By Di Marco, Annalise; Gonzalez Paz, Odalys; Fini, Ivan; Vignone, Domenico; Cellucci, Antonella; Battista, Maria Rosaria; Auciello, Giulio; Orsatti, Laura; Zini, Matteo; Monteagudo, Edith; et al
From Molecular Pharmaceutics (2019), 16(5), 2069-2082. Language: English, Database: CAPLUS, DOI:10.1021/acs.molpharmaceut.9b00042
Investigating Blood-Brain Barrier (BBB) Permeability in Huntington’s Disease Drug Development
Huntington’s disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (HTT) protein. For drug candidates targeting HD, the ability to cross the blood-brain barrier (BBB) and reach the site of action is critical for achieving pharmacological activity.
Utilizing a BBB Model for Permeability Assessment
To evaluate the BBB permeability of selected compounds, we implemented an in vitro BBB model consisting of primary porcine brain
endothelial cells and rat astrocytes. This two-dimensional model was designed to rank and prioritize compounds for in vivo pharmacokinetic and brain penetration studies, offering an efficient method for screening potential HD therapeutics.
Characterizing the BBB Model
The model was characterized using a set of carefully selected validation markers based on their functional significance at the BBB. Key characteristics, such as functional tight junctions, high transendothelial electrical resistance (TEER), and the activity of both influx and efflux transporters, were confirmed. These features are essential for mimicking the selective barrier properties of the human BBB.
Correlation with In Vivo Data
The permeability of fifty-four structurally diverse, known compounds was determined using this model. Results showed a strong correlation with in situ brain perfusion data from rodent studies, underscoring the model’s predictive reliability. This correlation supports the model’s role in refining compound selection and enhancing the efficiency of CNS drug discovery.
Application in Huntington’s Disease Research
We applied this model to evaluate the BBB permeability of new HD drug candidates from various chemical classes. The good correlation between in vitro and in vivo brain permeation data demonstrated the model’s effectiveness in optimizing CNS drug properties. This approach is crucial for guiding the selection of lead compounds in the drug discovery process.