sepharose beads conjugated to pegylated RI-peptide. It bound and retained biotinylated Aβ42 (spiked) from a buffer solution or in presence of sera. Sera from mice, rat and humans and plasma from humans were spiked with Aβ42 were tested for binding by Amytrapper, in vitro. Amytrapper specifically and reproducibly bound biotinylated Aβ42 in the above experiments in a concentration dependent manner. The proposed phase 2 research is a logic extension of the successful phase 1 outcome. In this proposal, in addition to the Amy trapper column, we plan to introduce an added innovation in the form of an Amytrapper catheter [a medically viable catheter coated inside with the RI-PEG] and test them out in vitro and in vivo. Therefore, in Aim 1, we will generate and characterize large scale quantities Amytrapper sepharose beads. In Aim 2, Amytrapper-catheter will be generated and characterized in collaboration with a CRO who is specialized in catheters that are commercially available. In Aim 3, we plan to demonstrate in vivo target [Aβ] engagement by the API in a mouse model challenged with Aβ injections directly into the brain using a push-pull microdialysis apparatus. In Aim 4, we will study efficacy of the two Amytrapper devices in a rat model of Alzheimer’s Disease. Evaluations will include biochemical, immuno-histological, and behavioral parameters. We expect that the catheter would provide advantages such as ease of use and storage just like a saline drip. At the end of this study, we would have enough data to support the FDA approval of these new devices for eventual first in human [FIH] study. We present well defined goals with realistic milestones and deliverables together with a viable commercialization plan that is supported by established players and partners. We believe that treatments targeting Aβ may be beneficial to amyloid toxicity in AD patients and improve their living conditions. We also believe we can succeed in creating this device soon for human use.Alzheimer’s Disease (AD) is a common disease leading to dementia affecting millions of people worldwide. One of the many targets in treatment for AD is amyloid-beta, which has been implicated as one of the precursors initiating Alzheimer’s. Unfortunately, treatment options to date are limited or have limited effects. Recombinant Technologies (RTL) which owns a patent on active pharmacological ingredient (API) has demonstrated proof of concept for this drug in vitro and in animal model. Incorporating the same API, RTL designed and developed an extra-corporeal device, namely, Amytrapper in the preceding phase 1. Encouraged by the results of the phase 1 research, RTL now plans to perform additional research and development on Amytrapper. In the phase 2 proposal, RTL has added to the innovation by replacing the column with a medically viable catheter device coated with the API to capture circulating amyloid. Both the column and the catheter will be tested and compared. The proposed innovative devices may lead to achieving a novel treatment strategy that improves the lives of patients with AD.