Vascular Physiology and Protein Disposition in a Preclinical Model of Neurodegeneration

Boswell, C. Andrew; Mundo, Eduardo E.; Johnstone, Bernadette; Ulufatu, Sheila; Schweiger, Michelle; Bumbaca, Daniela; Fielder, Paul J.; Prabhu, Saileta; Khawli, Leslie A.

doi:10.1021/mp3004786

Cited by 8 publications

(9 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is now being argued that these disease models are mostly reflective of the asymptomatic phase of the disease [55]. In the case of amyotrophic lateral sclerosis (ALS), transgenic mice having a G39A mutant form of human superoxide dismutase (SOD1) showed no differences in permeability across disease model and wild type control groups for both small molecule and large molecule markers [56]. Regarding Huntington's disease (HD), current rodent models provide a poor representation of the disease course and outcomes [57,58].…”

Section: Contradictory Findings Across Animal Models Of Neurological mentioning

confidence: 99%

In vitro modeling of the neurovascular unit: advances in the field

Bhalerao

Sivandzade

Archie

et al. 2020

Fluids Barriers CNS

113

103

View full text Add to dashboard Cite

The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS). Over time, various model systems have been established to simulate the complexities of the BBB. The development of realistic in vitro BBB models that accurately mimic the physiological characteristics of the brain microcapillaries in situ is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the Neurovascular Unit (NVU) would provide an invaluable tool that would aid in dissecting out the pathological factors, mechanisms of action, and corresponding targets prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many fundamental changes in the last few years with the introduction of novel tools and methods to improve existing models and enable new ones. The development of CNS organoids, organ-on-chip, spheroids, 3D printed microfluidics, and other innovative technologies have the potential to advance the field of BBB and NVU modeling. Therefore, in this review, summarize the advances and progress in the design and application of functional in vitro BBB platforms with a focus on rapidly advancing technologies.The BBB consists of highly specialized vascular endothelial cells (EC) lining the brain microvessels in juxtaposition with closely associated pericytes [1], extracellular matrix components, and astrocytic end-feet processes [2]. Along with other cells such as neurons and microglia, this cellular milieu modulates the BBB properties, supports its viability and functions [3]. At the brain microvascular level, the BBB functions as a highly dynamic and active interface between the systemic circulation and the CNS. The BBB maintains a stable brain environment to protect the CNS from unsolicited cells, bacteria, viruses, and potentially harmful substances (either endogenous or exogenous) apart from protecting against systemic fluctuations. The BBB also regulates the transport of essential molecules and nutrients necessary to maintain the optimal CNS environment and support neuronal activities [4]. The BBB responds to many physiological and pathological cues, including rheological changes [5], inflammatory stimuli, oxidative stress [6], diabetes, and hypercholesterolemia [7-10], acute brain injury [3], etc. The intrinsically unique and utmost complex functional interaction between the BBB endothelium and the surrounding cellular milieu (including astrocytes, pericytes, neurons, microglia, myocytes as well as specialized cellular compartments such as endothelial glycocalyx [11,12] has been termed "neurovascular unit (NVU)" [2,13]. In addition, the basement membrane, which exerts essential functions in cellular support and signal transduction,

show abstract

Section: Contradictory Findings Across Animal Models Of Neurological mentioning

confidence: 99%

In vitro modeling of the neurovascular unit: advances in the field

Bhalerao

Sivandzade

Archie

et al. 2020

Fluids Barriers CNS

113

103

View full text Add to dashboard Cite

show abstract

“…On the other hand, to evaluate the in vivo PK and tissue distribution of antibodies, intravenous injection of radiolabeled antibody followed by collection of blood and tissue samples from the CNS at different time points (“cut and count”) can be used as assays for sensitive uptake analysis [ 30 ]. Such an approach, however, is tedious and requires a large number of animals to ensure the reproducibility and reliability of the results.…”

Section: Current In Vitro and In Vivo Methodologies For Measuring Brain Access Of Antibodies: Advantages And Limitationsmentioning

confidence: 99%

“…Another advantage is that molecular imaging methods have good spatial resolution (0.35–1.5 mm), allowing differentiation of tracer uptake on the suborgan level. Accordingly, the importance of spatial resolution in understanding therapeutic protein distribution within the brain has been the subject of several studies in which differences in brain penetration and distribution related to drug format are characterized [ 30 , 37 , 38 ].…”

Section: Current In Vitro and In Vivo Methodologies For Measuring Brain Access Of Antibodies: Advantages And Limitationsmentioning

confidence: 99%

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Kouhi

Pachipulusu

Kapenstein

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.

show abstract

“…The same approach was used to calculate total blood volumes of rats and mice from our previously reported studies [21,[23][24][25][26][27][28], and blood volumes were normalized to body weight (kg) for comparison across species.…”

Section: Methodsmentioning

confidence: 99%

“…For biologic drugs with minimal cell partitioning (e.g., antibodies), blood correction of whole tissue concentrations and subsequent conversion into interstitial fluid concentrations requires knowledge of the fractional composition of vascular and interstitial spaces, respectively, within each tissue [7,8]. We previously reported measurement of tissuelevel vascular volumes (V v ), interstitial volumes (V i ), and rates of blood flow (Q) in several immunocompromised mouse strains [21][22][23][24][25]. More recently, we expanded our investigations to include immunocompetent mice [26,27] and rats [28], but comparable experimental data in primates remains unavailable for some parameters (e.g., V i ) and is reported only in limited tissues for others.…”

Section: Introductionmentioning

confidence: 99%

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

Mandikian¹,

Figueroa²,

Oldendorp³

et al. 2018

AAPS J

Self Cite

View full text Add to dashboard Cite

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue-and organ-level vascular volumes (V v), interstitial volumes (V i), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that V v , V i , and Q, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including V v in muscle, brain, and skin and Q in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.

show abstract

Vascular Physiology and Protein Disposition in a Preclinical Model of Neurodegeneration

Cited by 8 publications

References 46 publications

In vitro modeling of the neurovascular unit: advances in the field

In vitro modeling of the neurovascular unit: advances in the field

Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

Contact Info

Product

Resources

About