Therapy Clinical Trials Research Articles

An Overview of Recent Clinical Trials for Diabetic Foot Ulcer Therapies

Diabetic foot ulcers (DFUs) are a major complication of diabetes, leading to high mortality, reduced quality of life, neuropathy, ischemia, infection, and amputation risks. The prevalence of these ulcers is only on the rise as more people suffer from type 2 diabetes and obesity. The current wound management involves wound dressings, offloading, debridement, and infection control, but more must be done to keep up with the rising prevalence of DFUs and the strain they put on patients and the healthcare system. To find recent therapeutic advances in DFU treatment, we searched PubMed for novel therapeutics from the past 5 years. We found a diversity of promising interventions, including advanced wound dressings and topicals, physical energy-based therapies, regenerative scaffolds, and growth factor- and cell-based therapies. Recent therapies hold significant promise in healing more DFUs faster and more effectively. Providers should consider employing safe, novel therapeutics when standard dressings are not effective.

Unwanted or negative treatment reactions in digital psychological interventions for adolescents with chronic pain.

Reports of pain clinical trials evaluating psychological treatments often lack sufficient details on the potential and actual harm resulting from intervention. We aimed to understand how frequent and intense treatment reactions, conceptualized as unwanted symptoms, were in three clinical trials of digital Cognitive Behavioral Therapy (CBT) for adolescents with: (1) chronic primary pain, (2) sickle cell disease, and (3) chronic pancreatitis. We also aimed to understand any differences by demographic and clinical variables. Analyses were conducted with 246 youths (12-18 years old) experiencing chronic pain and one of their caregivers. 66% of the total sample was female. The number, intensity, and type of treatment reactions experienced were assessed post treatment. T-tests and Chi-squared tests were conducted to explore whether certain treatment reactions were more frequent as a function of baseline or clinical characteristics. 9% of participants experienced some negative treatment reaction. The average intensity of those events was very low on a 0-3 scale (M = 0.1, SD = 0.4). There were no differences in the prevalence or intensity as a function of participant's sex, age, race, or baseline pain intensity. However, baseline anxiety [t = -2.4 (244); p < .05] and baseline pain interference [t = -2.2 (223); p < .05] were significantly higher in those who experienced negative treatment reactions. A small number of participants reported experiencing negative treatment reactions, with a low intensity level. Those experiencing negative treatment reactions showed higher baseline anxiety and pain interference. Future research may build from our example to standardize collection of harms data in trials of psychological interventions.

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management.

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials.

138 Results of a randomized, double-blind, placebo-controlled phase II clinical trial of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) in moderate to severe acne vulgaris

138 Results of a randomized, double-blind, placebo-controlled phase II clinical trial of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) in moderate to severe acne vulgaris

Potential biomarkers for MCL1 inhibitor sensitivity

MCL1 is an anti-apoptotic member of the BCL2 protein family, and its overexpression is associated with poor prognosis across various cancers. Small molecule inhibitors targeting MCL1 are currently in clinical trials for TNBC and other malignancies. However, one major challenge in the clinical application of MCL1 inhibitors is the inherent or acquired resistance to these drugs. Additionally, there is a lack of predictive biomarkers to identify which tumors will respond to MCL1 inhibition. We identified a four-gene functional signature that promotes MCL1 inhibitor resistance in TNBC cells. This gene signature (GS) can distinguish resistant from sensitive TNBC cell lines. Factors encoded by these four genes promote MCL1 inhibitor resistance at least in part through regulation of the ERK signaling pathway. This mechanism involves the upregulation of BCL2 and the downregulation of BIM, which contribute to the inhibitor resistance. Thus, we have discovered a functional GS that drives MCL1 inhibitor resistance. Currently, the MCL1 inhibitor GS-9716 is in clinical trials for TNBC therapy. If validated in clinical samples, this GS could potentially serve as a predictive biomarker for therapy response and help guide the selection of combination therapies to enhance the effectiveness of MCL1 inhibitors.

Trends in the application of metal Nanobiomaterials in cancer therapy clinical trials

BackgroundCancer is recognized as a major public health problem worldwide, which brings a large number of deaths and serious economic burden. Traditional cancer treatments generally have problems such as limited application, large side effects, and drug resistance. With the rise of nanomedicine technology, its unique advantages in precision drug delivery, imaging sensitivity, assisted drug release, and enhanced drug properties have brought new hope to cancer patients. These therapies, including photothermal therapy, drug delivery, and immunotherapy, use various nanoparticles such as gold and iron-oxide to improve targeted treatment and reduce side effects. The increasing interest in sustainable NP production and safety concerns has driven new research into biocompatible and eco-friendly methods. This study aims to analyze the current research status and global trends in cancer therapy using nanoparticles through a bibliometric analysis.MethodsThe Web of Science Core Collection database was searched for publications related to NP-based cancer therapies from January 1995 to December 2023. A bibliometric analysis was conducted using using Bibliometrix Online Analysis Platform, HistCite Pro 2.1, VOSviewer version 1.6.20 and RStudio version 4.3.1, covering metrics like the number of publications, citations, countries, institutions, journals, authors, references, and keywords.ResultsA total of 452 articles published in 233 journals. The number of publications on clinical cancer therapy with metal Nanomaterials has shown consistent annual growth. China and Chinese Academy of Sciences were the leading country and institution contributing to this field, respectively. The most prolific author was Zangeneh Mohammad Mahdi, and Biomaterials was the most prolific journal. Key research hotspots identified include keywords such as “gold nanoparticles”, “delivery”, “drug delivery,” “green synthesis,” and “cytotoxicity.”ConclusionThis is one of the first studies to perform a bibliometric analysis and visualization of publications onclinical cancer therapy with metal Nanomaterials, offering valuable insights for researchers. Future studies should focus on enhancing the efficacy, biocompatibility, and sustainable synthesis of nanoparticles, with an emphasis on their use in personalized medicine and photodynamic therapy.

Abstract B023: Cell-free HPV-DNA dynamics during induction chemotherapy and response-stratified de-escalation in viral-mediated oropharyngeal cancer

Abstract Background: Cell-free HPV-DNA (cfHPV-DNA) in plasma represents a promising biomarker to grade treatment response and monitor for persistence/recurrence. We evaluated the dynamic changes of cfHPV-DNA during induction chemotherapy followed by response-stratified de-escalation in HPV associated (HPV+) oropharyngeal squamous cell cancer (OPSCC). Methods: A prospective biomarker clinical trial of response-stratified de-escalation therapy was conducted. Eligible patients had loco-regional HPV+ OPSCC and received induction chemotherapy with carboplatin and paclitaxel for three cycles followed by risk and response-stratified de-escalation with transoral robotic surgery (TORS), de-escalated radiation (RT) to 50Gy with or without cisplatin, or standard RT to 70Gy with cisplatin. Patients with deep response (&amp;gt;=50% tumor shrinkage per RECIST 1.1) qualified for de-escalated therapy. Cell-free HPV-DNA was measured using a CLIA-certified HPV-SEQ assay that utilizes NGS technology to detect and quantify HPV16 and HPV18 DNA in plasma at baseline, after each cycle of induction chemotherapy, during radiation, and post-treatment surveillance at 3, 6, 9, 12, 18, and 24 months following treatment. Results: Forty-six eligible patients were enrolled, with 464 cfHPV-DNA plasma samples analyzed (median 10 samples per patient). There were five recurrences (10.9%), all detected by HPV-SEQ. Baseline cfHPV-DNA was detected in 44/46 patients (96%). Patients with rapid early cfHPV-DNA clearance after one 3-week cycle of induction (&amp;gt;=95% clearance) predicted deep radiographic response following induction therapy (p=0.003). The detection of cfHPV-DNA at 3 months or later after treatment was associated with worse progression free survival (PFS), with 2-year PFS of 25% (95% CI 0.012-0.65) compared with patients without detectable cfHPV-DNA of 100% (95% CI 1.0-1.0); p&amp;lt;0.001). The longest lead-time from positive cfHPV-DNA to developing recurrent disease was 25 months. Conclusion: Rapid early clearance of cfHPV-DNA during induction has utility in predicting response to treatment. Detectable cfHPV-DNA following treatment is strongly associated with worse PFS. A subsequent trial using cfHPV-DNA to select patients for treatment de-escalation is ongoing. Clinicaltrials.gov ID: NCT04572100 Citation Format: Ari Rosenberg, Evgeny Izumchenko, John Cursio, Augustin Vannier, Aditya Juloori, Rohan Katipally, Rifat Hasina, Frederick Jones, Anna Starus, Elizabeth Blair, Daniel J. Haraf, Alexander T. Pearson, Everett E. Vokes, Nishant Agrawal. Cell-free HPV-DNA dynamics during induction chemotherapy and response-stratified de-escalation in viral-mediated oropharyngeal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B023.

Abstract 4115645: NLRP3 Inflammasome Inhibition With Dapansutrile in Type 2 Diabetes and Elevated Systemic Inflammation: Rationale and Design of the DAPAN-DIA study

Background: Monoclonal antibodies against IL-1β decrease inflammation, improve insulin secretion and glycaemia, and reduce residual CV risk, but must be injected and are associated with higher incidence of fatal infection. There remains an unmet need for an oral treatment for T2D patients at risk for cardiometabolic complications to safely reduce IL-1β-mediated inflammation chronically&amp;with low risk of immunosuppression. In an initial dose-range finding study in heart failure patients with T2D, we reported evidence of anti-hyperglycaemic efficacy and improvement in LVEF with dapansutrile an oral specific inhibitor of the NLRP3 inflammasome. Objectives: To investigate the potential of preventing the transition to organ complications, The EU funded consortium INTERCEPT-T2D in collaboration with US based biotech Olatec Therapeutics has launched a clinical trial of anti-inflammatory therapy with dapansutrile targeting T2D patients with low-grade inflammation. Methods: Dapansutrile in Diabetes and Complications (DAPAN-DIA, NCT06047262) aims to determine whether NLRP3 inhibition with dapansutrile has the potential to not only improve glycaemia but also reduce micro- and macro-vascular risk and complications from diabetes. DAPAN-DIA is a multicenter, pbo-controlled, prospective, randomized, double-blind trial conducted in Switzerland, France, Belgium and Germany. A total of 300 patients with T2D, HbA1c &gt;7.5% and hsCRP&gt;1.5 mg/L are being randomized to either dapansutrile 1000 mg BID or matching PBO tablets for 6 months (2:1 ratio dapansutrile: pbo). The primary endpoint is change from baseline HbA1c. Secondary endpoints include biomarkers associated with diabetic complications, progression of MASLD as well as chronic inflammation (IL-1 β, IL-6 and hsCRP). A subject-assessed QoL questionnaire is also collected. To detect an absolute difference of 0.5% in HbA1c between groups, approximately 300 subjects will be randomized 2:1 ratio to achieve 80% power, assuming a standard deviation of 1.2% in change from baseline in HbA1c at week 26. Results: The trial has launched and currently is enrolling subjects. Conclusions: DAPAN-DIA is the first placebo-controlled, adequately powered, large, multi-center study with an oral NLRP3-specific Inhibitor, dapansutrile. The trial will generate important data on a new clinically relevant dimension in T2D care where consideration at diagnosis of inflammatory parameters are of importance for the transition to T2D-related complications.

Safety outcomes and immunological correlates in a prospective clinical trial of immune checkpoint therapy plus debulking surgery for patients with metastatic renal cell carcinoma.

Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy.

Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI. We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6×1012 genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function. Median follow-up time was 45months (n= 4, three females and one male; age range: 5-10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%-67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges. A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI. This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research.

INNV-08. PRE-CLINICAL AND CLINICAL EVIDENCE FOR THE TREATMENT OF DMG/DIPG USING EMULATE THERAPEUTICS’ ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD SIGNAL TECHNOLOGY

Abstract EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds via a magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical studies demonstrate an effect in slowing down and inhibiting tumor growth. The results of feasibility (Phase I/II) clinical trials testing the EMTx technology for treating recurrent GBM (rGBM) were published in CNS Oncology (CNS Oncol 2023 Pages CNS102, Accession Number: 37462385 DOI: 10.2217/cns-2022-0016). Reported results suggest that the A1A signal is non-inferior to best supportive care (BSC) and when the A1A signal is combined with BSC, a 3-month increase in overall survival (OS) was observed. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured at under 12 months, with no clinical trials demonstrating a significant increase in OS in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program (Hælo® medical device) demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months, with median survival of 17 months. EMTx recently completed an orthotopic mouse model of DIPG at University of California San Francisco. The results from exposing the mice to the A1A signal demonstrated a significant survival advantage (P = 0.0163) via the slowing down of cell division. Data to be submitted for peer review publication. The animal model is encouraging and supports the observed results of our compassionate use program. EMTX will submit these results to the FDA for regulatory approval via the Humanitarian Device Exemption pathway. The company will conduct a study with DIPG patients from both the US and India. Subject to FDA protocol approval, 30-35 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best supportive care + single therapy (Hælo®) clinical trial.

Epigenetics in Heart Failure.

Heart failure is a clinical syndrome with rising global incidence and poor prognosis despite improvements in medical therapy. There is increasing research interest in epigenetic therapies for heart failure. Pathological cardiac remodelling may be driven by stress-activated cardiac signalling cascades, and emerging research has shown the involvement of epigenetic signals that regulate transcriptional changes leading to heart failure. In this review, we appraise the current evidence for the role of epigenetic modifications in heart failure. These include DNA methylation and histone modifications by methylation, acetylation, phosphorylation, ubiquitination and sumoylation, which are critical processes that establish an epigenetic pattern and translate environmental stress into genetic expression, leading to cardiac remodeling. We summarize the potential epigenetic therapies currently in development, including the limited clinical trials of epigenetic therapies in heart failure. The dynamic changes in the epigenome in the disease process require further elucidation, and so does the impact of this process on the development of therapeutics. Understanding the role of epigenetics in heart failure may pave the way for the identification of novel biomarkers and molecular targets, and facilitate the development of personalized therapies for this important condition.

Chemical adherence testing in the clinical management of hypertension: a scoping review.

Despite growing use, questions remain surrounding the utility, acceptability and feasibility of chemical adherence testing (CAT) as part of hypertension management in clinical practice. This scoping review aimed to (i) identify and summarise studies using CAT in hypertension management, and (ii) describe and critically evaluate how CAT is currently being used in the clinical management of hypertension. Peer-reviewed and published studies in English, reporting original research in any setting, with any study design, were included. Search concepts included hypertension, medication adherence, CAT, and their synonyms. Searches were carried out using Ovid Medline, EMBASE, and PsycInfo (EBSCO), alongside manual searching of reference lists. Using Covidence software, we screened titles and abstracts, followed by full-text articles. Data from the included articles were tabulated and summarised. Of the 618 studies identified, 48 were included. The studies cover diverse clinical settings, and were mostly observational in design. 7 studies reporting adherence analyses within clinical trials for hypertension therapies. The use of theoretical frameworks to guide reporting was rare, and there was considerable variation in key terminology and definitions, most notably in the definition of adherence. The current body of evidence demonstrates considerable variability in the approach to implementing CAT for hypertension management in clinical practice, and a paucity of randomised controlled trials to evaluate its impact. Future research could (i) adopt a cohesive theoretical framework including clear operational definitions to standardise the approach to this important topic; (ii) further explore the impact of CAT on clinical outcomes using RCTs.

Expression and distribution of rAAV9 intrathecally administered in juvenile to adolescent mice.

Intrathecal (IT) lumbar puncture delivery of recombinant adeno-associated virus serotype 9 (rAAV9) is a gene therapy approach being explored in preclinical studies and ongoing gene therapy clinical trials for neurological diseases. Few studies address IT rAAV9 vector distribution, tropism, and expression with respect to age of administration. Therefore, we IT delivered a rAAV9/GFP vector in mice at ages ranging from early postnatal development through adulthood (P10-P90). Tissues were assessed for transgene expression, cell tropism, and vector distribution. In the CNS, transduction was highest when delivered at post-natal day 10 (P10) and there was an age-dependent decline in transduction. We found higher transduction of astrocytes relative to neurons when rAAV9 was administered at younger ages and a switch to higher neuronal transduction with delivery at older timepoints. Biodistribution analysis of peripheral tissues showed that when delivered at P10, rAAV9 has the greatest distribution to the heart. Conversely, at P90 rAAV9 liver distribution was highest. As rAAV9 IT-delivered gene therapies continue to emerge for neurological diseases, careful consideration of the age of delivery should be taken in relation to the expected distribution and cell expression in animal models, and how this may translate to human studies.

Ranked Importance of Visual Function Outcome Measures in Choroideremia Clinical Trials.

Clinical trials of novel therapies for choroideremia require robust and clinically meaningful visual function outcome measures. Best-corrected visual acuity (BCVA) is mostly insensitive to changes in disease state, until late stages, and hence also to potential therapeutic gains after gene therapies. While the insensitivity of BCVA as an effective outcome measure is common wisdom, its low importance has not been rigorously demonstrated in the literature. This work uses statistical techniques to rank the relative importance of potential functional outcome measures in choroideremia. Retrospective dominance analysis was performed on data from a longitudinal interventional clinical trial performed at the Oxford Eye Hospital. Functional data from the untreated eye were analyzed and correlated with an anatomic measure of disease progression in the form of blue fundus autofluorescence area of the surviving outer retinal island. Each functional measure was then ranked in terms of variable importance. Microperimetry was the functional measure ranking first in terms of variable importance, followed by time since baseline visit, Pelli-Robson contrast sensitivity, high spatial frequency contrast sensitivity function, and low luminance visual acuity. Early Treatment Diabetic Screening chart BCVA under standard lighting conditions was ranked lowest among the panel of test modalities. Clinical trials in choroideremia for early and mid-stage disease would be justified in moving away from using standard BCVA as a clinical trial outcome measure as we have shown its sensitivity to be relatively low compared to microperimetry. We have also demonstrated how functional measures rank in terms of importance.

First, do no harm: the role of preclinical animal models in predicting adverse events in gene therapy clinical trials for Duchenne muscular dystrophy and X-Linked myotubular myopathy

The occurrence of severe adverse events (SAEs) in patients with Duchenne muscular dystrophy (DMD), X-linked myotubular myopathy (XLMTM), and other neuromuscular diseases treated with adeno-associated virus (AAV) constructs has prompted studies to improve the safety and efficacy of gene therapy. Physicians have weighed the medical tenet of “first, do no harm” against the perspective of patients with progressive life-threatening conditions who may accept greater risk. Regarding SAE pathogenesis, discussion has focused on total AAV exposure and patient mutations more likely to induce immunity, while stressing the limitations of animal models in predicting adverse events. Therapeutic strategies for reducing side effects have employed more myotropic AAV serotypes and efficient transgenes. Other recommendations include excluding certain DMD gene mutations associated with SAEs and substituting less immunogenic transgenes such as utrophin (DMD) and myotubularin-related protein (XLMTM). For the sake of preclinical studies, emphasis has been placed on outbred rodents and larger animals that better predict immunity. Here, the absence of side effects in canine DMD and XLMTM models might be explained partly by phenotypic differences between affected humans and dogs. Specifically, dystrophin- and myotubularin-deficient dogs exhibit milder lesions, including less muscle fat deposition and the absence of hepatopathy, respectively, which could lead to reduced immune responses to AAV constructs. To better predict future problems, thought should be given to tracking early subclinical markers of the innate immune response, especially complement activation. Regardless of steps taken to improve the predictive value of animal models for SAEs, some questions will only be answered through human clinical trials after carefully considering the risk-benefit ratio.

Prefrontal cortex engagement during an fMRI task of emotion regulation as a potential predictor of treatment response in borderline personality disorder.

Borderline personality disorder (BPD) is a severe mental illness, with high rates of co-morbid depression and suicidality. Despite the importance of optimizing treatment in BPD, little is known about how neural processes relate to individual treatment response. This study examines how baseline regional brain blood oxygen level dependent (BOLD) activation during a functional magnetic resonance imaging (fMRI) task of emotion regulation is related to treatment response following a six-month randomized clinical trial of Dialectical Behavior Therapy (DBT) or Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Unmedicated females with BPD (N = 37), with recent suicidal behavior or self-injury, underwent an fMRI task in which negative personal memories were presented and they were asked to distance (i.e., downregulate their emotional response) or immerse (i.e., experience emotions freely). Patients were then randomized to DBT (N = 16) or SSRI (N = 21) treatment, with baseline and post-treatment depression and BPD severity assessed. BOLD activity in prefrontal cortex, anterior cingulate, and insula was associated with distancing. Baseline BOLD during distancing in dorsolateral, ventrolateral, and orbital prefrontal cortex (dlPFC, vlPFC, OFC) differentially predicted depression response across treatment groups, with higher activity predicting better response in the SSRI group, and lower activity predicting better response in the DBT group. All female samples. Findings indicate that greater prefrontal engagement during emotion regulation may predict more antidepressant benefit from SSRIs, whereas lower engagement may predict better response to DBT. These results suggest different mechanisms of action for SSRI and DBT treatment, and this may allow fMRI to guide individualized treatment selection.

Widespread Adoption of Precision Anticancer Therapies After Implementation of Pathologist-Directed Comprehensive Genomic Profiling Across a Large US Health System.

Precision therapies and immunotherapies have revolutionized cancer care, with novel genomic biomarker-associated therapies being introduced into clinical practice rapidly, resulting in notable gains in patient survival. Despite this, there is significant variability in the utilization of tumor molecular profiling that spans the timing of test ordering, comprehensiveness of gene panels, and clinical decision support through therapy and trial recommendations. To standardize testing, we designed a pathologist-directed test ordering system at the time of diagnosis using a 523-gene DNA/RNA hybrid comprehensive genomic profiling (CGP) panel and extensive clinical decision support tools. To comprehensively characterize the clinical impact of this protocol, we developed a novel natural language processing (NLP)-based approach to extract clinical features from physician chart notes. We assessed test actionability rates, therapy choice, and outcomes across a set of 3,216 patients with advanced cancer. We observed 49% of patients had at least one actionable genomic biomarker-driven-approved and/or guideline-recommended targeted or immunotherapy (IO) and 53% of patients would have been eligible for a precision therapy clinical trial from three large basket trials. When assessing CGP versus an in silico 50-gene panel, 67% of tumors compared with 33% harbored actionable alterations including clinical trials. Among patients with 6 months or more of follow-up, over 52% received a targeted therapy (TT) or IO, versus 32% who received conventional chemotherapy alone. Furthermore, patients receiving TT had significantly improved overall survival compared with patients receiving chemotherapy alone (P < .001). Overall, these data represent a major shift in standard clinical practice toward molecularly guided treatments (targeted and immunotherapies) over conventional systemic chemotherapy. As guidelines continue to evolve and more precision therapeutics gain approval, we expect this gap to continue to widen.

Challenges in Cardiomyopathy Gene Therapy Clinical Trial Design.

Gene therapy has emerged as a possible treatment for progressive, debilitating Mendelian cardiomyopathies with limited therapeutic options. This paper arises from discussions at the 2023 Cardiovascular Clinical Trialists Forum and highlights several challenges relevant to gene therapy clinical trials, including low prevalence and high phenotypic heterogeneity of Mendelian cardiomyopathies, outcome selection complexities and resulting regulatory uncertainty, and immune responses to the adeno-associated viral vectors that are being used in ongoing studies. Avenues to address these challenges such as natural history studies, external controls, novel regulatory pathways, and immunosuppression are discussed. Relevant cases of recent therapy approvals are highlighted. Ultimately, this work aims to broadly frame discussions on and provide potential future avenues for clinical trial design for rare cardiomyopathy gene therapies.