Drug development for CNS disorders: strategies for balancing risk and reducing attrition

Pangalos, Menelas N.; Schechter, Lee E.; Hurko, Orest

doi:10.1038/nrd2094

Cited by 306 publications

(252 citation statements)

References 120 publications

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“…As a result of the growing aging population worldwide, incidences of neurodegenerative diseases, in particular, are projected to increase considerably in the coming decades [1]. At present, there is a dearth of effective therapeutics for neurodegenerative diseases owing, in part, to the inherent difficulty of developing safe and efficacious drugs that will cross the blood-brain barrier (BBB).…”

Section: Introductionmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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Section: Introductionmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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“…Neurological and psychiatric diseases together affect over 35% of the adult population [1][2][3] , and often involve the dysfunction of neural circuits defined by specific spatial locations and cell types [4][5][6][7][8] . However, conventional pharmacological treatments for such diseases act throughout the brain, leading to significant side-effects.…”

Section: Introductionmentioning

confidence: 99%

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

et al. 2018

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Neurological and psychiatric diseases often involve the dysfunction of specific neural circuits in particular regions of the brain. Existing treatments, including drugs and implantable brain stimulators, aim to modulate the activity of these circuits, but are typically not cell type-specific, lack spatial targeting or require invasive procedures. Here, we introduce an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, called acoustically targeted chemogenetics, or ATAC, uses transient ultrasonic opening of the blood brain barrier to transduce neurons at specific locations in the brain with virally-encoded engineered G-protein-coupled receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. We demonstrate this concept in mice by using ATAC to noninvasively modify and subsequently activate or inhibit excitatory neurons within the hippocampus, showing that this enables pharmacological control of memory formation. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds, thereby overcoming some of the key limitations of conventional brain therapies.

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“…There is pressing unmet clinical and health economic need for neurotherapeutic drugs that prevent or slow disease progression, relieve symptoms and improve quality of life in acute and chronic progressive disorders of the central nervous system (CNS) (Miller, 2012;Pangalos et al, 2007). Given the complexity of multiple pathological processes in neurodegeneration, it is increasingly recognized that pharmacological interventions capable of modifying multiple pathogenic mechanisms may offer therapeutic advantages over strategies targeting a single injury process (Cavalli et al, 2008;Geerts, 2009;Geldenhuys et al, 2011;Stoica et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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Drug development for CNS disorders: strategies for balancing risk and reducing attrition

Cited by 306 publications

References 120 publications

Developing Therapeutic Antibodies for Neurodegenerative Disease

Developing Therapeutic Antibodies for Neurodegenerative Disease

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

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