Blowing up Neural Repair for Stroke Recovery

The repair and recovery of the brain after stroke is a field that is emerging in its preclinical science and clinical trials. However, recent large, multicenter clinical trials have been negative, and conflicting results emerge on biological targets in preclinical studies. The coalescence of negative clinical translation and confusion in preclinical studies raises the suggestion that perhaps the field of stroke recovery faces a fate similar to stroke neuroprotection, with interesting science ultimately proving difficult to translate to the clinic. This review highlights improvements in 4 areas of the stroke neural repair field that should reorient the field toward successful clinical translation: improvements in rodent genetic models of stroke recovery, consideration of the biological target in stroke recovery, stratification in clinical trials, and the use of appropriate clinical trial end points.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Biomolecules ◽

10.3390/biom10030391 ◽

2020 ◽

Vol 10 (3) ◽

pp. 391 ◽

Cited By ~ 6

Author(s):

Margaux Teil ◽

Marie-Laure Arotcarena ◽

Emilie Faggiani ◽

Florent Laferriere ◽

Erwan Bezard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Clinical Trials ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Curative Treatment ◽

Preclinical Studies ◽

Cytoplasmic Inclusions ◽

The Many ◽

The Brain

Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Nanomedicinal Strategies as Emerging Therapeutic Avenues for the Management Cerebral Ischemia

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666201102100330 ◽

2020 ◽

Vol 19 ◽

Author(s):

Saman Fatima ◽

Syed Naved Quadri ◽

Shaheda Parveen ◽

Sarwar Beg ◽

Md Abul Barkat ◽

...

Keyword(s):

Clinical Trials ◽

Ischemic Stroke ◽

Cerebral Ischemia ◽

Health Risks ◽

Global Scale ◽

Preclinical Studies ◽

Neuronal Regeneration ◽

Stroke Patients ◽

Mortality And Morbidity ◽

The Brain

: Amongst the various diseases on global scale, the second leading cause of mortality and morbidity is ischemic stroke due to the unavailability of an effective therapy. With the growing occurrence and its related health risks along with the absence of effective therapeutics, the ischemic stroke demands the continued and intensive research to explore the effective and safe therapeutics. These therapies may positively affect the numerous pathways associated with neuroprotection thus, extending the advantages to a larger population of stroke patients. Several preclinical studies employing neuroprotectants have shown promising outcomes, but failed in clinical trials either because of the lack of safety or efficacy. The blood brain barrier (BBB) restricts delivery of various potent neuroprotectants to the specific areas of the brain. The application of nanovehicles for delivery of drugs in the brain however, could revolutionize the treatment of ischemic stroke. These nanovehicles loaded with the drug could readily traverse the BBB via carrier, receptor and adsorptive-mediated endocytosis into the brain without compromising the integrity of BBB. Recent advances in neuronanotherapeutics have resulted in the improved neuronal regeneration and recovery after the ischemic stroke. In this review, we have attempted to discuss unexploited neuronanotherapeutics potentials to treat and manage ischemic stroke.

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The Use of Hydrogel-Delivered Extracellular Vesicles in Recovery of Motor Function in Stroke: A Testable Experimental Hypothesis for Clinical Translation including Behavioral and Neuroimaging Assessment Approaches

10.20944/preprints202005.0460.v1 ◽

2020 ◽

Author(s):

Magdalini Tsintou ◽

Kyriakos Dalamagkas ◽

Tara L Moore ◽

Yogesh Rathi ◽

Marek Kubicki ◽

...

Keyword(s):

Tissue Engineering ◽

Extracellular Vesicles ◽

Neural Tissue ◽

Clinical Translation ◽

Neural Repair ◽

Cns Repair ◽

Structural Support ◽

Working Together ◽

The Brain

Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate (NHP) models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimage analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans.

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Registry of Multicenter Clinical Trials: Twelfth and Thirteenth Report – 1990–1991

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646355 ◽

1992 ◽

Vol 68 (06) ◽

pp. 752-778 ◽

Cited By ~ 4

Author(s):

J P Boissel ◽

N Bossard

Keyword(s):

Clinical Trials ◽

Multicenter Clinical Trials

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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Clinical Trials Update

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-8.2.99 ◽

2009 ◽

Vol 8 (2) ◽

pp. 99-99

Keyword(s):

Clinical Trials ◽

Pulmonary Hypertension ◽

Preliminary Results ◽

Multicenter Clinical Trials

We would like to introduce you to a new section in Advances in Pulmonary Hypertension in which we highlight results from ongoing and recent clinical trials. The preliminary results of several multicenter clinical trials have recently been presented. In this issue, we will focus on the results of Freedom-C, which was presented in November of 2008, as well as the Walk-PHaSST study, which was stopped early in July 2009.

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Cell Therapy for Stroke: A Mechanistic Analysis

Neurosurgery ◽

10.1093/neuros/nyaa531 ◽

2020 ◽

Author(s):

Ben Jiahe Gu ◽

David K Kung ◽

Han-Chiao Isaac Chen

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cell Therapy ◽

Clinical Translation ◽

Stroke Survivors ◽

Cell Replacement ◽

Preclinical Data ◽

Promising Strategy ◽

Mechanistic Analysis

Abstract Cell therapy has been widely recognized as a promising strategy to enhance recovery in stroke survivors. However, despite an abundance of encouraging preclinical data, successful clinical translation remains elusive. As the field continues to advance, it is important to reexamine prior clinical trials in the context of their intended mechanisms, as this can inform future preclinical and translational efforts. In the present work, we review the major clinical trials of cell therapy for stroke and highlight a mechanistic shift between the earliest studies, which aimed to replace dead and damaged neurons, and later ones that focused on exploiting the various neuromodulatory effects afforded by stem cells. We discuss why both mechanisms are worth pursuing and emphasize the means through which cell replacement can still be achieved.

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Post-Stroke Social Isolation Reduces Cell Proliferation in the Dentate Gyrus and Alters miRNA Profiles in the Aged Female Mice Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22010099 ◽

2020 ◽

Vol 22 (1) ◽

pp. 99

Author(s):

Aleah Holmes ◽

Yan Xu ◽

Juneyoung Lee ◽

Michael E. Maniskas ◽

Liang Zhu ◽

...

Keyword(s):

Cell Proliferation ◽

Dentate Gyrus ◽

Social Isolation ◽

Census Data ◽

Elderly Women ◽

Stroke Recovery ◽

Tissue Loss ◽

Female Mice ◽

Post Stroke ◽

The Brain

Social isolation and loneliness are risk factors for stroke. Elderly women are more likely to be isolated. Census data shows that in homeowners over the age of 65, women are much more likely to live alone. However, the underlying mechanisms of the detrimental effects of isolation have not been well studied in older females. In this study, we hypothesized that isolation impairs post-stroke recovery in aged female mice, leading to dysregulated microRNAs (miRNAs) in the brain, including those previously shown to be involved in response to social isolation (SI). Aged C57BL/6 female mice were subjected to a 60-min middle cerebral artery occlusion and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. SI immediately after stroke led to significantly more brain tissue loss after stroke and higher mortality. Furthermore, SI significantly delayed motor and sensory recovery and worsened cognitive function, compared to PH. A decrease in cell proliferation was seen in the dentate gyrus of SI mice assessed by bromodeoxyuridine (BrdU) labeling. miRNAome data analysis revealed changes in several miRNAs in the brain, such as miR-297a-3p and miR-200c-3p, which are known to regulate pathways involved in cell proliferation. In conclusion, our data suggest that SI can lead to a poor post-stroke recovery in aged females and dysregulation of miRNAs and reduced hippocampal cell proliferation.

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