ALLELE BIOTECHNOLOGY AND PHARMACEUTICALS — Department of Health and Human Services SBIR Phase I: NIA

Description

Project Summary Abstract The goal of this project is to develop a tissue engineering technology applicable to stem cell based therapies for Alzheimerandapos s disease AD AD is the most common dementia and characterized by synaptic dysfunction and neuronal loss There is currently no effective cure for the disease Transplantation of human neural stem cells hNSCs to replace lost neurons is a promising strategy However the cells transplanted into the AD brain would face a toxic environment with elevated levels of the amyloid A peptides which would induce synaptic damage and cell death for implanted neurons How can we overcome this problem We previously identified the activity of synaptic protein takusan Tu et al Overexpression of takusan in rat primary neuronal cultures leads to enhancement of various synaptic properties including dendritic spine density and AMPA and NMDA mediated glutamate receptor activity Interestingly these are the synaptic properties that are attenuated by A exposure We then overexpressed takusan in cultured rat neurons and challenged them by soluble A oligomers Remarkably takusan expression mitigated synaptic loss in these neurons By deletion mapping and domain swapping we invented the synthetic aa long protein hD b in which we fused the human D takusan domain derived from discs large homolog DLG and a human PDZ binding C terminal sequence Overexpression of hD b in cultured rat neurons like that of full length takusan variants conferred protection against oA induced synaptic toxicity In the current proposal we will produce hNSCs expressing hD b and test whether this genetic modification is beneficial toward the development of a novel cell replacement therapy against AD This proposal allows us to leverage our expertise in stem cell technology at Allele Biotech Inc with the knowledge and invention of hD b protein by our academic collaborators Specific Aims are as follows Aim To produce human neurons hNs that express hD b in vitro Aim To test whether hNs expressing hD b are more resistant against oA induced synaptic toxicity compared to control hNs Aim To evaluate whether transplantation of hNSCs expressing hD b into the brain of human amyloid precursor protein hAPP transgenic mice hAPP J will rescue their behavioral and histological phenotypes This proposal consists of experiments that have been performed reagents tested and conclusions published in series of high quality papers using rat primary neurons Since the proposed work is a logical extension to human neurons we have high confidence that positive results will be obtained through a year phase SBIR effort Upon completion of phase we expect to continue to phase projects to perform additional animal testing aimed at near future IND and eventual partnership with pharmaceutical companies Project Narrative Transplantation of human neural stem cells hNSCs derived from human stem cells is a potentially powerful approach toward the treatment of Alzheimerandapos s disease AD However AD brains present toxic environment to incoming implanted neurons We therefore aim to develop a new technology in order to improve hNSCsandapos resistance against AD toxins