The neurotoxic amyloid plaques in the brain, characteristic of Alzheimer's disease (AD), are formed by aggregation of 2 overlapping fragments (AB1-40 and AB1-42) of the amyloid precursor protein. These A-beta peptides can cross the blood-brain barrier. Our long-term goal is to develop an effective therapy for Alzheimer's Disease, by using a subcutaneous hydrogel to recognize, concentrate and eliminate AB (beta amyloid) peptides and thereby halt deposition of plaque in the brain. In the Phase I research, we developed and demonstrated a propreirtary detox gel encompassing a retro-inverso peptide which acts like a """"""""sink"""""""" that draws the AB peptides, in vitro. The amount and rate of AB captured irreversibly (10 ug/100ul of gel in 2 hours, in vitro) could be used to produce the sink effect in humans. We now propose a more potent, specific and convenient therapeutic system in our Phase II proposal. In addition to using the detox depot we established in Phase I, we plan to improve the AB capture hydrogel formulation and evaluate its performance, in vivo, in a murine model of AD. Essentially, a solution containing a conjugate consisting of Abeta binding element linked to a polymer is mixed with a cross-linking reagent. This solution may be injected subcutaneously where it will rapidly become a solid hydrogel. The ability of the detox depot to decrease the level of the toxic aggregates of A-beta peptides in the brain will be evaluated. Several versions of the capture peptide will be included in the detox gels and tested for efficacy in AD mice. Evaluation parameters will include immunohistochemical and biochemical measurements. If successful, this detoxification depot will become a candidate for human use. Safety studies on the hydrogel performed in rats, rabbits and dogs demonstarted no toxicity. We hold rights to the 'intellectual property' and present a commercialization plan to perform future evaluations in partnership with a pharmaceutical firm. We have already made progress towards commercialization initiatives.
| Sundaram, Ranjini K; Kasinathan, Chinnaswamy; Stein, Stanley et al. (2012) Novel Detox Gel Depot sequesters ?-Amyloid Peptides in a mouse model of Alzheimer's Disease. Int J Pept Res Ther 18:99-106 |
