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Woburn, MA, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 97.47K | Year: 2005

DESCRIPTION (provided by applicant): We propose the development of a high-throughput analytic tool that can accurately assess passive permeability of drug-like molecules across the blood-brain barrier (BBB), using an artificial membrane measuring technique developed by plON. The parallel artificial membrane permeability assay (PAMPA) will incorporate a new, specially-designed permeability model based on the use of biomimetic membranes. The method will be suitable for screening large libraries of molecules, at about 1000 times lower cost than in vivo rodent-model measurements. The new PAMPA BBB barrier lipid will be optimized in composition, initially mimicking the lipid composition of endothelial cells, but "trained" to closely match available in situ brain perfusion data, derived from the "knockout" mouse (mdr1a(-/-)) model. To model the near zero thickness aqueous boundary layer environment in the brain microcapillaries, stirring will need to be performed on both sides of the membrane barrier in a specially-designed (plON) 96-well microtitre plate. We will use 39 identified drug molecules, whose highly-reliable knockout mouse in situ brain perfusion data are already available, as the training set for the new BBB-PAMPA model. With these, our aim in the new model is to reach the PAMPA vs. in situ linear-regression correlation coefficient, r2 > 0.9, without the use of in silico "booster" descriptors. However, as a backup, we will embrace the concept of in silicoenhanced measured data modeling, and will use this strategy as needed. The proposed high-throughput PAMPA BBB permeability technique is important to public health because it will allow large scale, low-cost compound screening producing data with enhanced downstream value earlier in discovery programs, thus eliminating molecules with questionable drugability characteristics sooner and help lower the current, estimated 98% attrition rate. This will contribute to the timely development of better medicines at lower cost.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 442.34K | Year: 2007

DESCRIPTION (provided by applicant): Central nervous system (CNS) - targeting drugs, such as antiretrovirals in the treatment of AIDS, need to cross the blood-brain barrier (BBB) in order to reach their therapeutic receptors inside the brain. A critical issue in the treatment of AIDS is that the HIV-1 virus can reside in hard-to-reach sanctuaries in the brain (mainly in macrophage cells). If a candidate molecule does not have the right physical properties to effectively cross the BBB, it cannot realize its therapeutic potential. Our proposal addresses this aspect, with two novel high-throughput assays for CNS drug transport across the BBB. In Phase I of the SBIR we developed a promising brain lipid (BL) parallel artificial membrane permeability assay (PAMPA), called BL-PAMPA, to predict the kinetic parameters, log PS (permeability-surface area product), measured by the in situ brain perfusion assay in P-glycoprotein deficient [mdr1a(-/-)] "knockout" mice. In Phase II, we will commercialize this brain lipid and other proprietary reagents. In Phase II, an additional high-throughput blood-brain barrier related assay based on binding gradients will be developed. The new assay will be used to predict rodent steady-state (pseudo-equilibrium) brain penetration, log BB. In our commercialization effort during the three-year Phase II period, we plan to design, make, and test (a) several proprietary reagent-containing buffers, (b) a special microtiter plate for endothelial cultured cell assays that account for the aqueous boundary layer effects, and (c) a blood brain barrier measuring instrument based on diode array UV spectrophotometry, which would increase the rate of data acquisition about 50 fold over currently available instruments.

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