Challenges in CNS drug development and the role of imaging

Howes, Oliver; Mehta, Mitul A.

doi:10.1007/s00213-021-05838-3

Cited by 18 publications

(9 citation statements)

References 16 publications

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“…The probability of in‐development CNS disorder drugs being commercially available is approximately two times lower, whereas the development and approval period is approximately two times higher, than that for other disease drugs 3 . The reasons for the low therapeutic success of CNS drug development include minimal or no understanding of the relevant pathophysiology of CNS disorders, difficulties in developing preclinical models and assessing target engagement, the presence of the blood–brain barrier (BBB), CNS‐mediated side effects, the lack of clinical scales of sensitivity, and interference with the therapeutic benefit of placebo effects 4–6 …”

Section: Introductionmentioning

confidence: 99%

“…or no understanding of the relevant pathophysiology of CNS disorders, difficulties in developing preclinical models and assessing target engagement, the presence of the blood-brain barrier (BBB), CNS-mediated side effects, the lack of clinical scales of sensitivity, and interference with the therapeutic benefit of placebo effects. [4][5][6] The major obstacle to drug entry into the brain is the presence of the BBB, composed of endothelial cells linking tight junctions. 7 The BBB, with its distinctive structure, maintains homeostasis by regulating efflux and influx, and protects the brain from pathogenic agents.…”

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confidence: 99%

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Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

Kang

2022

Bioengineering & Transla Med

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Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood-brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens-to-hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

Kang

2022

Bioengineering & Transla Med

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“…Unfortunately, this progress has not been sufficiently translated into successful treatments. Obstacles such as limited understanding of heterogeneous CNS disease etiologies, lack of predictive preclinical models and inefficient drug delivery to the brain remain a challenge in the field ( Morofuji and Nakagawa, 2020 ; Howes and Mehta, 2021 ). Taken together, these obstacles contribute to the high investment risk associated with brain drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Collaboration and knowledge integration for successful brain therapeutics – lessons learned from the pandemic

Loza

Hmeljak

Bountra

et al. 2022

Disease Models &Amp; Mechanisms

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Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as well as drug discovery paradigms in recent years, these have not been sufficiently translated into effective treatments. This Special Article expands on Keystone Symposia's pre- and post-pandemic panel discussions on translational neuroscience research. In the article, we discuss how lessons learned from the COVID-19 pandemic can catalyze critical progress in translational research, with efficient collaboration bridging the gap between basic discovery and clinical application. To achieve this, we must place patients at the center of the research paradigm. Furthermore, we need commitment from all collaborators to jointly mitigate the risk associated with the research process. This will require support from investors, the public sector and pharmaceutical companies to translate disease mechanisms into world-class drugs. We also discuss the role of scientific publishing in supporting these models of open innovation. Open science journals can now function as hubs to accelerate progress from discovery to treatments, in neuroscience in particular, making this process less tortuous by bringing scientists together and enabling them to exchange data, tools and knowledge effectively. As stakeholders from a broad range of scientific professions, we feel an urgency to advance brain disease therapies and encourage readers to work together in tackling this challenge.

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“…The diagnosis and treatment of central nervous system (CNS) disorders constitute a notable challenge in the field of modern therapeutics and advanced drug delivery systems, and it would appear such disorders are on the rise despite increasing appreciation and elucidation of underlying aetiology and pathophysiological mechanisms [1,2] The CNS therapeutics market is set to grow to EUR 114.4 billion in 2025, and a resurgence in the neuroscience field is predicted, which will be bolstered by novel drug delivery systems and new chemical entities (NCE's). The most recent global burden of disease (GBD) study published in the Lancet journal shows that the global burden of neurological disorder approaches the 14% value of overall disease modelled over a decade ago, accounting for 250,000 deaths relating to brain and central nervous system cancer and 100 million disability-adjusted life years relating to neurological disorders [3].…”

Section: Introductionmentioning

confidence: 99%

“…However, in many cases, the focus is on treatment efforts for specific disorders in isolation such as brain cancer, or indeed serve to appraise the critical quality attributes and behaviours of one nanomaterial in crossing the BBB. As such, the aim of this review is: (1) to summarise the BBB targeting strategies employed currently;…”

Section: Introductionmentioning

confidence: 99%

Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders

Lynch

Gobbo

2021

Nanomaterials

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Nanotheranostics constitute a novel drug delivery system approach to improving systemic, brain-targeted delivery of diagnostic imaging agents and pharmacological moieties in one rational carrier platform. While there have been notable successes in this field, currently, the clinical translation of such delivery systems for the treatment of neurological disorders has been limited by the inadequacy of correlating in vitro and in vivo data on blood–brain barrier (BBB) permeation and biocompatibility of nanomaterials. This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy and current non-animal-based models for assessing the safety and efficiency of such formulations. This review will also address current and future directions of select in vitro models for reducing the cumbersome and laborious mandate for testing exclusively in animals. It is hoped these non-animal-based modelling approaches will facilitate researchers in optimising promising multifunctional nanocarriers with a view to accelerating clinical testing and authorisation applications. By rational design and appropriate selection of characterised and validated models, ranging from monolayer cell cultures to organ-on-chip microfluidics, promising nanotheranostic particles with modular and rational design can be screened in high-throughput models with robust predictive power. Thus, this article serves to highlight abbreviated research and development possibilities with clinical translational relevance for developing novel nanomaterial-based neuropharmaceuticals for therapy in CNS disorders. By generating predictive data for prospective nanomedicines using validated in vitro models for supporting clinical applications in lieu of requiring extensive use of in vivo animal models that have notable limitations, it is hoped that there will be a burgeoning in the nanotherapy of CNS disorders by virtue of accelerated lead identification through screening, optimisation through rational design for brain-targeted delivery across the BBB and clinical testing and approval using fewer animals. Additionally, by using models with tissue of human origin, reproducible therapeutically relevant nanomedicine delivery and individualised therapy can be realised.

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Challenges in CNS drug development and the role of imaging

Cited by 18 publications

References 16 publications

Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery

Collaboration and knowledge integration for successful brain therapeutics – lessons learned from the pandemic

Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders

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