Therapeutic Window Of Opportunity Research Articles

Management of patients with Crohn's disease – from history to modern approaches

Since the isolation of Crohn's disease as a separate pathology, significant progress has been made both in the diagnosis of the disease and in approaches to the treatment of patients with this pathology. The active introduction of biologics and the top-down approach into clinical practice in patients with negative prognosis factors has led to a significant improvement in treatment results and prognosis in patients. The use of the most effective anti-inflammatory therapy during the «therapeutic window of opportunity» – up to 18 months – is the key to achieving remission, or minimal activity of Crohn's disease by suppressing inflammation and preventing irreversible structural damage to the intestinal wall and, as a result, the development of complications. The article presents an excursion into the history of the discovery of this disease, which is still far from its completion. The approaches to the treatment of patients with this pathology are highlighted with an explanation of the current position based on data from meta-analyses and systematic reviews. A demonstration of a patient with a penetrating phenotype of Crohn's disease in the form of a perianal lesion and a history of oncopathology is presented. Ustekinumab therapy can be considered as an optimal management strategy for patients with Crohn's disease with unfavorable prognosis factors.

Current Status of Machine Learning for Precision Rheumatology: Are We There Yet?

Autoimmune rheumatic diseases are often characterised by heterogeneity in presentation. The traditional approach to diseases guided by their phenotype may be suboptimal with the advent of precision medicine. Precision medicine is the integration and application of multiomics to predict the best-performing drug and its toxicity profile to derive optimal benefits. With novel drug discoveries and an expanding therapeutic armamentarium, it potentially aids in clinical and therapeutic decision-making, while saving time and averting adverse events. However, multiomics comes with ‘big data’, and owing to the costs, the sample size is usually small. Machine learning (ML) plays an important role in these scenarios where conventional statistics fall short. So, by integrating clinical data with the data from -omics, ML models can be built, which can accurately predict the clinical factors or even novel biomarkers that predict response. This approach has a potential for great benefit as valuable time or the ‘therapeutic window of opportunity’ would be saved, with fewer adverse events, eventually translating to lower damage accrual and better outcomes. Most of the evidence for the use of ML in precision rheumatology comes from rheumatoid arthritis and the factors predicting response to various drugs, including tumour necrosis factor inhibitors. This approach also has its limitations such as the lack of generalizability and the current scarcity of longitudinal data. These models must be tested in larger cohorts and population-based studies for validation, failing which there is a risk of apparent identification of multiple ‘novel’ biomarkers that may or may not be mechanistic.

Abstract B006: Targeting BARD1 in human pancreatic ductal adenocarcinoma: How to expand the target population of vulnerable tumors?

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the deadliest malignancy of the pancreas, with an overall five-year survival rate of only 12%. Despite therapeutic advances, effective therapies are still limited. It is now known that many of the DNA damage repair (DDR) genes that are mutated in PDAC are crucial for the proper functioning of the homologous recombination repair (HRR) pathway. Loss-of-function alterations in DDR genes such as BRCA1/2 mutations render PDAC cells vulnerable to certain DNA damage agents, for example, poly (ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Since this treatment strategy is currently limited to only 5-10% of PDAC patients, it underscores a dire need to find new therapeutic avenues and expand the PDAC patient population that could benefit from these therapies. We have recently published that BARD1 (BRCA1- Associated- Ring- Domain- 1), an obligate binding partner of BRCA1 in the process of HRR, is upregulated in PDAC cells exposed to PARPi/platinums. PDAC tissue microarray stained for BARD1 also shows higher BARD1 expression in PDAC tissues compared to normal pancreas. Here, we explored the effects of targeting BARD1 on PDAC cells. For this, we created genetic models of BARD1 inhibition and utilized these model systems to study if loss of BARD1 slows PDAC growth, invasion, and chemo-sensitizes PDAC cells to PARPis and DNA damage agents. Doxycycline inducible shRNA and BARD1 CRISPR KO models were created to inhibit gene expression of BARD1 in PDAC cells. Loss of BARD1 protein and mRNA expression was confirmed by western blot and qRT-PCR analyses. Using colony formation assays, Pico green cell survival assays, and Boyden matrigel invasion assays, we found that inhibition of BARD1 resulted in slower growth and decrease in invasion of pancreatic cancer cells in vitro. The expression levels of EMT markers such as zeb-1 and vimentin, were also decreased. These studies were recapitulated in a mouse xenograft subcutaneous model, where BARD1 CRISPR KO (+/- and -/-) and WT PDAC cells were injected subcutaneously on flanks of mice and tumor growth was monitored over time. Kaplan Meier curves were calculated and plotted using Log-rank test. We found that inhibiting BARD1 significantly (P=0.026) delayed PDAC tumor growth in vivo and extended survival (P<0.001). CRISPR KO of BARD1 also enhanced the efficacies of PARP inhibitors like olaparib, rucaparib and veliparib, and lowered their IC50s (fold changes >10). Our work indicates that targeting BARD1 affects key hallmarks of cancer (growth and invasion), such that the window of therapeutic opportunity is extended, which further allows chemo-sensitization of PDAC cells to DNA damaging agents. Our ongoing studies will explore if BARD1 loss is a predictive marker of PDAC sensitivity to other DNA-damaging agents besides PARPi and allow the development of therapeutic strategies to target BARD1 in PDAC. Citation Format: Aditi Jain, Rutuj P. Kusurkar, Eleanor Jenkins, Avinoam Nevler, Wei Jiang, Charles J. Yeo. Targeting BARD1 in human pancreatic ductal adenocarcinoma: How to expand the target population of vulnerable tumors? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B006.

Management of LHON ‐ An update

Leber hereditary optic neuropathy (LHON) is a devastating cause of blindness that predominantly affects young adult men. Over 90% of patients harbour one of three mitochondrial DNA point mutations, namely, m.3460G>A (MT‐ND1), m.11778G>A (MT‐ND4) and m.144484T>C (MT‐ND6). Idebenone is the only approved treatment for LHON. New evidence has refined the management guidelines for idebenone, in particular the duration of treatment and the therapeutic window of opportunity. Gene therapy using allotopic expression is an attractive strategy for LHON as it corrects the underlying mitochondrial DNA defect. Promising results have been obtained for the m.1178G>A (MT‐ND4) mutation for patients treated within 1 year of disease onset with an intravitreal injection of a modified adeno‐associated viral vector carrying the replacement gene.

The effects of hormone replacement therapy: а window of opportunity for the cardiovascular system

Coronary artery disease and stroke make up the greater part of the pattern of cardiovascular diseases (CVD). Their prevalence is increasing primarily due to death rates decline and life expectancy increase. However, CVDs remain the leading cause of death in both high/middle and low income countries (WHO, 2008). The burden of coronary heart disease and stroke is determined both by a significant decrease in patients’ quality of life and the economic expenditures of healthcare aimed at treating these conditions and managing their complications. The overall CVD risk is more or less the same in men and women, but a detailed analysis shows a clear dependence on the patient age. The CVD risk in men is comparable to the CVD risk in women of younger age groups, i.e. CVD incidence rates in women are about ten years behind such rates in men. CVDs are of major concern for women who enter menopause. The changing endocrine profile predisposes to an increase in the cardiovascular event rates due to a combination of risk factors such as visceral obesity, atherogenic dyslipidemia, impaired glucose regulation, homeostasis disorders, and vascular dysfunction. However, an independent association between age-related degenerative changes in the ovaries and CVD risk has been established primarily in women with premature and early menopause (<40– 45 years). Menopause hormone therapy (MHT) significantly reduces most CVD risks. The effectiveness of the prevention of irreversible effects of oestrogen deficiency is ensured by the timely MHT start during the very first pathological changes in female health or in the late stage of the menopausal transition/early postmenopausal stage (><60 years or within ten years after the last menstrual period). The concept of prescribing MHT within the “window of therapeutic opportunity” produces a favourable benefit-risk ratio for patients.>˂40– 45 years). Menopause hormone therapy (MHT) significantly reduces most CVD risks. The effectiveness of the prevention of irreversible effects of oestrogen deficiency is ensured by the timely MHT start during the very first pathological changes in female health or in the late stage of the menopausal transition/early postmenopausal stage (˂60 years or within ten years after the last menstrual period). The concept of prescribing MHT within the “window of therapeutic opportunity” produces a favourable benefit-risk ratio for patients.

Resolution of the III International menopause expert forum

The III International Menopause Expert Forum took place on November 24, 2021. The working group of the expert council included leading experts in endocrine gynaecology from Belarus, Armenia, Georgia, Kazakhstan, Kyrgyzstan, Uzbekistan, and Ukraine.To date, menopause hormone therapy (MHT) initiated during the “therapeutic window of opportunity” has proved to have a protective effect against various age-associated diseases. Despite this, the percentage of women using MHT remains low and, for example, in Ukraine and Kazakhstan, equals nearly 2%. However, only one in four of these women have been using MHT for more than a year. The main reasons for such low percentage of women using MHT are as follows:1. Low patient adherence to MHT (due to misunderstanding of the menopause factors, menopause symptoms, treatments, hormonophobia, poor communication with healthcare professionals etc.).2. Healthcare professional’s vigilance due to the possible risks associated with MHT (breast cancer, venous thromboembolism, cardiovascular diseases etc.).3. Healthcare professionals face difficulties during the MHT prescription or subsequent patient management (unplanned haemorrhages, concomitant pathologies in a woman, i.e. fibroids, varicose veins, arterial hypertension etc.). Aiming to improve medical care for menopausal women, experts attending the Forum focused on the latest data on the risks of breast cancer and venous thromboembolism, MHT effect on the risk of coronary heart disease and arterial hypertension, the potential of prescribing MHT to patients with uterine myoma and on increasing treatment adherence.

Abstract 3946: Development of selective small molecule AR-V7 inhibitors for prostate cancer treatment

Abstract Castration resistance prostate cancer (CRPC) is a lethal disease in which the expression of ligand-independent androgen receptor (AR) splice variants (AR-Vs) is associated with worse clinical outcomes. AR-V7 is the most prevalent variant in CRPC, it lacks the ligand binding domain and is constitutively active in the nucleus. We and others have showed that, AR-V7 expression confers resistance to the AR signaling inhibitors (abiraterone/enzalutamide) and to taxanes in vivo and in patients with metastatic CRPC. Since abiraterone/enzalutamide and taxanes represent the two most effective therapeutic modalities for men with CRPC, the development of selective AR-V7 inhibitors is a high priority, clinically unmet need. AR-V7 shares with full-length AR (AR-fl), high sequence homology, largely overlapping cistromes and gene transactivation profiles. To develop selective AR-V7 inhibitors, we sought to identify unique biological features of AR-V7, that differentiate it from AR-fl and therapeutically exploit them. Mechanistic studies showed that AR-V7 utilizes a unique nuclear import pathway, not shared by AR-fl. Using fluorescently tagged-AR-fl or AR-V7 proteins in conjunction with live cell imaging, FRAP assays and pathway inhibitors, we showed that AR-V7 exhibits fast nuclear import kinetics partially mediated by the dimerization D-box domain, independently of microtubules and importin α/β. Taken together, these data suggest that AR-V7 nuclear import mechanism is distinct providing a window of therapeutic opportunity to selectively target it. To identify AR-V7 selective inhibitors, we designed and performed a high throughput enzyme complementation screening (HTS) assay using nuclear AR-V7 as a surrogate for AR-V7 activity. We screened a chemical library of ~170K compounds and identified hit compounds inhibiting AR-V7 by proteasomal degradation. Among the degraders, we observed 2 main modes of action: I. compounds selectively degrading AR-V7 and II. compounds degrading both AR-fl and AR-V7. Ongoing efforts include medicinal chemistry for lead compound optimization and target validation experiments.In conclusion, we identified first-in-class selective AR-V7 inhibitors, with the potential to be clinically combined with existing, but mechanistically unrelated AR signaling inhibitors. Further mechanistic studies will elucidate their potential for future clinical development. Citation Format: CheukMan Cherie Au, Seaho Kim, Prerna Vatsa, Mohd Azrin Bin Jamalruddin, Michael Miller, Peter T. Meinke, Paraskevi Giannakakou. Development of selective small molecule AR-V7 inhibitors for prostate cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3946.

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients

IntroductionMechanical bowel obstruction is a frequent acute and life-threatening event in relapsed ovarian cancer. Salvage surgery after failure of all conservative approaches, resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate patients’ surgical and clinical outcome in these highly palliative situations. Previous, limited, data reported a high morbidity and mortality. However, recent surgical and therapeutical improvements in relapsed ovarian cancer (ROC) offer better identification of patients who might benefit from surgery in an effort to extend the window of opportunity to subsequently offer these patients novel systemic therapeutic approaches.Material and methodsAll subsequent ROC patients between 2012 and 2017 with acute mechanical bowel obstruction who underwent salvage extraperitoneal en bloc intestinal resection were retrospectively identified. Data were collected from two ESGO certified Ovarian Cancer Centers of Excellence (Charité Berlin and Imperial College London) and systematically evaluated regarding surgical and clinical outcomes.ResultsOverall, 87 ROC patients were included in the analysis (median age 56 years, range 24–88), 47% were platinum resistant. High grade serous was the most common histology (76%) while most of the patients (67%) had at least two previous lines of treatment. Mean observed OS was 7.8 months. After salvage surgery, 46% of the patients had a residual small bowel length < 180 cm and 18% > 180 cm resulting in 41% in need of total parental nutrition. In 80% of the patients a permanent stoma was necessary. 30d morbidity and mortality was 74% and 10%, respectively. More than half of the patients were able to receive further courses of chemotherapy after surgery.DiscussionSalvage surgery for bowel obstruction in ROC patients needs careful consideration and identification of optimal surgical candidates to have the maximal therapeutic benefit. Despite the challenging morbidity profile, most patients managed to proceed to subsequent novel and conventional systemic treatment and so have their window of therapeutic opportunity extended.

Vitamin C Administration by Intravenous Infusion Increases Tumor Ascorbate Content in Patients With Colon Cancer: A Clinical Intervention Study.

The use of high dose ascorbate infusions in cancer patients is widespread, but without evidence of efficacy. Several mechanisms whereby ascorbate could affect tumor progression have been proposed, including: (i) the localized generation of cytotoxic quantities of H2O2; (ii) ascorbate-dependent activation of the 2-oxoglutarate-dependent dioxygenases that control the hypoxia-inducible factors (HIFs) and that are responsible for the demethylation of DNA and histones; (iii) increased oxidative stress induced by dehydroascorbic acid. We hypothesize that the dysfunctional vasculature of solid tumors results in compromised delivery of ascorbate to poorly perfused regions of the tumor and that this ascorbate deficit acts as an additional driver of the hypoxic response via upregulation of HIFs. Using a randomized “therapeutic window of opportunity” clinical study design we aimed to determine whether ascorbate infusions affected tumor ascorbate content and tumor biology. Patients with colon cancer were randomized to receive infusions of up to 1 g/kg ascorbate for 4 days before surgical resection (n = 9) or to not receive infusions (n = 6). Ascorbate was measured in plasma, erythrocytes, tumor and histologically normal mucosa at diagnostic colonoscopy and at surgery. Protein markers of tumor hypoxia or DNA damage were monitored in resected tissue. Plasma ascorbate reached millimolar levels following infusion and returned to micromolar levels over 24 h. Pre-infusion plasma ascorbate increased from 38 ± 10 µM to 241 ± 33 µM (p < 0.0001) over 4 days and erythrocyte ascorbate from 18 ± 20 µM to 2509 ± 1016 µM (p < 0.005). Tumor ascorbate increased from 15 ± 6 to 28 ± 6 mg/100 g tissue (p < 0.0001) and normal tissue from 14 ± 6 to 21 ± 4 mg/100 g (p < 0.001). A gradient of lower ascorbate was evident towards the tumor centre in both control and infusion samples. Lower expression of hypoxia-associated proteins was seen in post-infusion tumors compared with controls. There were no significant adverse events and quality of life was unaffected by ascorbate infusion. This is the first clinical study to demonstrate that tumor ascorbate levels increase following infusion, even in regions of poor diffusion, and that this could modify tumor biology.Clinical Trial RegistrationANZCTR Trial ID ACTRN12615001277538 (https://www.anzctr.org.au/).

Reducing and managing chronic obstructive pulmonary disease exacerbations with tiotropium + olodaterol

Objective The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), respectively, as the initial and follow-up treatment choice in patients with chronic obstructive pulmonary disease (COPD) as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 recommendations—the impact of this treatment strategy on the reduction in the risk of exacerbations—and the importance of early therapeutic interventions. Methods For this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review. Results Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD. Conclusions The early stages of COPD may represent a “window of therapeutic opportunity” during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

A "Window of Therapeutic Opportunity" for Anti-Cytokine Therapy in Patients With Coronavirus Disease 2019.

The effects of cytokine inhibition in the different phases of the severe coronavirus disease 2019 (COVID-19) are currently at the center of intense debate, and preliminary results from observational studies and case reports offer conflicting results thus far. The identification of the correct timing of administration of anti-cytokine therapies and other immunosuppressants in COVID-19 should take into account the intricate relationship between the viral burden, the hyperactivation of the innate immune system and the adaptive immune dysfunction. The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise “window of therapeutic opportunity.” Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient’s immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease.

MONOCLONAL ANTIBODY GONE ROGUE: ALEMTUZUMAB CAUSING ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Anti-Glomerular basement membrane disease (anti-GBM), is a rare autoimmune process that can cause irreversible renal or lung injury. Here we discuss a case of Alemtuzumab induced anti-GBM. CASE PRESENTATION: A 46 year-old caucasian female with history of Multiple Sclerosis presented with flu-like symptoms, dizziness, nausea and vomiting ongoing for two weeks. Her physical exam was significant for dry mucous membranes and tachycardia. Her labs were significant for a BUN of 48 mg/dL and a creatinine of 6.8 mg/dL without any history of prior kidney disease. Renal biopsy revealed more than 90% glomerular involvement with necrotizing and crescentic proliferation, as well as positive linear staining along the glomerular basement membranes for IgG, Kappa, Lambda and C3. Anti-glomerular basement membrane antibodies were 189 units; thereby, Anti-GBM disease was diagnosed. Patient reported being on Alemtuzumab eight months prior to presentation. She was started on plasmapheresis, high dose prednisone and cyclophosphamide but therapy was stopped early due to nightly agitation and confusion likely related to sundowning, but the patient's family attributed it to the new therapy. Patient was discharged to inpatient rehab where she developed a right internal jugular vein thrombosis and was started on rivaroxaban. She later developed hemoptysis and had to be readmitted. Computed tomography scan of her lungs showed bi-apical and basilar dense airspace opacities with air bronchograms suggesting hemorrhagic infiltrates, findings were most consistent with diffuse alveolar hemorrhage. [Images A-C] Anti-GBM antibodies were elevated at 217 units. Patient was then restarted on plasmapheresis, steroids and cyclophosphamide and was able to complete therapy with slow but definite improvement. DISCUSSION: Alemtuzumab is a humanized monoclonal antibody that binds to CD52 (a cell-surface antigen present on T and B cells) and can be associated with anti-GBM disease that may present up to 40 months after the last dose.[1] Our case illustrates this lingering side effect and highlights the importance of taking a thorough history including previous and current medications. Our case shows the second reported case of Alemtuzumab induced anti-GBM with both renal and lung involvement [2] and the seventh case with renal involvement.[3-6] Our case is unique in the timing and course of development of kidney and lung injury, with about a month in between, while the first reported case showed a more rapid succession of kidney and lung injury. CONCLUSIONS: Alemtuzumab can be associated with autoimmune syndromes but clear screening tools and monitoring is not currently available. Further investigation is needed to identify a possible role for antibody monitoring in patients on Alemtuzumab. Reference #1: [1] Devonshire, V et al. Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations. J Neurol 2018. Reference #2: [2] Lapointe, E., Moghaddam, B., Barclay, K., Traboulsee, A., & Neufeld, P. (2018). Goodpasture’s Syndrome Following Alemtuzumab Therapy in Multiple Sclerosis. Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 45(6), 712-714. Reference #3: [3] Coles, AJ, Cox, A, Le Page, E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98-108 [4] Meyer, D, Coles, A, Oyuela, P, et al. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2013;2(1):60-63. [5] Phelps, R. Autoimmune events: nephropathies. Scientific exchange forum 2013. [6] Singer, BA, Alroughani, R, Brassat, D, et al. Durable improvements in clinical outcomes with alemtuzumab in patients with active RRMS in the absence of continuous treatment: 7-year follow-up of CARE-MS II patients (TOPAZ study). Poster 736. 7th joint ACTRIMS-ECTRIMS meeting, Paris. 2017. DISCLOSURES: No relevant relationships by Youssef Abouleish, source=Web Response No relevant relationships by Paul Marik, source=Web Response

Vogt–Koyanagi–Harada Is a Curable Autoimmune Disease

Purpose:It is crucial to subdivide Vogt–Koyanagi–Harada (VKH) disease into two subentities, initial-onset disease versus chronically evolving disease. For early diagnosis and precise follow-up of VKH choroiditis, the “Revised criteria for VKH” are no more sufficient for the appraisal of VKH and new biomarkers for disease activity are needed. It has been shown that, if initial-onset disease is treated promptly within the “therapeutic window of opportunity” and long enough with dual steroidal and non-steroidal immunosuppression, the disease can be cured in a large proportion of cases, an approach still contested. The proportion of chronic evolution and/or sunset-glow fundus (SGF) following steroidal monotherapy versus dual steroidal and non-steroidal immunosuppression was compared.Methods:A literature search was performed, identifying studies on initial-onset VKH treated either by steroidal monotherapy or dual immunosuppression. Evolution toward chronicity and/or SGF was compared in both groups.Results:Twenty studies were identified with reported long-term outcomes. In 16 studies, 802 patients received steroidal monotherapy, while in 4 studies, 172 patients received dual steroidal and non-steroidal immunosuppression. Chronic evolution and SGF occurred, respectively, in 44% and 59% in the corticosteroid-alone group versus 2.3% and 17.5% in the dual therapy group with no chronic evolution in three studies and no SGF in two studies.Conclusions:Chronic evolution and SGF are significantly less frequent in initial-onset VKH when treated with immediate dual steroidal and non-steroidal immunosuppression with a high proportion of healed cases. This combined approach seems recommended in the management of initial-onset VKH disease.

Abstract TP100: Post-Transcriptional Inactivation of MMP-12 Immediately After Reperfusion Facilitates Neurological Recovery After Ischemic Stroke

Introduction: We recently showed in a rodent model of transient focal cerebral ischemia that matrix metalloproteinase-12 (MMP-12) induction in the ischemic brain promotes post-stroke blood-brain barrier disruption, apoptosis, demyelination, and infarction. The purpose of the present study is to investigate the role of elevated MMP-12 on post-stroke neurological function and to identify the time window of therapeutic opportunity for MMP-12 suppression. Methods: Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats (n =8-15/group) were administered with either MMP-12 shRNA or scrambled shRNA sequence (vehicle control) expressing plasmids (1 mg/Kg; intravenous) formulated as nanoparticles. The differences in sample size of various cohorts were attributed to the exclusion criteria followed, high mortality rate in vehicle control-treated group, and sample size required for statistical analysis. To assess the reflex, balance, sensory, and motor functions, rats from various cohorts were subjected to modified neurological severity scoring (mNSS), adhesive removal test, beam walk test and rotarod test at day 1, 3 and 5 of reperfusion. To assess the time window of therapeutic opportunity, various cohorts of rats were treated at 5 min, 3h, and 6h of reperfusion. Investigators blinded to study groups analyzed all outcome parameters. Results: The post-stroke percent survival rate in cohorts treated with MMP12shRNA expressing plasmids range from 82 to 89 as compared to 67 in vehicle control-treated group. The cohort of rats treated at 5 min of reperfusion with MMP-12snRNA expressing plasmids showed significantly better functional recovery as assessed by various neurological tests. However, delayed administration of MMP-12snRNA expressing plasmid (either at 3h or 6h of reperfusion) failed to promote any significant improvement in post-stroke neurological recovery. Conclusions: Post-stroke induction of MMP-12 in the ischemic brain contributes to neurological deficits and impedes recovery. MMP-12 targeting treatments immediately after reperfusion could offer substantial therapeutic benefits.

Long-Term Follow-Up of Retinal Degenerations Associated With LRAT Mutations and Their Comparability to Phenotypes Associated With RPE65 Mutations.

PurposeTo investigate the natural history in patients with LRAT-associated retinal degenerations (RDs), in the advent of clinical trials testing treatment options.MethodsA retrospective cohort of 13 patients with LRAT-RDs.ResultsTwelve patients from a genetic isolate carried a homozygous c.12del mutation. One unrelated patient carried a homozygous c.326G>T mutation. The mean follow-up time was 25.3 years (SD 15.2; range 4.8–53.5). The first symptom was nyctalopia (n = 11), central vision loss (n = 1), or light-gazing (n = 1), and was noticed in the first decade of life. Seven patients (54%) reached low vision (visual acuity < 20/67), four of whom reaching blindness (visual acuity < 20/400), respectively, at mean ages of 49.9 (SE 5.4) and 59.9 (SE 3.1) years. The fundus appearance was variable. Retinal white dots were seen in six patients (46%). Full-field electroretinograms (n = 11) were nondetectable (n = 2; ages 31–60), reduced in a nonspecified pattern (n = 2; ages 11–54), or showed rod–cone (n = 6; ages 38–48) or cone–rod (n = 1; age 29) dysfunction. Optical coherence tomography (n = 4) showed retinal thinning but relative preservation of the (para-)foveal outer retinal layers in the second (n = 1) and sixth decade of life (n = 2), and profound chorioretinal degeneration from the eighth decade of life (n = 1).ConclusionsLRAT-associated phenotypes in this cohort were variable and unusual, but generally milder than those seen in RPE65-associated disease, and may be particularly amenable to treatment. The window of therapeutic opportunity can be extended in patients with a mild phenotype.Translational RelevanceKnowledge of the natural history of LRAT-RDs is essential in determining the window of opportunity in ongoing and future clinical trials for novel therapeutic options.

British Society for Gene and Cell Therapy Annual Conference Wednesday 19th June – Friday 21st June 2019 University of Sheffield, Sheffield, UK www.bsgct.org

British Society for Gene and Cell Therapy Annual Conference Wednesday 19th June – Friday 21st June 2019 University of Sheffield, Sheffield, UK www.bsgct.org

Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats.

Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti-neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages.

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition.

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.

Supporting recovery from brain injury.

A window of therapeutic opportunity could widen beyond the initial phase of brain injury