Alzheimer's disease (AD), Huntington disease (HD) and a range of other neurodegenerative disorders including Parkinson's disease (PD) and other movement disorders share, as a common pathological feature, the presence of fibrillar aggregates of protein known as amyloid.
In each case these deposits result from misfolding of a particular disease-associated protein that causes it to aggregate, extracellularly as amyloid plaques in AD (β amyloid or Aβ) or intracellularly as inclusion bodies in HD (huntingtin) or Lewy bodies in PD (α-synuclein).
The aggregation of these proteins is influenced by several factors, which include variations in the primary amino acid sequence caused by inherited genetic mutations and changes in the local biochemical environment including pH, oxidative stress and other cellular components such as biological metals. Loss of the normal tight regulation of the transport and tissue distribution of biological metals such as copper and zinc is a feature of the ageing brain and is exacerbated in age related neurodegenerative disorders. Unregulated interactions of the misfolded proteins with these metals may exacerbate oxidative stress, leading to a toxic, vicious cycle.
Prana Biotechnology has observed that Metal-Protein Attenuating Compounds (MPACs) improve Alzheimer's-like changes in the brain by preventing a build up of beta-amyloid deposits, which destroy cognitive function.
Prana has developed a proprietary library of more than 1000 MPACs which target these interactions, preventing target protein aggregation and consequent toxic gain of function.
Our focus has been to build a pipeline of compounds targeting indications with unmet medical needs in neurodegeneration – from blockbuster indications such as Alzheimer's disease to specialist orphan central nervous system (CNS) indications.
Prana's lead compound PBT2 is a small molecule that reversibly binds and transports copper and zinc within neurons and across synapses. It has been designed to inhibit this metal-mediated aggregation, short circuit the oxidative stress cascade and restore correct metal distribution within the synapse. This detoxification of the synaptic environment results in neuroprotection and restoration of neuronal function. PBT2 has demonstrated beneficial effects on cognition. PBT2 is nearing completion in Phase 2 trials as a novel therapy for Alzheimer’s and Huntington’s disease. These trials are reporting in early 2014.
PBT434 is also being advanced as a treatment for Parkinson’s disease and other movement disorders, and in the past has received funding from the Michael J Fox Foundation. PBT519 is also being advanced as a treatment for brain cancer. Novel MPACs are under screening and assessment for therapeutic applications in neurodegenerative diseases.