Dual Intracellular and Extracellular Expression Technology (dIEE) for Parkinson’s Disease
Abstract
Alpha-synuclein (a-syn) is a key player in the pathogenesis of Parkinson's Disease (PD), a devastating
neurodegenerative illness that will afflict over 920,000 Americans by 2020. Oligomers and aggregates of this
presynaptic-vesicle-associated protein characterize major pathological findings in PD that correlate well with
progressive motor neuron functional decline. While a-syn is normally localized intracellularly at synapses, during
PD, oligomeric a-syn can spread damage extracellularly in a defined path through the brain in a prion-like
manner, where the altered conformation of oligomeric a-syn catalyzes creation of increased aberrant a-syn.
Pathological a-syn then creates at least three challenges for a potential therapeutic: a) block intracellular
initiation-activity, b) clear intracellular pathological a-syn, and c) clear toxic extracellular a-syn to prevent
progression. To address these problems, we have designed a recombinant adeno-associated viral (AAV) vector
to achieve long-term, stable central nervous system (CNS) delivery of an antibody. This vector will
simultaneously deliver an intracellular anti-oligomeric a-syn single-chain intrabody (iAb) combined with a
secreted extracellular anti-a-syn N-Terminal antibody (sAb). Our novel dual intrabody/antibody approach
employs proprietary dual Intracellular and Extracellular Expression technology (dIEE). We hypothesize that the
combined effect of the anti-a-syn intrabody and secreted antibody will reduce alpha-synuclein-mediated
pathology with concomitant improvement of PD. In addition, AAV delivery addresses the blood brain barrier
(BBB) problem of systemic antibody therapy and represents a novel and potentially practical approach for the
treatment of additional neurodegenerative diseases. In Phase I, we will identify potent anti-oligomeric human a-
syn antibodies, construct the vectors, and test their expression in vitro and in the brains of recipient mice. We
are optimistic that our AAV dual expression system for simultaneous delivery of anti-oligomeric-a-syn intrabodies
and antibodies to the brains of affected patients will provide a novel restorative therapy for PD.
