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Stroke continues to be a serious and significant health problem in the USA and worldwide. This article will emphasize the need for good laboratory practices, transparent scientific reporting, and the use of translational research models representative of the disease state to develop effective treatments. This will allow for the testing and developm...
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... the National Institure of Neurological Disorders and Stroke (NINDS) rt-PA and ECASSIII trials as examples, the stroke patient population had the characteristics described in Table 1. The most pertinent aspects are that strokes occur in a mixed gender aged population, particularly those with a his- tory of hypertension or diabetes, which is usually controlled by one or more pharmaceuticals. ...
Context 2
... is also significant information available in the liter- ature regarding the group of refractory diabetic patients en- rolled in the NINDS rt-PA trial [8] and the ECASS III trial [4], which includes a small percentage of patients with diabetes (Table 1). It is extremely difficult to treat diabetic stroke patients since they do not respond [3] or have an attenuated response to standard dose thrombolytic therapy [43][44][45]. ...
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... ALS research illustrates data robustness issues, with treatments effective in animal models often failing in human studies [57]. On the other hand, the variability in experimental protocols and tools affects how generalizable the results are [58,59]: drugs effective across diverse laboratory settings tend to promise better outcomes in human studies [60]. In addition, outcomes from animal and early clinical studies must align with actual clinical needs [59]. ...
There is an ongoing debate about the value of animal experiments to inform medical practice, yet there are limited data on how well therapies developed in animal studies translate to humans. We aimed to assess 2 measures of translation across various biomedical fields: (1) The proportion of therapies which transition from animal studies to human application, including involved timeframes; and (2) the consistency between animal and human study results. Thus, we conducted an umbrella review, including English systematic reviews that evaluated the translation of therapies from animals to humans. Medline, Embase, and Web of Science Core Collection were searched from inception until August 1, 2023. We assessed the proportion of therapeutic interventions advancing to any human study, a randomized controlled trial (RCT), and regulatory approval. We meta-analyzed the concordance between animal and human studies. The risk of bias was probed using a 10-item checklist for systematic reviews. We included 122 articles, describing 54 distinct human diseases and 367 therapeutic interventions. Neurological diseases were the focus of 32% of reviews. The overall proportion of therapies progressing from animal studies was 50% to human studies, 40% to RCTs, and 5% to regulatory approval. Notably, our meta-analysis showed an 86% concordance between positive results in animal and clinical studies. The median transition times from animal studies were 5, 7, and 10 years to reach any human study, an RCT, and regulatory approval, respectively. We conclude that, contrary to widespread assertions, the rate of successful animal-to-human translation may be higher than previously reported. Nonetheless, the low rate of final approval indicates potential deficiencies in the design of both animal studies and early clinical trials. To ameliorate the efficacy of translating therapies from bench to bedside, we advocate for enhanced study design robustness and the reinforcement of generalizability.
... They were housed under standard conditions, including ad libitum feeding and drinking and a 12 h light/12 h dark cycle (the light was turned on at 8:00 h and turned off at 20:00 h). This study was designed and conducted according to the STAIR/RIGOR guidelines [14,16] regarding physiological monitoring, gender consideration, power analysis and sample size calculations, simple randomization, predefined exclusion criteria, allocation concealment, blinded assessment of several outcomes at different endpoints, and conflict of interest statements. The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were followed (https://arriveguidelines.org/; accessed on 21 April 2024). ...
ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials.
... All experiments were performed and reported in accordance with followed ARRIVE and RIGOR guidelines [45]. All procedures were approved by the Experimental Animal Ethics Committee of Capital Medical University. ...
... Unfortunately, after nearly 200 clinical trials, all attempts at neuroprotection for ischemic stroke clinically have failed. The Stroke Treatment Academic Industry Roundtable (STAIR) first met and published recommendations in 1999 specifically to address stroke preclinical studies intended to increase success of stroke therapeutics brought to clinical trials Albers et al., 2011;Lapchak et al., 2013). STAIR meetings consist of academic physicians, industry representatives, and regulators that have met multiple times since the initial 1999 meeting to provide updates to the STAIR criteria, adapting to continuing stroke clinical trial outcomes Saver et al., 2009;Albers et al., 2011). ...
... The STAIR criteria were created as preclinical study recommendations with the purpose of enhancing the success of stroke treatments, neuroprotective specifically. Current STAIR recommendations and updates designed to be utilized as an outline for preclinical stroke studies are summarized below Lapchak et al., 2013 Saver et al., 2009;Albers et al., 2011;Lapchak et al., 2013;Jovin et al., 2016). When designing preclinical trials for a potential stroke therapeutic, it is suggested that one should address each of the 10 STAIR recommendations listed above as well as additional STAIR recommendations directly related to the specific study focus. ...
... The STAIR criteria were created as preclinical study recommendations with the purpose of enhancing the success of stroke treatments, neuroprotective specifically. Current STAIR recommendations and updates designed to be utilized as an outline for preclinical stroke studies are summarized below Lapchak et al., 2013 Saver et al., 2009;Albers et al., 2011;Lapchak et al., 2013;Jovin et al., 2016). When designing preclinical trials for a potential stroke therapeutic, it is suggested that one should address each of the 10 STAIR recommendations listed above as well as additional STAIR recommendations directly related to the specific study focus. ...
Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.
... While these studies highlight the promising potential of gene therapy for neurorepair and functional recovery there is caution when advancing the translation of preclinical studies. For example, translating preclinical stroke research has not proven successful, and a number of recommendations and guidelines have been put forth by the Stroke Therapy Academic Industry Roundtable (STAIR) to overcome this challenge, including the rigorous testing and replication of potential therapeutics in more than one preclinical model [43]. ...
... However, this is difficult due to two main elements: (1) the equivalent cellular processes thought to underlie post-stroke neuroregenerative and neuroplastic processes (thought to recapitulate processes that occur in development to some degree) occur in an abbreviated time frame compared to those observed in the clinic (reviewed by [56]); and (2) spontaneous recovery of most widely validated post-stroke behavioral tests (including those used here) can occur within weeks in rodents models, as opposed to the persistent, attenuated timeframes seen in human stroke survivors. As such, the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations [43] suggest that rodent stroke models include long-term outcomes measuring at least 2-3 weeks after stroke. In this study, our 9-week timeline exceeding this recommendation is considered chronic in terms of rodent stroke models [57], and importantly, it was still able to detect deficits in untreated controls that were significantly improved in Neurod1-treated animals. ...
Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor Neurod1 is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory–motor cortex stroke. We used an adeno-associated virus to deliver Neurod1 from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using Cre-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of Neurod1 in the stroke-injured brain is sufficient to enhance neural repair.
... Meanwhile, it has been argued that different study designs such as duration and time-points of monitoring or implementation of different neurologic scoring scales (Sugawara et al. 2008;McBride et al. 2018;Katz et al. 1995;Garcia et al. 1995;Bederson et al. 1986;Wu et al. 2017), and in some cases, lack of procedure-or time-matched Sham controls could make interpretation of results subjective and contradictory and may not accurately capture the deficits caused by SAH and therapeutic effects of new drugs being evaluated (Jeon et al. 2009). The discrepancy in these findings using different SAH models emphasizes the importance of developing a standardized neurobehavioral testing regime for experimental SAH to allow for better comparison between research groups (Fisher et al. 2009;Marbacher et al. 2018;Suzuki and Nakano 2018;Lapchak et al. 2013). ...
Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm leads to delayed vasospasm and neuroischemia, which can result in profound neurologic deficit and death. Therapeutic options after SAH are currently limited to hemodynamic optimization and nimodipine, which have limited clinical efficacy. Experimental SAH results in cerebral vasospasm have demonstrated the downregulation of nitric oxide (NO)-protein kinase G (PKG) signaling elements. VP3 is a novel cell permeant phosphopeptide mimetic of VASP, a substrate of PKG and an actin-associated protein that modulates vasorelaxation in vascular smooth muscle cells. In this study, we determined that intravenous administration of high doses of VP3 did not induce systemic hypotension in rats except at the maximal soluble dose, implying that VP3 is well-tolerated and has a wide therapeutic window. Using a single cisterna magna injection rat model of SAH, we demonstrated that intravenous administration of low-dose VP3 after SAH improved neurologic deficits for up to 14 days as determined by the rotarod test. These findings suggest that strategies aimed at targeting the cerebral vasculature with VP3 may improve neurologic deficits associated with SAH.
... Our experiments were conducted in healthy young males without comorbid conditions to limit experimental variability and to remove the confounding variable of estrogen effects at the BBB. 15 Specificity of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg in 100% ethanol, IV; Millipore-Sigma), a known Oatp transport inhibitor, injected at the same time as atorvastatin. ...
Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.
... Rehabilitation increased use of the impaired forelimb; however, this effect was predominately driven by two inter-ventions with unclear treatment onset (Kim 2012a, b). Effect sizes presented as mean difference (MD), percent change in impaired forelimb use, with 95% CI success [29,[88][89][90][91][92][93][94], yet for reasons unknown, adherence to these guidelines remains far from universal [67]. Preclinical successes will continue to fail to translate if we do not disrupt this norm. ...
... We encourage research groups to include formal training on best practices in research and statistics when onboarding new members. Familiarization with best practice guidelines (i.e., ARRIVE [89,92,93], RIGOR [90]), how compliance to these guidelines is assessed (i.e., CAMARADES [31], SYRCLE [32]), and what these guidelines look like in practice are equally important skills to preclinical researchers as learning animal husbandry or basic surgical techniques. ...
... Roadmap to improving the quality of preclinical rehabilitation researchElementAction GoalScientific rigor Use the RIGOR[90], ARRIVE[89,93], SYRCLE[32], and CAMARADES[31] guidelines and checklists to inform decision making during experimental design. Consult the CONSIGN tool[94] to ensure selection of appropriate control groups (Phase: experimental planning) ...
Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2–8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.
... This study was performed in accordance with the guidelines provided by the National Institutes of Health (NIH) and followed RIGOR guidelines. 69 Young male and female C57BL/6J mice (2-month) were purchased from Jackson Laboratory and acclimatized for a minimum of 1 month before use. Aged female C57BL/6J mice (18-20 months) were raised in our animal facilities. ...
The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young males, but not in young females after experimental stroke. In contrast, mucin-related genes were enhanced in young females and contributed to mucus formation that maintains the distance between the host and gut bacteria. Bacterial community profiling was done using universal amplification of 16S rRNA gene sequences. The sex-specific colonic epithelial defense responses after stroke in young females were reversed with ovariectomy and led to a shift from a predominately mucin response to the enhanced AMP expression seen in males after stroke. Estradiol (E2) replacement prior to stroke in aged females increased mucin gene expression in the colonic ECs. Interestingly, we found that E2 treatment reduced stroke-associated neuronal hyperactivity in the insular cortex, a brain region that interacts with visceral organs such as the gut, in parallel to an increase in the composition of Lactobacillus and Bifidobacterium in the gut microbiota. This is the first study demonstrating sex differences in host defense mechanisms in the gut after brain injury.
... The STAIR and RIGOR guidelines recommend that doseresponse research is undertaken for all putative cerebroprotectants to determine the maximum and minimum doses for a given therapeutic window to improve translation efforts (Lapchak et al., 2013;Lyden et al., 2021). There have been some TH investigations into alternate dose-response data such as depth after focal ischemia. ...
Decades of animal research show therapeutic hypothermia (TH) to be potently neuroprotective after cerebral ischemic injuries. While there have been some translational successes, clinical efficacy after ischemic stroke is unclear. One potential reason for translational failures could be insufficient optimization of dosing parameters. In this study, we conducted a systematic review of the PubMed database to identify all preclinical controlled studies that compared multiple TH durations following focal ischemia, with treatment beginning at least 1 hour after ischemic onset. Six studies met our inclusion criteria. In these six studies, six of seven experiments demonstrated an increase in cerebroprotection at the longest duration tested. The average effect size (mean Cohen's d ± 95% confidence interval) at the shortest and longest durations was 0.4 ± 0.3 and 1.9 ± 1.1, respectively. At the longest durations, this corresponded to percent infarct volume reductions between 31.2% and 83.9%. Our analysis counters previous meta-analytic findings that there is no relationship, or an inverse relationship between TH duration and effect size. However, underreporting often led to high or unclear risks of bias for each study as gauged by the SYRCLE Risk of Bias tool. We also found a lack of investigations of the interactions between duration and other treatment considerations (e.g., method, delay, and ischemic severity). With consideration of methodological limitations, an understanding of the relationships between treatment parameters is necessary to determine proper "dosage" of TH, and should be further studied, considering clinical failures that contrast with strong cerebroprotective results in most animal studies.
