Development of PTI-125-DX, a blood-based diagnostic for Alzheimer's disease - Abstract
PTI is developing PTI-125-DX, a novel, quantitative blood-based diagnostic candidate for
Alzheimer's disease (AD). A non-invasive and inexpensive AD diagnostic is sorely needed,
particularly one with the ability to detect early pathological changes that precede cognitive
symptoms. PTI-125-DX measures the ratio of two protein fragments in plasma and is a
companion diagnostic/biomarker for our therapeutic candidate PTI-125. PTI-125 disrupts and
prevents filamin A (FLNA)'s association with the a7-nicotinic acetylcholine receptor (a7nAChR),
which amyloid beta 1-42 (Aß42) hijacks to hyperphosphorylate tau protein. We have tested over
220 plasma samples and show two orders of magnitude significant differences between patients
with AD diagnoses (confirmed by imaging or CSF markers) and age-matched normal controls.
These two groups are distinguished with 98-100% accuracy. In one of two blinded studies, PTI-
125-DX distinguished MCI with confirmed AD pathology (MCI-AD) from MCI with suspected non-
amyloid pathology (MCI-SNAP) with 92% accuracy; in the other, this distinction needs
confirmation by imaging. In this proposal, we will compare additional MCI-AD and MCI-SNAP
samples and determine disease specificity of the assay by testing archived plasma samples from
patients with dementia with Lewy bodies, Frontotemporal Dementia and Parkinson's disease
alongside AD, MCI-AD, MCI-SNAP, early-onset familial AD (FAD), cancer and elderly or young
controls. As PTI-125-DX is currently in Western blot format, we will develop an ELISA assay and
compare it to an automated Western blot format using ProteinSimple's WesTM. In Phase II, we will
generate proprietary antibodies by immunizing with carefully selected peptides and recombinant
proteins; these polyclonal antibodies will be screened and tested to determine optimal
combinations. The corresponding immunogens will then be used to develop monoclonal
antibodies. The sandwich ELISA we envision will capture all fragments of interest and separately
detect two specific protein fragments. With final monoclonal antibodies and a final ELISA (or Wes)
format selected, we will perform a new blinded study of up to 250 de-identified plasma samples
from the AIBL study. At the conclusion of this work, PTI-125-DX will be ready for
commercialization or partnering.
