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bioRxiv2019

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by the MPO-H2O2-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gq-independent transient rise in intracellular Ca2+ and recruitment of {beta}-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

pharmacology and toxicology↗

bioRxiv2018

The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection

Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host - a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.\n\nAuthor SummaryCandida auris has emerged as a major health concern to hospitalized patients and nursing home subjects. C. auris strains display multidrug resistance to current antifungal therapy and cause lethal infections. We have determined that C. auris harbors homologs of C. albicans Als cell surface proteins. The C. albicans NDV-3A vaccine, harboring the N-terminus of Als3p formulated with alum, generates cross-reactive antibodies against C. auris clinical isolates and protects neutropenic mice from hematogenously disseminated C. auris infection. Importantly, the NDV-3A vaccine displays an additive protective effect in neutropenic mice when combined with micafungin. Due to its proven safety and efficacy in humans against C. albicans infection, our studies support the expedited testing of the NDV-3A vaccine against C. auris in future clinical trials.

microbiology↗

bioRxiv2018

Use of an individual-based model of pneumococcal carriage for planning a randomized trial of a vaccine

For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is more common and longer in duration than disease, and hence is often a more convenient endpoint for clinical trials of vaccines against these bacteria. However, using a carriage endpoint entails specific challenges. Carriage is almost always measured as prevalence, whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample size requirements, its impact on prevalence must first be estimated. The relationship between incidence and prevalence (or duration and prevalence) is convex, saturating at 100% prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less than its proportional effect on incidence or duration. This relationship is further complicated in the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates rapidly with frequent exposures in early years of life, creating potentially complex interactions with the vaccines effect. We conducted a simulation study to predict the impact of an inactivated whole cell pneumococcal vaccine--believed to reduce carriage duration--on carriage prevalence in different age groups and trial settings. We used an individual-based model of pneumococcal carriage that incorporates relevant immunological processes, both vaccine-induced and naturally acquired. Our simulations showed that for a wide range of vaccine efficacies, sampling time and age at vaccination are important determinants of sample size. There is a window of favorable sampling times during which the required sample size is relatively low, and this window is prolonged with a younger age at vaccination, and in a trial setting with lower transmission intensity. These results illustrate the ability of simulation studies to inform the planning of vaccine trials with carriage endpoints, and the methods we present here can be applied to trials evaluating other pneumococcal vaccine candidates or comparing alternative dosing schedules for the existing conjugate vaccines.\n\nAuthor SummaryStreptococcus pneumoniae, a bacterium carried in the nasopharynx of many healthy people, is also a leading cause of bacterial pneumonia, sepsis, and ear infections in children aged five years and younger. Vaccines targeting select strains of S. pneumoniae have been effective, and the development of new vaccines, particularly those that target all strains, can further lower disease burden. For clinical trials of these vaccines, the number of study participants needed depends on the expected effect of the vaccine on a conveniently measured outcome: asymptomatic carriage. The most economical way to test a vaccine for its effect on carriage is by measuring prevalence at a specific time, and comparing vaccinated to unvaccinated participants. The relationship between incidence (or duration) and prevalence is complex, and changes with time as children develop natural immunity. We explored this relationship using a mathematical model. Given a vaccine efficacy, our computer simulations predict that fewer study participants are needed if they are vaccinated at a younger age, taken from a population with intermediate levels of transmission, and sampled for carriage at a certain time window: 9 to 18 months after vaccination. Our study illustrates how simulation studies can help plan more efficient vaccine trials.

epidemiology↗

bioRxiv2025

Novel RNA Polymerase I and Cyclin Dependent Kinase combination therapy for the treatment of aggressive Acute Myeloid Leukemia.

Despite advances in therapy, specific subtypes Acute Myeloid Leukaemia (AML) remains largely incurable. The first-in-class RNA Polymerase I (Pol I) inhibitor, CX-5461, has demonstrated promising activity in both haematological malignancies and solid tumours by selectively inhibiting ribosome biogenesis to induce nucleolar stress, a critical vulnerability in rapidly proliferating cancer cells. CX-5461 has undergone clinical trials for the treatment of both solid and haematological malignancies, and 2nd generation Pol I inhibitor PMR-116 has also entered clinical trials, underscoring the translational potential of drugs that target RNA Polymerase I. To enhance the therapeutic efficacy of Pol I inhibition and prevent the emergence of resistance, we conducted a cell line-based unbiased screen of FDA-approved drugs to identify compounds that might synergise with CX-5461. This screen revealed that the pan-CDK inhibitors Dinaciclib and Flavopiridol enhance nucleolar stress pathway (NSP) activation and are strong candidates for combinatorial therapy with CX-5461. Further analysis showed that the combination of CX-5461 and Dinaciclib acts synergistically across a genetically diverse panel of human AML cell lines. This synergy is dependent on an intact NSP, with both agents independently stabilising p53, but with distinct phenotypic outcomes: Dinaciclib induces rapid apoptosis, whereas CX-5461 primarily enforces cell cycle arrest. This functional complementarity results in efficient tumour cell clearance and likely accounts for the delayed onset of therapy resistance. Importantly, combination treatment with CX-5461 and Dinaciclib significantly improved survival in murine models of AML and reduced colony formation in primary human AML samples. Together these findings provide preclinical evidence for a novel combination treatment strategy that leverages nucleolar stress and cell cycle control to enhance treatment outcomes in AML, paving the way for clinical translation of Pol I-CDK co-targeting therapies.

cancer biology↗

bioRxiv2022

Evaluating the efficacy of commercially available antisense oligonucleotides to reduce mouse and human tau in vivo

Tauopathies, including Alzheimers disease (AD), are neurodegenerative diseases characterized by the accumulation of tau protein encoded by the MAPT (Microtubule Associated Protein Tau) gene. Various strategies targeting mechanisms to reduce tau pathology have been proposed and several tau-directed therapies are being investigated in clinical trials. Our lab previously developed a novel strategy to lower tau protein levels using antisense oligonucleotides (ASOs), showing that human tau (hTau) reduction in aged PS19 tauopathy mice reversed phosphorylated tau pathology, spared neurons, and prolonged survival. Currently, the tau-lowering ASO is being evaluated in the clinical trials with successful phase 1b results. Similarly, preclinical and clinical studies have demonstrated the use of other ASOs as effective therapeutic strategies. Acquiring ASOs for research purposes may be limited by partnerships with pharmaceutical companies. However, ASOs can be obtained through commercial vendors. The current study evaluates the efficacy of mouse and human tau-targeting ASOs obtained from a commercial vendor in various mouse models. We show that mice treated with purchased ASOs distribute among various brain cell types including neurons, microglia, and astrocytes. Mice treated with tau lowering ASOs show decreased mouse or human tau mRNA and protein levels. In addition, human tau lowering ASO-treated PS19 mice showed decreased phosphorylated tau (AT8) and gliosis relative to saline-treated PS19 mice. The results obtained in PS19 mice are consistent with data obtained from our previous study using a non-commercial tau-lowering ASO. Overall, the present study demonstrates the efficacy of commercially-available tau targeting ASOs in vivo to support their broad use by researchers.

neuroscience↗

bioRxiv2020

ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.

microbiology↗

bioRxiv2021

Standard PBMC cryopreservation selectively decreases detection of nine clinically-relevant T-cell markers

Biobanking is an operational component of various epidemiological studies and clinical trials. Although peripheral blood is routinely acquired and stored in biobanks, the effects of specimen processing on cell composition and clinically-relevant functional markers of T cells still require a systematic evaluation. Here we assessed 25 relevant T-cell markers and showed that the detection of nine membrane markers, e.g., PD-1, CTLA4, KLRG1, CD25, CD122, CD127 and others reflecting exhaustion, senescence and other functions was reduced among at least one T-cell subset following standard processing, although the frequency of CD4, CD8 and regulatory T cells was unaffected. Nevertheless, a six-month-long cryopreservation did not impair the expression levels of many other membrane and all the eight tested intracellular lineage or functional T-cell markers. Our findings uncover that several clinically-relevant markers are particularly affected by processing and the interpretation of those results in clinical trials and translational research should be done with caution.

immunology↗

bioRxiv2023

ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor, currently in Phase-1 anticancer clinical trials. Here, we tested tizaterkibs efficacy against permanent NIHL in mice at doses equivalent to what humans are currently prescribed in clinical trials. The drug given orally 24 hours after noise exposure, protected an average of 20-25 dB SPL in three frequencies, in female and male mice, had a therapeutic window >50, and did not confer additional protection to KSR1 genetic knockout mice, showing the drug works through the MAPK pathway. Tizaterkib shielded from noise-induced cochlear synaptopathy, and a 3-day, twice daily, treatment with the drug was the optimal determined regimen. Importantly, tizaterkib was shown to decrease the number of CD45 and CD68 positive immune cells in the cochlea following noise exposure, which could be part of the protective mechanism of MAPK inhibition.

neuroscience↗

bioRxiv2025

The Critical and Unexpected Role of a Methyl Group in Interleukin-17A Inhibitors

Interleukin-17 (IL-17) is a pro-inflammatory cytokine primarily secreted by Th17 cells. It plays a crucial role in the bodys immune defense against fungal and bacterial pathogens. However, an imbalance in IL-17 production can contribute to the development of autoimmune and inflammatory disorders. Therapeutic strategies targeting IL-17, such as blocking antibodies like secukinumab (Cosentyx), have been successfully developed. These antibodies are currently employed in the treatment of various conditions, including psoriasis, psoriatic arthritis, and ankylosing spondylitis. More recently, a small molecule inhibitor of IL-17, LY3509754, progressed to clinical trials but was halted during Phase 1 due to unfavorable hepatotoxicity. Two derivatives, compounds 7 and 8, did not advance to clinical trials due to safety concerns. These three compounds (7, 8, and the original lead compound, presumably implied) share a common difluoro substituent, which was hypothesized to be the cause of the observed safety issues. In subsequent structure-activity relationship (SAR) studies, replacing the difluoro substituent with a single methyl group (resulting in compound 9) unexpectedly led to a significant improvement in cellular activity. Furthermore, compound 9 exhibited a very low unbound fraction and reduced liver distribution, ultimately translating to high in vivo efficacy with a sufficient safety margin. This seemingly minor methyl substitution transformed the compound into a highly promising preclinical candidate (compound 9), now slated for further development. Co-development inquiries are welcome. Please contact us at enan1@dcpc.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/680113v2_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@3f31adorg.highwire.dtl.DTLVardef@d6873forg.highwire.dtl.DTLVardef@494af7org.highwire.dtl.DTLVardef@1d8b7eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Limitations of the radiotheranostic concept in neuroendocrine tumors due to lineage-dependent somatostatin receptor expression on hematopoietic stem and progenitor cells

Radiopharmaceutical therapy (RPT) has become an effective treatment option for neuroendocrine tumors (NETs) and castration-resistant prostate cancer and is in clinical development for a growing number of indications. One of the major advantages of theranostic RPT is that the distribution of radiopharmaceuticals in the human body can be imaged, and radiation doses to the patients organs can be calculated. However, accurate dosimetry may be fundamentally limited by microscopic heterogeneity of radiopharmaceutical distribution. We developed fluorescent analogs of somatostatin-receptor-subtype 2 (SSTR2) targeting Lutetium-177 labelled radiopharmaceuticals that are clinically used in patients with neuroendocrine tumors (NETs) and studied their uptake by hematopoietic stem and progenitor cells (HSPC). Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) showed high and specific SSTR2-ligand uptake, which was at similar levels as neuroendocrine tumor cells. Furthermore, they displayed a several-fold higher uptake of SSTR2-antagonists than of SSTR2-agonists. HSPC treatment with a 177Lu-labelled antagonist and agonist showed a stronger reduction of HSC proliferation by the antagonist. Due to the scarcity of HSCs and MPPs, their contribution to total bone marrow uptake of SSTR2-ligands is not detectable in imaging-based dosimetry studies. This likely explains why SSTR2-antagonists caused pancytopenia in clinical trials despite safe dosimetry estimates. In conclusion, target expression heterogeneity can lead to underestimation of radiopharmaceutical toxicity and should be considered when designing clinical trials for new radiopharmaceuticals. The implications of our findings go beyond somatostatin receptor-targeted radiopharmaceuticals and suggest more generally that first-in-human studies should not only be guided by radiation dosimetry from imaging studies but should also include careful escalation of the administered therapeutic activity. The MMC technology is modular and can be applied to other peptide or protein-based radiopharmaceuticals to study cellular distribution and potential bone marrow uptake prior to clinical testing.

cancer biology↗

bioRxiv2020

Continuous administration of the p38α inhibitor neflamapimod during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level

There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and there is growing interest in developing therapies that widen the treatment initiation window and promote functional recovery through increasing synaptic plasticity. The p38 mitogen-activated protein kinase is an already proven target for acute experimental stroke intervention and was hypothesized to also contribute to neuroinflammation-mediated impairment of recovery during the subacute phase. Neflamapimod, an orally bioavailable, brain-penetrant, potent and selective small molecule p38 inhibitor was evaluated as a subacute phase stroke treatment to promote recovery in this research study. Neflamapimod administration at two clinically relevant dose levels was initiated outside of the previously characterized neuroprotection window of less than 24 hours after stroke for p38 inhibitors to rats after transient middle cerebral artery occlusion. Continuous administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at four- and six-weeks post stroke in a dose-dependent manner. Neflamapimod also demonstrated beneficial effects on additional measures of sensory and motor function and resulted in a dose-related increase in the terminal brain-derived neurotrophic factor protein level in both the injured and uninjured brain hemisphere. Variable interleukin-1{beta} levels were detected in the injured brain hemisphere at study termination in a subset of the animals within every test group, implying ongoing, chronic inflammation, however, no clear neflamapimod effect on interleukin-1{beta} production was observable. The dose-related in vivo efficacy of neflamapimod offers the possibility of both expanding the window for initiation of therapy after stroke and for improving recovery after a completed stroke. Since neflamapimod is already in mid-stage clinical trials for Alzheimers disease and related dementias, the current results make it especially attractive for evaluation in a proof-of- concept clinical trial as therapeutic to promote recovery after ischemic stroke.

pharmacology and toxicology↗

bioRxiv2024

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs

The clinical use of interleukin-2 and -12 cytokines against cancer is limited by their narrow therapeutic windows due to on-target, off-tumor activation of immune cells when delivered systemically. Engineering IL-2 and IL-12 to bind to extracellular matrix collagen allows these cytokines to be retained within tumors after intralesional injection, overcoming these clinical safety challenges. While this approach has potentiated responses in syngeneic mouse tumors without toxicity, the complex tumor-immune interactions in human cancers are difficult to recapitulate in mouse models of cancer. This has driven an increased role for comparative oncology clinical trials in companion (pet) dogs with spontaneous cancers that feature analogous tumor and immune biology to human cancers. Here, we report the results from a dose-escalation clinical trial of intratumoral collagen-binding IL-2 and IL-12 cytokines in pet dogs with malignant melanoma, observing encouraging local and regional responses to therapy that may suggest human clinical benefit with this approach.

cancer biology↗

bioRxiv2019

Brain morphology predicts long-term placebo response in multiple sclerosis patients

Although significant insights have been gained into the neural mechanisms of acute placebo responses, less is known about the mechanisms of longer-term placebo responses, such as those seen in clinical trials, or the interactions between these mechanisms and brain disease. We examined neuropathological and morphological brain correlates of placebo responses in a randomized clinical trial of a controversial endovascular treatment ("liberation therapy") for multiple sclerosis. Patients were randomized to receive either balloon or sham extracranial venoplasty and followed for 48 weeks. The trial did not support therapeutic efficacy of venoplasty, but a subset of both venoplasty- and sham-treated patients reported an improvement in health-related quality of life that peaked at 12 weeks following treatment, suggesting a placebo response. Placebo responders had higher lesion activity than placebo non-responders. Although placebo responders did not differ from non-responders in terms of total normalized brain volume, regional grey or white matter volume or cortical thickness, graph theoretical analysis of cortical thickness covariance showed that placebo non-responders had a more homogenous cortical thickness topology with a more small-world-like architecture. In placebo non-responders, lesion load inversely predicted cortical thickness in primary somatosensory and motor areas, association areas, precuneus and insula, primarily in the right hemisphere. In placebo responders, lesion load was unrelated to cortical thickness. The neuropathological process in MS may result in a cortical configuration that is less suited to functional integration and less capable of generating a sustained placebo response.

neuroscience↗

bioRxiv2018

Effects of daily L-dopa administration on learning and brain structure in older adults undergoing four weeks of cognitive training: a randomised, parallel-group, double-blind, placebo-controlled trial.

BackgroundCognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. MethodsParticipants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide or placebo prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were masked to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54. FindingsBetween January 1st and October 10th 2017, we screened 235 people from the population in Stockholm, Sweden and randomly assigned 63 eligible subjects to receive L-dopa (n=32) or placebo (n=31) during cognitive training. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0{middle dot}267 SDs; 95% CI [-0{middle dot}498, -0{middle dot}036]; p=0{middle dot}024). Change in verbal intelligence did not significantly differ between the groups (-0{middle dot}081 SDs, 95% CI [-0{middle dot}242, 0{middle dot}080]; p=0{middle dot}323). Adverse events occurred for 10 subjects (31%) in the active and for 7 participants (23%) in the control groups. InterpretationThe results speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. FundingEuropean Research Council (ERC Grant agreement #617280-REBOOT), Wallenberg Clinical Scholars, and Stiftelse Stockholms Sjukhem. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWhilst pharmacological treatments have so far been largely unsuccessful in making an impact on age-related cognitive decline, recent findings have suggested small improvements of cognitive performance in older people by combining cognitive training with a healthy diet and aerobic exercises. Both exercise and dietary factors may exhibit plasticity-enhancing properties, and therefore increase effectiveness of cognitive training. In related basic research, dopaminergic signaling has been implicated in brain plasticity. An extensive PubMed search was conducted during the preparatory stage of the study (September 2014-July 2016) to investigate the role of dopamine signaling in neural plasticity and learning, as well as the effects of its deterioration on these characteristics in aging and neurodegenerative disorders. As a result, we found a substantial number of studies reporting acute improvements in cognitive performance and learning by administration of exogenous dopamine precursor L-dopa. A similar search was conducted specifically for this drug to evaluate its pharmacological and safety profile. We found a large body of basic research on both animal models and humans that supported the role of dopamine signaling in learning and plasticity. In addition, two smaller studies reported promising effects of repeated L-dopa administration on learning in the healthy younger population. In all studies, standard small-dose (100mg) L-dopa interventions were safe and well-tolerated. Added value of this studyOur study is the first of its kind to evaluate effects of repeated pro-dopaminergic medication on learning during cognitive training and cognitive performance in healthy older adults. Our results do not support the hypothesis of plasticity- and learning-promoting effects of enhanced dopaminergic neurotransmission by administration of exogenous dopamine precursor L-dopa in the healthy older population. The findings indicate that L-dopa treatment may in fact be detrimental to learning and cognitive performance and lead to structural brain changes within the dopaminergic circuit. Implications of all the available evidenceThe results put constraints on the hypothesis of a key role of the deteriorated dopaminergic system in age-related decline of learning abilities, and speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system. Our findings also raise concerns about usefulness of novel L-dopa-containing supplements that claim to have neuroprotective and learning-enhancing properties, and present an urgent need to carefully investigate the cognitive outcomes of early pro-dopaminergic interventions in clinical populations often receiving substantially larger doses of L-dopa.

clinical trials↗

bioRxiv2018

NDV-3A vaccination protects mice from Candida albicans biofilm infection

NDV-3A, a novel fungal vaccine undergoing clinical trials, contains a recombinant version of the Candida albicans rAls3 N-terminus protein (rAls3p-N) in aluminum hydroxide. In a Phase 1b/2a clinical trial, NDV-3A protected women from recurrent vulvovaginal candidiasis. Here, we reveal that active immunization in mice with NDV-3A induces high titers of anti-rAls3p-N antibodies that interfere with C. albicans ability to adhere to and invade endothelial cells, and form biofilm in vitro. The anti-rAls3p-N antibodies also protect against C. albicans biofilm formation in a central venous catheter mouse model. Finally, anti-rAls3p-N antibodies significantly inhibit yeast dispersal from the hyphal layers of biofilms. Overall these preclinical studies suggest that NDV-3A may serve as an immunotherapeutic strategy for prevention of infections on indwelling medical devices.

immunology↗

bioRxiv2018

Use of IFNγ/IL10 ratio for stratification of hydrocortisone therapy in patients with septic shock

BackgroundLarge clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may however benefit depending on their individual immune response.\n\nMethodsWe performed an exploratory analysis of the CORTICUS trial database employing machine learning to a panel of 137 variables collected from 83 patients (60 survivors, 23 non-survivors) including demographic and clinical measures, organ failure scores, leukocyte counts and circulating cytokine levels. The identified biomarker was validated against data collected from patients enrolled into a cohort of the Hellenic Sepsis Study Group (HSSG) (n=162) and two data sets of two other clinical trials. Ex vivo studies were performed on this biomarker to assess a possible mechanistic role.\n\nResultsA low serum IFN{gamma}/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this ratio for a decision rule, we found significant improvement in survival in the groups of patients being in compliance with the prediction rule (discovery set: OR=3.03 [95% Cl: 1.05-8.75], P=0.031, validation set: OR=2.01 [95% CI: 1.04-3.88], P=0.026). Applying the rule to two further, smaller datasets showed the same tendency. Mechanistic studies revealed that IFN{gamma}/IL10 was negatively associated with pathogen load in spiked human blood. An in silico analysis of published IFN{gamma} and IL10 values in bacteremic and non-bacteremic SIRS patients supported this association between the ratio and pathogen burden.\n\nConclusionIf confirmed prospectively, the IFN{gamma}/IL10 ratio could be used as a rapidly available theranostic for use of hydrocortisone therapy in septic shock.

immunology↗

bioRxiv2021

Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury

Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 hours after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 hours after injury makes MINO plus NAC a promising candidate to treat clinical TBI.

neuroscience↗

bioRxiv2024

Interaction between native and prosthetic visual responses in optogenetic visual restoration

Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light sensitive opsins into the surviving neurons of inner retina. While up until now the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. Yet, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures moreover may serve to track treatment efficiency in clinical trials.

neuroscience↗