Neu Gene Research Articles

Clinicopathological Study of Prostate Diseases and Its Correlation with PSA Level, Size of Prostate and Gleason’s Scoring System in Case of Prostatic Carcinoma

Background: Prostate gland diseases significantly impact adult males globally, with an increasing prevalence due to aging populations. The primary conditions affecting the prostate are inflammation, benign prostatic hyperplasia (BPH), and tumors, with BPH being the most common. Prostatic carcinoma is also prevalent, with a high lifetime risk. Prostate cancer incidence increases with age, and early detection relies on digital rectal examination, transrectal ultrasonography, and PSA testing. Aim of the study: The study aims to find out correlation between PSA, Gleasons scoring system and HER-2/NEU gene in prostatic cancer. Methods: This study, conducted from July 2017 to June 2019 at BIRDEM General Hospital, enrolled 110 male patients aged 50-100 with clinical signs of prostatic diseases. Patients provided written informed consent and met specific inclusion criteria. Specimens were obtained via TURP, simple or radical prostatectomy, preserved in 10% neutral buffered formalin and examined for pathological lesions. PSA levels were measured using an immunoassay, and Gleason scoring was used for carcinoma categorization. Data were collected via questionnaires and analyzed using SPSS software. Result: The study analyzed 110 prostatic disease cases, with patients averaging 67.7 years. The most common diagnosis was BPH with inflammation (50.9%), followed by BPH without inflammation (35.5%) and adenocarcinoma (13.6%). Urgency (80%), increased micturition frequency (78.2%), poor stream (78.2%), and urinary retention (77.3%) were the most common symptoms. There was a significant correlation between serum PSA levels and prostate size (p < 0.001), with higher PSA levels indicating larger prostates and a higher likelihood of adenocarcinoma. The most frequent Gleason score was 4+4=8 (40%). HER2/neu overexpression showed a marginal correlation with PSA levels (p=0.053). Conclusion: The study found that the most common age group for prostatic diseases was 61-70 years. Benign prostatic hyperplasia (BPH) was the most frequent lesion. Grade II (31-50g) prostate size was common on ultrasound. Most patients had a PSA level of 0-5 ng/ml, aiding early diagnosis and reducing morbidity

Her-2/neu gene amplification and its correlation with other prognostic factors in Iranian breast cancer patients.

Breast cancer is one of the most common diseases in females, arising from overexpression of a variety of oncogenes like HER2/neu. The amplification rate of this gene is variable in different breast cancer patients. In this study, the amplification of the HER2/neu oncogene was distinguished in breast cancer patients and its correlation with prognostic factors. Also, the simultaneous effect of prognostic factors on the occurrence of a specific prognostic factor was investigated. The multiplex PCR technique was used to assay the amplification of the HER2/neu oncogene in breast cancer patients. After extracting DNA from 100 tumor tissue and 8 normal breast tissue samples, the amplification of the HER2/neu gene was distinguished by the co-amplification of a single-copy reference gene, γ-IFN, and the target gene HER2/neu in the PCR reaction and using the Gel analyzer software. SPSS 23 and STATA 9.1 software were used for statistical analysis. The HER2/neu gene was amplification in 30% of the tumor samples. The statistical analysis showed a statistically significant relationship between HER2/neu gene amplification and progesterone receptors. Amplification of the HER2/neu gene significantly increases the chance of lymph node involvement. Also, the amplification of this gene in tumors with histological grade II tissue is more than grade I. The amplification of the HER2/neu gene can be used as an independent prognostic factor in predicting lymph node involvement and histological grade in breast cancer patients.

Circulating tumour DNA analysis and new uses of anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer

Currently, tumour tissue biopsy to determine RAS/BRAF gene alterations, assess microsatellite instability status, and determine HER‑2/neu gene amplification/hyperexpression is the gold standard of diagnosis and allows the selection of optimal molecularly targeted therapy when considering treatment strategies for patients with metastatic colorectal cancer. However, biopsy does not fully reflect the existing intratumoural heterogeneity and clonal evolution of tumour cells, which can often be the cause of therapeutic failures. In recent years, liquid biopsy has attracted increasing attention as an additional and potentially alternative non-invasive tool for molecular tumour profiling. Assessment of circulating tumour DNA allows changes in the genetic status of the tumour to be monitored and the «burden» of disease to be measured dynamically in real time. Advances in liquid biopsy technology have led to promising new strategies for the management of patients with metastatic colorectal cancer in late-line therapy. The standard drug arsenal in this group of patients is limited to either repeat administration of previously effective therapy or regorafenib and the combination of trifluridine/tipiracil with bevacizumab, which are characterized by limited clinical activity. However, thanks to the discovery of the NeoRAS wild-type phenomenon and the rechallenge strategy of anti-EGFR monoclonal antibodies based on the study of clonal selection and evolution of tumour cells, the administration of epidermal growth factor inhibitors in a molecularly selected by liquid biopsy population is accompanied by good tolerability and efficacy. Numerous clinical studies are ongoing to further understand the mechanisms of tumour resistance and to develop new evidence-based treatment approaches in order to realise the concept of personalised medicine.

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Casimersen (AMONDYS 45™): An Antisense Oligonucleotide for Duchenne Muscular Dystrophy.

Casimersen (AMONDYS 45TM) is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer subclass developed by Sarepta therapeutics. It was approved by the Food and Drug Administration (FDA) in February 2021 to treat Duchenne muscular dystrophy (DMD) in patients whose DMD gene mutation is amenable to exon 45 skipping. Administered intravenously, casimersen binds to the pre-mRNA of the DMD gene to skip a mutated region of an exon, thereby producing an internally truncated yet functional dystrophin protein in DMD patients. This is essential in maintaining the structure of a myocyte membrane. While casimersen is currently continuing in phase III of clinical trials in various countries, it was granted approval by the FDA under the accelerated approval program due to its observed increase in dystrophin production. This article discusses the pathophysiology of DMD, summarizes available treatments thus far, and provides a full drug review of casimersen (AMONDYS 45TM).

Abstract CT193: Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity of AST-021p, a novel cancer vaccine targeting HSP90-derived epitopes in advanced solid tumor patients (CornerStone-002)

Abstract Background: AST-021p is an "off-the-shelf" therapeutic cancer vaccine composed of two peptides, AST-021p4 and AST-021p5, derived from MHC class II-specific epitopes of Hunam HSP90 protein. Both peptides serve as antigenic determinants for HSP90 and act as a tumor-associated antigen (TAA) inducing activation of type 1 helper T cells (Th1). Th1 cell immunologically elicited by AST-021p secrete cytokines, including IFN-γ, and activate local antigen presenting cells (APC) enhancing cross priming at the tumor site. This immunological activity, through the mechanism of cross priming, sequentially leads to the activation of cytotoxic T cells and epitope spreading. In preclinical studies using the MMTV neu gene overexpressing mouse model, the administration of the HSP90 peptide vaccine, AST-021p, significantly inhibited tumor growth. Based on these scientific rationales, The first-in-human (FIH) study was conducted to evaluate the safety, tolerability, and immunogenicity of AST-021p in advanced solid tumor patients have no treatment option. Methods: Phase 1 study (CornerStone-002, NCT No.: 04864418) was conducted on patients with recurrent or metastatic solid tumors for whom applicable standard treatment options were unavailable (patient enrollment period: June 9, 2021, to June 14, 2023). Four-dose cohorts of AST-021p (Cohort 1: 1.2mg, Cohort 2: 2.4mg, Cohort 3: 3.6mg, Cohort 4: 4.8mg) received three vaccinations at 2-week intervals (Priming immunization) followed by boosting immunization with 4-week interval based on PI's discretion. Enrolling one patient initially in the lowest dose cohort, Cohort 1 (1.2mg), dose escalation occurred sequentially after confirming safety and tolerability. Subsequently, each dose cohort (Cohort 2: 2.4mg, Cohort 3: 3.6mg, Cohort 4: 4.8mg) enrolled six patients each for vaccination. Antigen-specific immune response was assessed by IFNγ ELISPOT using PBMCs from the subjects at baseline, 4 weeks, and 8 weeks. Results: During the study period, a total of 22 patients were enrolled (Cohort 1: 1, Cohort 2: 6, Cohort 3: 8, Cohort 4: 7). The median age of the patients was 66, with a gender distribution of 14 males and 8 females. Among the 22 patients, 20 completed the priming immunization with 3 vaccinations, and 7 of them proceeded with the boosting immunization. A total of 75 adverse events were reported in 21 patients (95.5%). Adverse drug reactions (ADRs) occurred in 15 patients (68.2%), accounting for 92 cases. The most common ADR was injection site reaction (ISR), observed in 15 patients (68.2%), with 35 cases and all reactions were graded as 1 or 2. Serious adverse events (SAEs), including gastrointestinal hemorrhage, vomiting, and aspiration, were observed in 3 patients (13.6%), totaling 3 cases. However, these events were unrelated to AST-021p. Conclusions: This study, as the first-in-human (FIH) administration of the AST-021p, demonstrated safety and tolerability across all four dose groups. Plus, optimal immunogenic dose (OID) and recommended phase 2 dose (RP2D) were confirmed based on AST-021p-specific immunogenicity and safety. Citation Format: Eun Joo Kang, Kyoungmin Lee, In Ho Kim, Ju Won Kim, Jwa Hoon Kim, Soohyeon Lee, Jiwon Lee, Kabsoo Shin, Sejun Park, Joori Kim, Hyun Won Shin, Kyong Hwa Park. Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity of AST-021p, a novel cancer vaccine targeting HSP90-derived epitopes in advanced solid tumor patients (CornerStone-002) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT193.

1659. Prokinetic Antibiotic Agents in the Neonatal Intensive Care Unit: Ripe for Antibiotic Stewardship Efforts!

Abstract Background Intolerance to enteral nutrition among infants in the neonatal intensive care unit (NICU) may lead to the use of prokinetic agents to improve gastric emptying and feeding tolerance. Two such oral prokinetic agents are erythromycin and amoxicillin-clavulanate that have been used in cases of dysmotility due to intestinal failure. However, dosing strategies vary and the recommended duration of therapy has not been determined. Moreover, the use of these oral antibiotics in the NICU may fall under the radar of neonatal antimicrobial stewardship programs. Our objective was to quantify their use in the Level 4 outborn NICU at Nationwide Children’s Hospital, Columbus, OH in order to inform antibiotic stewardship efforts. Methods This was a retrospective cohort study of all infants who received enteral erythromycin or amoxicillin-clavulanate in the NICU. The number of doses of each antibiotic was obtained from the Nationwide Children’s Hospital Pharmacy database. Pertinent clinical, laboratory, and outcome data were obtained. Results From January 1, 2022 to April 30, 2023, 15 infants in the NICU received ≥1 dose of erythromycin ethylsuccinate and 19 infants received ≥1 dose of amoxicillin-clavulanate enterally. Erythromycin was always used to improve motility while amoxicillin-clavulanate served as a prokinetic agent in 53% of infants in whom it was prescribed. Demographics and reason for initiation are provided in Table 1. The median (IQR) doses per patient for erythromycin was 64 (28, 125; dosing interval varied from every 6 to every 8 hours) and for amoxicillin-clavulanate was 50 (9, 105) doses per patient (majority of doses were given on a BID schedule). Characteristics of infants who received prokinetic agents in the NICU Conclusion Enteral erythromycin and amoxicillin-clavulanate have not been the target of antimicrobial stewardship programs. These antibiotics may contribute to dysbiosis and adverse events in NICU infants. An automatic stop time with a time-out when ordered in the electronic health record may be a viable strategy to reduce overutilization of these antibiotics. Disclosures Pavel Prusakov, PharmD, Merck & Co: Grant/Research Support|Merck & Co: Employee Michael Storey, PharmD, MS, CSL Behring: Advisor/Consultant|Sarepta Therapeutics: Advisor/Consultant

2065. Efficacy of D-peptide-conjugated Antisense Compounds Against Pseudomonas aeruginosa

Abstract Background Pseudomonas aeruginosa (PA) causes significant morbidity and mortality in immunocompromised hosts and those with cystic fibrosis. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense compounds designed to target specific genes and prevent translation. PPMOs with L-isomer peptides (L-PPMOs) were previously shown to have in vitro and in vivo activity. However, L-PPMOs are vulnerable to degradation by host proteases. We hypothesize that PPMOs with a D-isomer peptide (D-PPMOs) may be a more stable and potent alternative. We aimed to characterize the activity of L- and D-isomers in PA strains using planktonic and biofilm assays as well as an infected mouse model. Methods All L- and D-PPMOs were synthesized by Sarepta Therapeutics, Inc. We tested L- and D-isomers of the (RXR)4XB (X for 6-aminohexanoic acid and B for β-Ala) and R6G peptide [(Arg)6-Gly]. PMOs for rpsJ (ribosomal protein) and acpP (fatty acid synthesis protein) were conjugated to the 3’ end of each peptide. Minimum inhibitory concentration (MIC) assays were performed in unique lab and clinical (including MDR) isolates using MOPS medium. Strain PAO1 biofilms were grown in MBEC plates for 24 hours, with PPMOs then dosed every 8 hours for 24 hours, followed by colony enumeration. For in vivo studies, mice were infected with strain PA103 intratracheally and given intranasal PPMO at 6 hours post-infection. Lung burden was determined at 24 hours post-infection. Results MIC values of D-R6G-RpsJ and D-R6G-AcpP were comparable to their L-isomers, but D-RXR-RpsJ showed an improved MIC90 of 0.5 μM compared to the L-RXR-RpsJ MIC90 of 16 μM (Table 1). Both isomers demonstrated reduction of 48-hour biofilm to various degrees. D-PPMO biofilm reduction ranged from 1.5 logs to > 3 logs (D-R6G-AcpP and D-RXR-RpsJ, respectively). L-PPMO biofilm reduction ranged from 2 logs to > 4 logs. D-PPMOs were superior to their L-PPMO counterparts in our delayed in vivo acute pneumonia model, with most D-PPMOs resulting in an additional 50% decrease in lung burden. Conclusion D-PPMOs show similar or improved activity in vitro and in vivo when compared to L-PPMOs at the same dosage. Future studies will investigate the pharmacology of D-PPMOs, as they may represent a more biologically robust alternative to L-PPMOs for PA infections. Disclosures David E. Greenberg, MD, University of Texas Southwestern Medical Center: Dr. Greenberg has numerous patents on PPMOs

Delandistrogene Moxeparvovec: First Approval.

Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS®) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138kDa) version of the dystrophin protein expressed in normal muscle cells (427kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4through 5years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 1014 vector genomes per kg of body weight or 10mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5years with DMD and a confirmed mutation in the DMD gene.

Extracellular matrix remodelling and stiffening contributes to tumorigenesis of salivary carcinoma ex pleomorphic adenoma——A study based on patient-derived organoids

BackgroundSalivary carcinoma ex pleomorphic adenoma (CXPA) is defined as a carcinoma that develops from benign pleomorphic adenoma (PA). Abnormally activated Androgen signaling pathway and amplification of HER-2/neu(ERBB-2) gene are known to be involved in CXPA tumorigenesis. Recent progress in tumour microenvironment research has led to identification that extracellular matrix (ECM) remodelling and increased stiffness act as critical contributing role in tumour carcinogenesis. This study examined ECM modifications to elucidate the mechanism underlying CXPA tumorigenesis.ResultsPA and CXPA organoids were successfully established. Histological observation, immunohistochemistry (IHC), and whole-exome sequencing demonstrated that organoids recapitulated phenotypic and molecular characteristics of their parental tumours. RNA-sequencing and bioinformatic analysis of organoids showed that differentially expressed genes are highly enriched in ECM-associated terms, implying that ECM alternations may be involved in carcinogenesis. Microscopical examination for surgical samples revealed that excessive hyalinized tissues were deposited in tumour during CXPA tumorigenesis. Transmission electron microscopy confirmed that these hyalinized tissues were tumour ECM in nature. Subsequently, examination by picrosirius red staining, liquid chromatography with tandem mass spectrometry, and cross-linking analysis indicated that tumour ECM was predominantly composed of type I collagen fibers, with dense collagen alignment and an increased level of collagen cross-linking. IHC revealed the overexpression of COL1A1 protein and collagen-synthesis-related genes, DCN and IGFBP5 (p < 0.05). Higher stiffness of CXPA than PA was demonstrated by atomic force microscopy and elastic imaging analysis. We utilized hydrogels to mimic ECM with varying stiffness degrees in vitro. Compared with softer matrices (5Kpa), CXPA cell line and PA primary cells exhibited more proliferative and invasive phenotypes in stiffer matrices (50Kpa, p < 0.01). Protein-protein interaction (PPI) analysis of RNA-sequencing data revealed that AR and ERBB-2 expression was associated with TWIST1. Moreover, surgical specimens demonstrated a higher TWIST1 expression in CXPA over PA. After knocking down TWIST1 in CXPA cells, cell proliferation, migration, and invasiveness were significantly inhibited (p < 0.01).ConclusionDeveloping CXPA organoids provides a useful model for cancer biology research and drug screening. ECM remodelling, attributed to overproduction of collagen, alternation of collagen alignment, and increased cross-linking, leads to increased ECM stiffness. ECM modification is an important contributor in CXPA tumorigenesis.

One-year Data from ENDEAVOR, a Phase 1b Trial of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD) (S48.003)

One-year Data from ENDEAVOR, a Phase 1b Trial of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD) (S48.003)

Long-term Safety and Efficacy in Patients with DMD 4 Years Post-Treatment with Delandistrogene Moxeparvovec (SRP-9001) in a Phase 1/2a Study (P3-8.006)

Long-term Safety and Efficacy in Patients with DMD 4 Years Post-Treatment with Delandistrogene Moxeparvovec (SRP-9001) in a Phase 1/2a Study (P3-8.006)

Integrated Analyses of Data from Clinical Trials of Delandistrogene Moxeparvovec (SRP-9001) in Duchenne Muscular Dystrophy (DMD) (S48.006)

Integrated Analyses of Data from Clinical Trials of Delandistrogene Moxeparvovec (SRP-9001) in Duchenne Muscular Dystrophy (DMD) (S48.006)

Evaluating Pharmacology and Efficacy of Delandistrogene Moxeparvovec in Young and Aged DMDmdx Rats (P3-8.008)

<h3>Objective:</h3> The purpose of this preclinical study is to evaluate the myocardial efficacy and safety of intended commercial process delandistrogene moxeparvovec (SRP-9001) material in Duchenne muscular dystrophy (DMD)^mdx rats. DMD^mdx rats are a valuable alternative animal model of DMD, as they demonstrate cardiac dysfunction that recapitulates cardiac dysfunction of patients with DMD. <h3>Background:</h3> Gene transfer therapy is a promising treatment for patients with DMD. Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. <h3>Design/Methods:</h3> We performed systemic, intravenous delivery of intended commercial process delandistrogene moxeparvovec material in young (21–35 days old) and aged (3–5 months old) DMD^mdx rats. The older rats demonstrate a more severe phenotype in terms of fibrosis or cardiac disease progression. Rats received a dose of 1.33×10¹⁴ vg/kg or 7.00×10¹³ vg/kg. Ambulation activity was recorded via the Photobeam Activity System Open Field. Echocardiograms and histological analysis of fibrosis were used to evaluate cardiac disease. <h3>Results:</h3> Data from 12 weeks and 24 weeks post-systemic delivery demonstrated no evidence of cardiac toxicity. Importantly, there were no deaths attributed to treatment. Compared with the saline control, intended commercial process delandistrogene moxeparvovec material increased ambulation and vertical activity in young DMD^mdx rats and improved cardiac function. Protein expression was broadly distributed across skeletal muscle, the diaphragm and the heart. <h3>Conclusions:</h3> Taken together, these findings confirm expression in cardiac muscle of rats, as expected, and support the potential myocardial efficacy and safety of delandistrogene moxeparvovec. Further results of cardiac disease phenotypes at 12 and 24 weeks post-systemic delivery utilizing several indicators of cardiac function will also be presented. <b>Disclosure:</b> Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Christopher Wier has received personal compensation for serving as an employee of Sarepta Therapeutics. Christopher Wier has stock in Sarepta Therapeutics. Dr. Cooper-Olson has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Cooper-Olson has stock in Sarepta Therapeutics. Ms. Wheeler has nothing to disclose. Miss Anderbery has nothing to disclose. Ms. Kempton has received personal compensation for serving as an employee of Sarepta Therapeutics. Ms. Kempton has stock in Sarepta Therapeutics. Ms. Clements has received personal compensation for serving as an employee of Sarepta Therapeutics . Ms. Clements has stock in Sarepta Therapeutics. Mrs. Adegboye has nothing to disclose. Dr. Haile has nothing to disclose. Ms. Peterson has nothing to disclose. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

Analysis of Vector Shedding Following Treatment with Delandistrogene Moxeparvovec (SRP-9001), an Investigational rAAVrh74-Based Gene Therapy for Duchenne Muscular Dystrophy (DMD) (P5-8.013)

<h3>Objective:</h3> To evaluate extent and magnitude of vector shedding following delandistrogene moxeparvovec (SRP-9001) administration. <h3>Background:</h3> Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. The hypothetical risk of seroconversion in naive individuals through exposure to vector shed from treated patients is a point to consider for healthcare providers and the Duchenne community. <h3>Design/Methods:</h3> We evaluated extent of vector shedding and clearance following a single administration of delandistrogene moxeparvovec (1.33×10¹⁴ vg/kg body weight) in ENDEAVOR (NCT04626674; Study 103; N=20), a Phase 1 study in patients with DMD. Delandistrogene moxeparvovec vector exposure in saliva, urine, and feces was quantified by droplet digital polymerase chain reaction. In a nonclinical study, we tested naive mice to determine risk of AAVrh74 seroconversion following mucosal vector exposure, with doses based on exposure levels (vector genome copies) demonstrated in nonclinical and clinical studies. Mice were exposed to AAVrh74.CMV.eGFP via optic exposure and intramuscularly. Antibody levels were measured by AAVrh74 ELISA at baseline and 4 weeks post-delivery. <h3>Results:</h3> Following treatment in ENDEAVOR, the percentage decrease in amount of vector shed was &gt;99% in saliva (n=12), urine (n=18), and feces (n=11) by Week 4. In mice, topical optical delivery of the AAVrh74 vector at relevant concentrations did not produce seropositivity or detectable vector genomes throughout tissues at doses based on clinical vector shedding levels. <h3>Conclusions:</h3> Clinical findings show that peak vector shedding occurs in the first few days after delandistrogene moxeparvovec administration and exponentially declines to insignificant levels by Week 4. In mice, seroconversion was not observed by relevant exposure route at relevant concentrations. Results suggest that the risk of seroconversion following exposure to vector shed by individuals treated with AAVrh74-based gene therapy may be very low. <b>Disclosure:</b> Jyoti Malhotra has nothing to disclose. Dr. Smith has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc. Dr. Smith has stock in Sarepta Therapeutics. Sarah Lewis has received stock or an ownership interest from Sarepta. Mrs. Zhang has nothing to disclose. Mr. Asher has received personal compensation for serving as an employee of Sarepta Therapeutics. Mr. Asher has stock in Sarepta Therapeutics. Shufang Wang has received personal compensation for serving as an employee of Sarepta Therapeutics INC. Shufang Wang has received stock or an ownership interest from Sarepta Therapeutics INC. Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

PK/PD Modeling to Inform Clinical Development of an Adeno-associated Virus Gene Transfer Therapy for Duchenne Muscular Dystrophy (S48.005)

<h3>Objective:</h3> To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between tissue vector genome exposure, biological efficacy and functional outcome in an animal model of Duchenne muscular dystrophy (DMD) (DMD^mdx mice) following treatment with delandistrogene moxeparvovec (SRP-9001). <h3>Background:</h3> Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. <h3>Design/Methods:</h3> We evaluated vector biodistribution, expression, and clinical dose selection of delandistrogene moxeparvovec using a novel application of a PK and PD modeling approach applied to data collected from DMD^mdx mice. We analyzed PK/PD relationships between dose, tissue vector genome exposure, SRP-9001 dystrophin protein expression (percent dystrophin positive fibers [PDPF] and western blot), and functional improvement (relative specific force from tibialis anterior and diaphragm). <h3>Results:</h3> Linear kinetics with a dose-proportional increase in tissue drug exposure were demonstrated across the nearly 10-fold dose range (4.43×10¹³–4.01×10¹⁴ vg/kg), and in all tissues. The relationship between tissue vector exposure and PD endpoints (PDPF, motor function outcome) showed a saturable response across a wide range of vector exposures. The vector exposure at 1.33×10¹⁴ vg/kg (the clinical dose) approached the maximum treatment response. Relative specific force and PDPF were significantly correlated (<i>P</i>=4.43×10⁻⁶). However, the relationship appeared to be nonlinear, with increased PDPF expression approaching the maximal functional improvement. Relative specific force and western blot were not significantly correlated. <h3>Conclusions:</h3> For the first time, biodistribution, biomarker and functional efficacy data were used to quantify and demonstrate PK/PD relationships for an adeno-associated virus (AAV)-based gene transfer therapy in a DMD animal model. The results continue to support the expected therapeutic benefit and clinical dose of delandistrogene moxeparvovec, an AAV-based gene transfer therapy. <b>Disclosure:</b> Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Dr. Snedeker has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Snedeker has stock in Sarepta Therapeutics. Dr. Haile has nothing to disclose. Christopher Wier has received personal compensation for serving as an employee of Sarepta Therapeutics. Christopher Wier has stock in Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

EMBARK, a Phase 3 Trial Evaluating Safety and Efficacy of Delandistrogene Moxeparvovec (SRP- 9001) in Duchenne Muscular Dystrophy (DMD): Study Design and Baseline Characteristics (P5-8.012)

EMBARK, a Phase 3 Trial Evaluating Safety and Efficacy of Delandistrogene Moxeparvovec (SRP- 9001) in Duchenne Muscular Dystrophy (DMD): Study Design and Baseline Characteristics (P5-8.012)

Motor Outcomes to Validate Evaluations in Facioscapulohumeral muscular dystrophy (MOVE FSHD): Preliminary Baseline Characteristics (S7.004)

Motor Outcomes to Validate Evaluations in Facioscapulohumeral muscular dystrophy (MOVE FSHD): Preliminary Baseline Characteristics (S7.004)

A Novel Homozygous Variant in the CHRNE Gene in 2 Siblings with Congenital Myasthenic Syndrome (P9-9.009)

<h3>Objective:</h3> To report a homozygous variant of uncertain significance in the CHRNE gene in two siblings presenting with symptoms consistent with congenital myasthenic syndrome that is responsive to pyridostigmine. <h3>Background:</h3> A 17-year-old female and a 9-year-old male born to consanguineous parents, with no significant perinatal complications or family history, developed predominantly proximal weakness around 4–5 years of age. The sister additionally developed bilateral fatigable ptosis. Both siblings underwent genetic testing that revealed a homozygous mutation in the CHRNE gene for a variant of uncertain clinical significance, c.322C&gt;T (p.Pro108Ser). Since the mutation was in the CHRNE gene, which codes for the epsilon subunit of the acetylcholine receptor, the brother was initially treated with fluoxetine, which had no response. The sister was previously treated with pseudoephedrine for 2 weeks without response. Both siblings began a trial of pyridostigmine and showed improvement of their symptoms, contrary to slow-channel mutation cases that can worsen with acetylcholinesterase inhibitors. EMG/NCS with RNS on the sister was performed 48 hours after stopping pyridostigmine and showed significant decrements on RNS of the left facial nerve and left spinal accessory nerve. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> Not applicable <h3>Conclusions:</h3> Two siblings born to consanguineous parents both shared a homozygous mutation in the CHRNE gene, presenting similarly with symptoms consistent with congenital myasthenic syndrome, responded favorably to pyridostigmine. Given then, we rationalize that the homozygous c.322C&gt;T (p.Pro108Ser) variant in the CHRNE gene causes an acetylcholine receptor deficiency type of congenital myasthenic syndrome. <b>Disclosure:</b> Dr. Chan has nothing to disclose. Ms. Emery has nothing to disclose. Ermal Aliu has nothing to disclose. Dr. Naik has nothing to disclose. Dr. Paul has nothing to disclose. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Audentes Therapeutics. Dr. Kumar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PTC therapeutics. Dr. Kumar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sarepta. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avexis. Dr. Kumar has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PTC therapeutics. The institution of Dr. Kumar has received research support from PTC therapeutics. The institution of Dr. Kumar has received research support from Sarepta Therapeutics. The institution of Dr. Kumar has received research support from Novartis. The institution of Dr. Kumar has received research support from Fibrogen . Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Draft Report Reviewer with PCORI Health Care Horizon Scanning System.

Use of a Standardized Communication Card Facilitated Patient-as-Teacher Training on Communication Skills and Improved Patient Care in the Neurology Clerkship (P3-2.001)

Use of a Standardized Communication Card Facilitated Patient-as-Teacher Training on Communication Skills and Improved Patient Care in the Neurology Clerkship (P3-2.001)