Long-term Efficacy Studies Research Articles

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

A tacrolimus-eluting nerve guidance conduit enhances regeneration in acritical-sized peripheral nerve injury rat model.

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered.

ANTIMICROBIAL EFFECT OF TOOTHPASTES CONTAINING BIRCH EXTRACT AND NANO-HYDROXYAPATITES

The study investigates the antimicrobial efficacy of toothpaste formulations incorporating nano-hydroxyapatite (nHAP) and birch extract. Toothpastes were evaluated for their ability to inhibit bacterial growth, with observations revealing varied sensitivities among bacterial species to different formulations. Notably, toothpastes containing both nHAP and zinc exhibited heightened antimicrobial activity, while the addition of birch extract introduced variability in inhibition reactions across species. Further analysis delineated differences in effectiveness between nHAP-only and nHAP-birch extract formulations, suggesting the role of secondary metabolites in enhancing antibacterial properties. The study highlights toothpaste P11 as the most effective inhibitor of bacterial growth, offering a balanced combination of remineralization and antibacterial properties, except for S. mutans strain. Future research directions include time-course tests to assess long-term efficacy and oral microbiome studies to understand broader effects on oral microflora, informing the development of more targeted oral care products.

Real-world evidence demonstrates an appropriate atrial fibrillation population for hybrid convergent approach versus stand-alone cryoballoon ablation: A long-term safety and efficacy study.

A hybrid convergent approach (endocardial and epicardial ablation) demonstrated superior effectiveness in a recent randomized study for long-standing persistent atrial fibrillation (LSPAF). Yet, there is a lack of real-world, long-term evidence as to which patients are best candidates for a hybrid convergent approach compared to standard endocardial cryoballoon pulmonary vein isolation (CB PVI). This single-center, retrospective analysis spanning from 2010 to 2015 compared two distinctly different atrial fibrillation (AF) cohorts; one treated with stand-alone cryoablation and one treated with a hybrid convergent approach. Baseline characteristics described candidates for each approach. The following criteria were utilized to determine CB PVI candidacy: (1) paroxysmal AF (PAF) (stage 3A) with failed class I/III antiarrhythmic drug (AAD) or (2) persistent/LSPAF (stage 3B/3C/3D) with failed class I/III AAD unwilling to undergo hybrid procedure. Selection criteria for the hybrid procedure included: (1) PAF refractory to both class I/III AAD and prior CB PVI (stage 3D) or (2) persistent/LSPAF (stage 3B/3C/3D) with failed class I/III AAD agreeable to hybrid procedure. Prior sternotomy was excluded. Serial electrocardiograms and continuous monitoring evaluated primary efficacy outcome of time-to-first recurrence of atrial arrhythmia after a 90-day blanking period. Secondary outcomes were procedure-related complications and AAD use (at discharge, 12, and 36 months). Kaplan-Meier methods evaluated arrhythmia recurrence. Of 276 patients, 197 (64.2 ± 10.6 years old; 66.5% male; 74.1% 3A-PAF; 18.3% 3B/3D-persistent AF; 1.0% 3C-LSPAF; 6.6% undetermined) underwent CB PVI and 79 (61.4 ± 8.1 years old; 83.5% male; 41.8% 3D-PAF; 45.5% 3B/3D-persistent AF; 12.7% 3C/3D-LSPAF) underwent hybrid procedure. Arrhythmia freedom through 36 months was 55.2% for CB PVI and 50.4% for hybrid (p = .32). Class I AAD utilization at discharge occurred in 38 (19.3%) patients in the CB PVI group and 5 (6.3%) patients in the hybrid group (p = .01). CB PVI class I AAD utilization at 12 months occurred in 14 (9.0) patients versus 0 patients for hybrid convergent (p = .004). Patients with one or more adverse event were as follows: two (1.0%) in the CB PVI group (both transient phrenic nerve palsy) and three (3.7%) in the hybrid group (two with significant bleeding and one with wound infection) (p = .14). This study demonstrated that patients with more complex forms of AF (3D-PAF or 3B/3C/3D-persistent/LSPAF) could be well managed with a convergent approach. In a real-world evaluation, outcomes match safety and efficacy thresholds achieved for patients with earlier, less complex AF etiologies treated by CB PVI alone.

Diagnosis and treatment of dyslipidemia in children and adolescents

Background: Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide, including in South Korea. Dyslipidemia is an independent risk factor for the development of atherosclerotic cardiovascular diseases. There is strong evidence that atherosclerosis begins early in life and that elevated lipid levels in childhood predict elevated lipid levels into adulthood.Current Concepts: A universal approach for cholesterol screening in all children is recommended. Lipid profiles should be studied for all children aged 9 to 11 years and then for those aged 17 to 21 years, as cholesterol levels may vary after puberty. The non-fasting lipid profile can be as useful in detecting severe genetic dyslipidemias as the fasting lipid profile and thus can be used as a first-line screening in children. The initial treatment for dyslipidemia in a child always begins with a 6-month trial of lifestyle modifications, such as improvements in dietary and physical activity patterns. Statins are as effective in children as in adults and can lower low-density lipoprotein cholesterol levels by up to 50%. Therefore, they are considered first-line therapy for children who meet the criteria for pharmacological therapy.Discussion and Conclusion: Statins and non-statin lipid-lowering agents can lower cholesterol levels with minimal adverse effects in children and adolescents with hypercholesterolemia. However, limited data is currently available on the long-term safety and efficacy of lipid-lowering agents in the pediatric population. Furthermore, non-statin lipid-lowering agents are used far less frequently in children. Therefore, further long-term safety and efficacy studies on lipid-lowering agents in pediatric populations and clinical trials with non-statin lipid-lowering agents are required.

Stability and Retention of Nanoemulsion Formulations Incorporating Lavender Essential Oil

Lavender essential oil (LEO) is applied topically for its soothing properties, serving not only as an antiseptic in wound care but also as an insect repellent. This study investigates the impact of carrier systems on LEO encapsulation, stability, and release kinetics for potential skincare applications. The LEO carrier impact on skin hydration and barrier function was also evaluated. Conventional emulsions (CEs) and nanoemulsions (NEs) with (CELs and NELs, respectively) and without LEO incorporation were analyzed for physicochemical properties, stability, and release mechanisms. The droplet size distribution and ζ-potential remained consistent in both CE and CEL, showing the minimal influence of LEO on those parameters. NE and NEL exhibited enhanced stability and higher LEO retention compared to CE and CEL (37.38 mg/mL ± 0.48 mg/mL and 50.96 mg/mL ± 2.00 mg/mL, respectively, p < 0.05), suggesting NE as a superior carrier system for LEO delivery. NEL retained LEO over 60 days at 4 °C without a significant reduction while CEL showed a notable reduction of 94.93% ± 0.08%. Release kinetics analysis showed zero-order release kinetics of LEO from both CEL and NEL (R2: 0.973 and 0.952, respectively), revealing a diffusion-based mechanism, particularly evident in NE formulations, supporting the controlled and sustained release of LEO constituents. NEL also promoted quicker skin barrier repair and enhanced skin hydration, sustaining effects for up to 120 min post application, surpassing CEL’s performance. These findings contribute to understanding the carrier system effects on LEO delivery and underscore NE as a promising vehicle for skincare applications. Further research should explore underlying mechanisms and conduct long-term safety and efficacy studies to fully exploit the therapeutic potential of NE in dermatological applications.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48Weeks: 307 Open-Label Extension Study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6g/dL; female, ≥ 12g/dL) were assessed as percentage of patients with data available and no transfusions 60days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. ClinicalTrials.gov identifier, NCT03531255.

Long-term efficacy and safety of dutasteride 0.5 mg in Korean men with androgenetic alopecia: 5-year data demonstrating clinical improvement with sustained efficacy.

Dutasteride 0.5 mg is a dual inhibitor of 5α-reductase type I and II and was approved in Korea in 2009 for treating androgenetic alopecia (AGA) in men. We investigated the 5-year efficacy and safety of dutasteride 0.5 mg in Korean men with AGA using the basic and specific (BASP) classification. This retrospective analysis included 99 male AGA patients aged ≥18 years who were treated with dutasteride 0.5 mg for at least 5 years from October 2009 to December 2016 at Kyung Hee University Hospital in Gangdong. Patient photographs were scored using the BASP classification, and the Investigator Global Assessment (IGA) was performed using a seven-point scale. Patient improvement (IGA score ≥1) and prevention of disease progression (IGA score ≥0) were 89.9% (89/99) and 93.9% (93/99), respectively. According to the BASP classification, 52.5% (52/99) of the basic type, 75% (15/20) of the specific F type, and 82.2% (60/73) of the specific V type showed clinical improvement after 5 years of treatment. Dutasteride demonstrated long-term safety and efficacy in Korean male patients with AGA over a period of at least 5 years, with results comparable to those of other long-term efficacy studies of finasteride 1 mg in male patients with AGA.

Beyond the Scalpel: Advancing Strategic Approaches and Targeted Therapies in Nonexcisable Melanomas.

Melanoma in challenging anatomical locations such as the face, acral surfaces, and mucosal areas presents unique hurdles for surgical excision. This review examines alternative nonsurgical treatment modalities in the context of these complexities, addressing the gaps in current guidelines and the varied efficacy of existing therapies. A comprehensive literature search was conducted using PubMed, Embase, and Web of Science databases. The review focuses on peer-reviewed articles discussing nonsurgical treatment options for melanoma in complex anatomical locations. Articles were screened by three independent researchers, ensuring a broad analysis of topical agents, immunotherapies, radiotherapies, and targeted therapies. The review highlights significant advancements in localized treatments such as imiquimod and intralesional therapy with talimogene laherparepvec (T-VEC), which show promise in managing nonexcisable melanomas. BRAF and MEK inhibitors, as well as checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 pathways, demonstrate improved survival rates but pose challenges with resistance and systemic side effects. Radiotherapy serves as an adjunctive strategy due to melanoma's inherent radioresistant properties. Despite advancements, there is a notable absence of comprehensive, evidence-based protocols to guide the treatment of melanoma in these critical areas. This paper underscores the need for standardized treatment guidelines that account for the efficacy, side effects, and psychosocial impacts of therapies. Future research should focus on refining existing treatments and exploring innovative modalities to enhance patient outcomes in the management of nonexcisable melanomas. Comprehensive guidelines and long-term efficacy studies are essential to optimize care and improve the quality of life for patients afflicted with melanoma in challenging anatomical locations.

Graves’ disease – management of Graves’ orbitopathy and thyrotoxicosis, including new therapies

Graves' disease (GD) is the most common cause of hyperthyroidism in countries with adequate iodine supply, and its main extrathyroid manifestation is thyroid orbitopathy. For many years, thyrotoxicosis has been treated with antithyroid drugs, radioactive iodine therapy and thyroidectomy, and glucocorticoids have remained the standard treatment of thyroid eye disease (TED). Currently, there is a growing trend of using targeted therapies in the treatment of thyroid orbitopathy (TO). The significant development of immunobiology, a better understanding of the pathophysiology of the disease and a multitude of studies on new therapies give hope for better treatment results and an improvement in the quality of life of patients. The aim of the paper is to discuss the current principles of management of Graves' disease, including thyroid orbitopathy, with particular emphasis on new therapeutic methods. The potent role of K1-70TM and small molecule thyroid stimulating hormone (TSH) receptor antagonists in the treatment of hyperthyroidism is indicated. Not only do we point out the promising outcomes of combining glucocorticoids with mycophenolates, but also highlight the use of teprotumumab, rituximab, cyclosporin A, azathioprine, methotrexate, tocilizumab and sirolimus in the therapy of active moderate to severe form of orbitopathy. The protective and supportive effect of statins in the treatment of TED is noted. The limitations of the research results mentioned in the paper are remarked and the need for further randomized studies of long-term safety and efficacy in a larger group of patients is underlined.

0522 CPAP Improves Cognition in Brain-Healthy Males: Secondary Analysis of a Randomized Trial

Abstract Introduction Obstructive sleep apnea (OSA) is associated with cognitive impairments. However, in many adequately powered randomized trials, there is weak or no evidence for the causal effect of treating OSA on cognition. A common characteristic of these randomized trials is heterogeneous participants. We hypothesize that there is a subset whose cognition could be improved by OSA treatment using CPAP. Methods This is a secondary analysis of the Apnea Positive Pressure Long-term Efficacy Study (APPLES), a randomized, double-blind, two-arm, sham-controlled, multicenter trial. The primary analysis had adult participants with baseline AHI ≥10/hour. We restricted to those with both baseline polysomnogram and outcome available: n=787. The outcome is 6-month Sustained Working Memory Overall index at mid-day, which was not significantly different in the primary analysis. The original exposure is randomized active- or sham-CPAP. However, the adherence rate (≥4 hours for >70% nights in 1-month) is higher for active than sham (chi2 p< 0.001). Therefore, we re-defined a non-randomized exposure as both under active-CPAP and being adherent (n=165) vs. all others (n=622). To account for confounding, covariates were clustered into 17 groups, plus age, sex, education, and baseline cognition. Individual treatment effect (ITE) was estimated using matching, which finds a matched group for each individual with similar covariates but opposite exposure. The ITE is the difference between two potential outcomes: the counterfactual outcome from the mean outcome of the matched group, and the factual outcome as observed. Results The overall ITE was non-significant compared to 0 (t-test p=0.4). A subset of 285 (Group 1) could have improved cognition if under active-CPAP and adherent (average ITE 0.68, p< 0.001); another subset of 328 (Group 2) could have worsened cognition (average ITE -0.64, p< 0.001). Group 1 is characterized by more males, higher baseline cognitive scores, lower EEG-derived brain age index, and slightly more depression; the opposite for Group 2. Conclusion Assuming the ITE is unbiased, relatively brain-healthy males with OSA can improve their cognition once OSA is treated by CPAP. Support (if any) MBW was supported by NIH (R01NS102190, R01NS102574, R01NS107291, RF1AG064312). RT received support from RF1AG064312. AVZ received the Parker B. Francis Fellowship award. JJL was supported by NIH UL1TR002541.

0480 Psychoactive Substance Use and Sleep Characteristics Among Individuals with Untreated Obstructive Sleep Apnea

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent airway obstruction causing intermittent hypoxia, arousal from sleep, and autonomic instability, and is associated with a variety of long-term health sequala. The fragmented sleep resulting from these respiratory events leads to disruption in normal sleep architecture and progression to deeper stages of sleep, a potential mediator for some of the functional and neurocognitive impairments seen in this population. Similarly, psychoactive substance use (i.e., nicotine, alcohol, and caffeine) impacts sleep architecture in healthy individuals, but their effects in those with OSA have not been well described. We aimed to describe the association between psychoactive substance use and sleep characteristics and daytime symptoms in individuals with untreated OSA. Methods We performed a secondary, cross-sectional analysis of The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Exposures included current smoking, alcohol, and caffeine use in individuals with untreated OSA. Outcome domains included subjective and objective sleep characteristics, daytime symptoms, and co-morbid conditions. Linear or logistic regression assessed the association between substance use and each domain (e.g., self-reported sleep duration, total polysomnographic sleep time, sleepiness, and anxiety). Results Of the 919 individuals with untreated OSA, 116 (12.6%) were current cigarette smokers, 585 (63.7%) were moderate or heavy alcohol users, and 769 (83.7%) were moderate or heavy caffeine users. Current smokers exhibited lower sleep duration (0.3 hours) and longer sleep latency (5 minutes) compared with non-smokers (all p-values< 0.05). REM sleep increased in those with moderate and heavy alcohol use (2.5 and 5% of total sleep time respectively), and moderate caffeine use (2%, all p-values < 0.05)). The combined smoker plus caffeine group exhibited shorter sleep duration (0.4 hours) and higher risk for chronic pain [Odds Ratio (95%CI) = 4.83 (1.57, 14.9). . Conclusion Both psychoactive substances and untreated OSA impact normal sleep architecture, their cumulative effect may have clinical implications in this subgroup. Stimulating or sedating substances may be used in OSA patients to mitigate daytime and nighttime symptoms respectively. Further investigation into the effects substances have on this population may present opportunities to better understand disease mechanisms and increase the effectiveness of treatment in OSA Support (if any)

Tissue-engineered vocal fold replacement in swine: Methods for functional and structural analysis.

We have developed a cell-based outer vocal fold replacement (COVR) as a potential therapy to improve voice quality after vocal fold (VF) injury, radiation, or tumor resection. The COVR consists of multipotent human adipose-derived stem cells (hASC) embedded within a three-dimensional fibrin scaffold that resembles vocal fold epithelium and lamina propria layers. Previous work has shown improved wound healing in rabbit studies. In this pilot study in pigs, we sought to develop methods for large animal implantation and phonatory assessment. Feasibility, safety, and structural and functional outcomes of the COVR implant are described. Of eight pigs studied, six animals underwent COVR implantation with harvest between 2 weeks and 6 months. Recovery of laryngeal tissue structure was assessed by vibratory and histologic analyses. Recovery of voice function was assessed by investigating acoustic parameters that were derived specifically for pigs. Results showed improved lamina propria qualities relative to an injured control animal at 6 months. Acoustic parameters reflected voice worsening immediately after surgery as expected; acoustics displayed clear voice recovery in the animal followed for 6 months after COVR. These methods form the basis for a larger-scale long-term pre-clinical safety and efficacy study.

Nicotine, alcohol, and caffeine use among individuals with untreated obstructive sleep apnea.

Psychoactive substance use (i.e., nicotine, alcohol, and caffeine) has substantial effects on sleep architecture in healthy individuals, but their effects in those with obstructive sleep apnea (OSA) have not been well described. We aimed to describe the association between psychoactive substance use and sleep characteristics and daytime symptoms in individuals with untreated OSA. We performed a secondary, cross-sectional analysis of The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Exposures included current smoking, alcohol and caffeine use in individuals with untreated OSA. Outcome domains included subjective and objective sleep characteristics, daytime symptoms, and comorbid conditions. Linear or logistic regression assessed the association between substance use and each domain (e.g., self-reported sleep duration, total polysomnographic sleep time, sleepiness, and anxiety). Of the 919 individuals with untreated OSA, 116 (12.6%) were current cigarette smokers, 585 (63.7%) were moderate or heavy alcohol users, and 769 (83.7%) were moderate or heavy caffeine users. Participants were on average 52.2±11.9years old, 65.2% were male with a median BMI of 30.6 (IQR: 27.2, 35.9, kg/m2). Current smokers exhibited lower sleep duration (0.3h), longer sleep latency (5min) compared with non-smokers (all p-values < 0.05). People with heavy or moderate alcohol use exhibited more REM sleep (2.5 and 5% of total sleep time respectively), as did those with moderate caffeine use (2%, p-values < 0.05). The combined smoker plus caffeine group exhibited shorter sleep duration (0.4h, p-value < 0.05) and higher risk for chronic pain [Odds Ratio (95%CI) = 4.83 (1.57, 14.9) compared with non-users. Psychoactive substance use is associated with sleep characteristics and clinically relevant correlates in people with untreated OSA. Further investigation into the effects that various substances have on this population may present opportunities to understand disease mechanisms more fullyand increase the effectiveness of treatment in OSA.

Voice recovery in eight Yucatan mini-pigs after vocal fold implantation surgery

As there currently exists no standardized framework to assess pig voice health, and voice parameters designed for humans do often not work on aperiodic pig voice, new approaches must be developed. We performed cell-based outer vocal fold replacement (COVR) surgery in six Yucatan mini-pigs (with two pigs in the control group) and tracked functional and structural voice recovery over up to six months. Recovery of voice function was assessed by tracking acoustic parameters and spectrograms in three pigs. Structural recovery was assessed by histologic analysis and Amino Acid Quantitation after harvest of vocal fold tissue in three pigs each. The results of functional analysis reflect expected voice worsening right after surgery and gradual recovery in one pig that was tracked the longest. Structural analysis shows small differences in fiber directionality between control group and pigs after surgery. Increasing amounts of detected amino acid markers for collagen and elastin over time after surgery may hint on gradual structural recovery. With this preliminary work, we form the basis for a larger long-term pre-clinical safety and efficacy study of COVR implantation.

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

NANOTECHNOLOGY IN U.S. MEDICAL DIAGNOSTICS: A COMPREHENSIVE REVIEW

This comprehensive review evaluates the advancements, potential, and ethical implications of nanotechnology in medical diagnostics within the U.S. healthcare system. The primary objective was to assess how nano-tools are revolutionizing early disease detection and management. The methodology involved a systematic review of peer-reviewed literature, focusing on studies published between 2000 and 2023. Data sources included academic databases such as PubMed, Scopus, and Web of Science, supplemented by secondary sources like journals and conference proceedings. The study emphasized the historical development of nanotechnology in diagnostics, current innovations, and future prospects in the field. Key findings reveal significant advancements in nano-diagnostic tools, highlighting their increased sensitivity and specificity in early disease detection. Innovations such as nano-enabled imaging and targeted drug delivery systems have shown potential in personalizing patient care. However, the study also identified challenges, including ethical concerns related to patient privacy, data security, and the need for comprehensive regulatory frameworks. The review concludes that while nanotechnology in diagnostics offers transformative potential, it also presents unique challenges. Recommendations for industry leaders and policymakers include fostering innovation within ethical and safety boundaries, investing in research, and establishing clear regulatory guidelines. Future research directions emphasize long-term efficacy and safety studies, cost-effective manufacturing processes, and exploring new applications in disease management. This study underscores the pivotal role of nanotechnology in shaping the future of healthcare diagnostics.

Ponesimod: An Oral Second-Generation Selective Sphingosine 1-Phosphate Receptor Modulator for the Treatment of Multiple Sclerosis.

To describe the safety, efficacy, and potential role in therapy of ponesimod, which was recently approved by the Food and Drug Administration (FDA) as a therapeutic option for the treatment of multiple sclerosis (MS). A PubMed literature search using the following terms: ponesimod and MS (January 1, 2012-October 31, 2022). FDA product labeling was also reviewed for pertinent data sources. All relevant English-language articles examining efficacy and/or safety of ponesimod were considered for inclusion. Ponesimod is an orally administered second-generation sphingosine 1-phospate (S1-P) receptor modulator classified as a disease modifying treatment (DMT) for MS. Clinical studies have shown that ponesimod prevents relapse in patients with relapsing-remitting MS (RRMS) and has superior efficacy compared with teriflunomide. Nasopharyngitis, upper respiratory tract infections, headache, high blood pressure, and liver dysfunction were some of the common adverse effects associated with ponesimod. Dyspnea, bradyarrhythmias, atrioventricular conduction delays, and macular edema were some of the rare but serious adverse effects associated with ponesimod. Some advantages of ponesimod over other S1-P receptor modulators approved for RRMS include selectivity for the S1-P1 receptor and short half-life, which allows for quick reversal of immunosuppressive effects. However, data from long-term efficacy and safety studies and more direct comparison studies with other DMTs are required. Currently available data suggest that ponesimod is a useful addition to other high-efficacy DMTs available to treat patients with MS.

Hereditary glaucoma: clinical and genetic characteristics

The review is devoted to the genetic nature of congenital glaucoma (CG) and presents clinical and genetic forms of hereditary glaucoma and single nucleotide polymorphisms identified by genome-wide association studies (GWAS). Glaucoma is a genetically heterogeneous disease, and patients with the same clinical diagnosis often have different molecular causes. The role of mutations in the CYP1B1 gene has been proven in the pathogenesis of hydrophthalmos; the MYOC gene — in juvenile open-angle glaucoma; the PAX6 gene — in aniridia; mutations in the PITX2, FOXC1 genes have been identified in Axenfeld-Rieger anomaly/syndrome. It has been established that 4–43% of patients with open-angle glaucoma have a family history of a mutation in the MYOC, OPTN or TBK1 genes. Genetic studies of glaucoma are the first steps to developing a new generation of personalized treatments. The article describes the key features of the pathogenesis of various genetic forms of glaucoma and the possible course of its therapy. However, gene therapy requires further study of both long-term effects and efficacy. Molecular genetic diagnosis of glaucoma allows for personalized genetic counseling of family members with consideration of the genetic risks.

Sustained Factor VIII Activity Following Single Dose of Non-Viral Integrating Gene Therapy

The current first-line treatment for Hemophilia A patients is factor replacement therapy and/or bi-specific antibodies; however, these treatments require continuous infusions over the course of the patient's life, and patients continue to have breakthrough bleeds, representing a high unmet need for a non-viral gene therapy. Unlike conventional AAV gene therapies, our proprietary piggyBac® DNA delivery platform facilitates stable genomic insertion of a therapeutic transgene as a means of developing lifelong cures of hereditary genetic deficiencies such as hemophilia A. The Super piggyBac (SPB) transposase enzyme functions by excising a DNA cargo flanked by SPB recognition ITRs and inserting into TTAA genomic sites. We have developed a non-viral, nanoparticle-based delivery system to enable piggyBac-based gene therapy. This system entails two liver-tropic nanoparticles: a lipid nanoparticle encapsulating the SPB transposase formulated as mRNA, and a second nanoparticle encapsulating a plasmid comprising the human FVIII gene, promoter, and piggyBac ITRs. This non-viral strategy provides certain advantages over AAV-based approaches: increased transgene cargo capacity beyond 4.7 kb, stable integration of the FVIII transgene into the genome, the potential for re-dosing, and potentially simpler manufacturing processes, relative to AAV-based vector production. Optimization of the human FVIII transposon was conducted, specifically to elucidate the role of promoter, transgene sequence, and UTR elements in FVIII antigen levels. A panel of transposons was prepared and FVIII levels assessed following single administration in vivo to wild type mice. The transposons with the highest FVIII performance were subsequently evaluated in long-term efficacy studies. Initial proof-of-concept studies demonstrated that LNPs separately optimized for SPB mRNA or FVIII transposon DNA delivery can be co-administered intravenously to mice. We observed that transposase mRNA delivered to the liver is converted to protein rapidly and expressed for several days. Transposon DNA delivered to mouse liver results in expression of functional human FVIII protein, though at sub-therapeutic levels at the doses evaluated here. Co-administration of the transposon and transposase nanoparticles resulted in sustained FVIII antigen levels in the anticipated therapeutic range (>50% of normal) in wild type animals. We observed a more dramatic response when the dual-nanoparticle system was evaluated in neonatal (post-natal day 1) wild type mice. Mice were co-administered the SPB mRNA LNP and the human FVIII transposon nanoparticle. Control mice were co-administered the same dose of a catalytically dead SPB transposase, which is unable to mediate genomic integration. FVIII protein reached therapeutic levels in plasma and were sustained over the full study duration (5 months), whereas control animals exhibited negligible (<2%) human FVIII levels. These findings illustrate the utility of the piggyBac DNA delivery system for treating genetic disease early in life, enabled by stable integration. Thus, piggyBac platform avoids the transient efficacy typical of conventional non-integrating gene therapy approaches. To further validate this long-term durability, a six-month efficacy study was conducted in a mouse model of hemophilia A (FVIII exon 16−/−/CD4−/−, C57BL/6). This model is deficient in FVIII as well as CD4, allowing measurement of FVIII activity levels afforded the absence of an immune response to human FVIII. We observed that a single treatment yielded 30 - 150% of human FVIII activity in a dose-responsive manner, which was generally sustained over the duration of the study. Mice treated with the same dose of human FVIII transposon and the catalytically dead transposase exhibited negligible (<2%) human FVIII activity at all timepoints evaluated. In conclusion, our results demonstrate the novelty of our piggyBac® platform and approach in providing a potential lifelong functional cure for hemophilia A. By providing stable transgene expression through genomic integration, this technology has the potential to greatly improve the lives of hemophilia A patients.