Diagnosis, assessment and monitoring of Huntington’s disease (HD) requires measurement of a complex array of motor, cognitive and psychiatric symptoms over sustained periods. However, the prodromal stages often span over a decade with symptoms presenting in a non-linear manner with short term fluctuations. This presents challenges for investigational drug development as treatment effects may become masked. To help address this issue, a number of digital health technology tools are being investigated for use in HD studies with increasing degrees of utility and sophistication. Herein we outline how remote passive monitoring technologies could be integrated into managed care of HD patients, and have the potential to inform algorithms and digital tools which could be used to improve our understanding of disease trajectories and improve early detection rates. Steps to implementation and the potential to derive learnings from adjacent technologies is presented, affording a key opportunity for next- generation approaches to patient monitoring. Measures derived from such technologies will also provide data to capture disease progression and treatment effects with high fidelity and granularity, and complement existing clinical research outcomes (clinROs) and patient reported outcomes (PRO’s). Given the ethical, economic, and societal burden presented by neurodegenerative diseases, such developments could have long term impact in managed healthcare.
Alternative splicing and alternative promoters generate splicing variants to expand proteomic and transcriptional diversity to orchestrate physiological activities and dictate tumorigenesis. Splicing variants are attractive tumor-associated antigens (TAAs) for the clinical development of cancer therapies. Here, recent progress in claudin-18 isoform 2 (CLDN18.2)- and fibroblast growth factor receptor 2 isoform b (FGFR2b)-targeted therapeutics is summarized, and perspectives in this field are discussed. Zolbetuximab and bemarituzumab are first-generation monoclonal antibodies (mAbs) targeting CLDN18.2 and FGFR2b, respectively, while next-generation biologics targeting these TAAs are emerging. Single-agent objective response rates of CLDN18.2-targeting mAb (omectatug), antibody–drug conjugates (ADCs, arcotatug tavatecan, BL-M05D1, garetatug rezetecan, JS107, sonesitatug vedotin and tecotabart vedotin), bispecific antibodies (emaretamig and givastomig) and chimeric antigen receptor T (CAR-T) cells (IMC002) were higher than that of zolbetuximab. Gastrointestinal toxicity, nausea and vomiting are common on-target/off-tumor adverse effects of CLDN18.2-targeted biologics, which are mitigated for arcotatug tavatecan and givastomig as a result of antibody engineering. Combination therapy of zolbetuximab plus chemotherapy is approved for the treatment of gastric and gastroesophageal junction cancer patients, while results of other CLDN18.2-targeting biologics in phase 3 clinical trials are anticipated with expectations for improved clinical activities and mitigated adverse events. Diagnostics detecting alternative isoforms and combination strategies using immune checkpoint inhibitors would address resistance mechanisms, such as epitope-losing isoform switching and immune evasion. Comparative studies on ADC monotherapy versus combination mAb-chemotherapy as well as the clinical development of bispecific ADCs and allogeneic CAR-T cells should further improve the clinical benefits of CLDN18.2- and FGFR2b-targeted therapies.
Brooke E. Harris, Brooke M. Seldin, Sam C. Towne, Orinda R. Hobson, Eli Zerpa, Victor Prima, H. Lee Sweeney, David W. Hammers
Systemic gene therapies utilizing recombinant adeno-associated virus (rAAV) are in the clinic for the treatment of rare monogenic diseases. This includes delandistrogene moxeparvovec for Duchenne muscular dystrophy (DMD), which uses AAVrh74 vector to deliver a micro-dystrophin transgene to striated muscle. While there have been cases of transformative benefits incurred from rAAV therapies, serious adverse events and mortalities have occurred. This study aimed to investigate short-term rAAV dynamics and long-term systemic responses to intravenous rAAV in the phase 1/2a delandistrogene moxeparvovec clinical trial (NCT03375164), which represents the most promising cases of micro-dystrophin gene therapy for DMD. Plasma and urine specimens from NCT03375164 were analyzed for rAAV using digital PCR and immunoblotting. The integrity and transduction competency of specimen-derived rAAV was evaluated in vitro. Systemic responses to rAAV treatment were investigated using the SomaScan proteomics platform. Preclinical antiviral responses to rAAV were assayed by real-time PCR in the livers of D2. mdx mice 1 week following systemic treatment with rAAV. Digital PCR revealed high rAAV content in the plasma at Day 1 following treatment, which substantially reduced by Day 7. Urinary rAAV content was low and variable in all samples tested. The majority of detected vector genomes were packaged in AAVrh74 particles in these specimens, and the vector contained in Day 1 plasma samples was confirmed to be transduction competent. SomaScan data revealed highly significant changes in 99 circulating proteins, which include markers associated with immune activation, interferon responses, complement pathways, and organ injury. Most traditional markers of muscle damage were not changed across the time course, with the limitation that no healthy or untreated DMD samples were analyzed. Features of antiviral and interferon-associated responses were identified in D2. mdx mice. Systemic rAAV treatments result in high levels of circulating and transduction-competent vector early after treatment in DMD boys and result in wide-spread activation of immune-associated markers. These findings will provide insights for future investigational study design and efforts to improve safety of rAAV gene therapies.
Morgan Williamson, Caleb Boren, Rahul Kumar, Lauren Gollahon
Human papillomavirus (HPV), a member of the Papillomaviridae family, infects a broad range of animal hosts and is responsible for the majority of cervical cancers and a substantial proportion of oropharyngeal cancers. Current treatment strategies for HPV-associated cervical disease depend largely on disease stage, with preinvasive and early invasive lesions commonly managed through surgical excision or radiation. Additionally, more advanced cases often require chemotherapy, immunotherapy, or combination regimens. Prophylactic vaccination remains the most effective preventive approach, and currently available vaccines, including Gardasil, Gardasil-9, and Cervarix, rely on L1-based virus-like particles (VLPs) to induce protective immunity. At the same time, increasing interest has emerged in the use of nanomaterials and viral capsids as platforms for targeted drug and gene delivery, alongside the development of higher-throughput methods for nanoparticle and viral characterization. Modified HPV capsids have shown promise for cell-specific targeting and more efficient cargo delivery with reduced off-target cytotoxicity. In this study, the HPV16 structural proteins L1 and L2 were fused to the N- and C-terminal halves of the Venus fluorophore, respectively, using a specially designed linker intended to preserve capsid assembly while reducing VLP aggregation associated with current production methods. The resulting bimolecular fluorescence complementation (BiFC)-based VLPs demonstrated reduced aggregation and improved total particle yield. In addition, the particles generated a detectable YFP signal, supporting fluorescence-based monitoring of VLP assembly and providing a potential basis for high-throughput particle characterization and sorting. This intrinsic fluorescent signal may also reduce reliance on separately packaged reporter constructs for downstream analysis.
Angel Alberto Justiz-Vaillant, Sachin Soodeen, Rodolfo Arozarena-Fundora, Patrick Eberechi Akpaka, Chandrashekhar Unakal
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory haematological malignancies, producing durable clinical responses in patients with otherwise limited therapeutic options. Despite these advances, significant biological, clinical, and economic barriers continue to limit its broader application, particularly in solid tumours. This literature review critically evaluates recent developments in CAR-T cell therapy, with emphasis on areas that have received limited discussion in previous reviews. Multi-target CAR strategies, including bispecific, tandem, and pooled CAR-T cell approaches, are comparatively assessed with respect to antigen escape, manufacturing complexity, therapeutic efficacy, and safety. Current challenges in solid tumour treatment are examined through evidence from clinical trials, highlighting key obstacles such as antigen heterogeneity, the immunosuppressive tumour microenvironment, poor cellular trafficking, and treatment-related failures that have informed the development of next-generation CAR constructs. Emerging approaches to overcoming antigen loss, including γδ CAR-T cells, are reviewed alongside their current limitations, including restricted ex vivo expansion, donor variability, isolation challenges, and uncertain long-term persistence. The review also addresses the growing importance of improving affordability and accessibility through allogeneic “off-the-shelf” CAR-T products, genome editing technologies, automated manufacturing platforms, and rational combination therapies designed to enhance efficacy while reducing treatment costs. In addition, advances in toxicity prediction are evaluated, focusing on biomarkers beyond interleukin-6, including ferritin, C-reactive protein, soluble interleukin-2 receptor alpha, and multiparametric cytokine signatures for the early identification of severe cytokine release syndrome. Collectively, these developments demonstrate that future progress in CAR-T cell therapy will depend not only on enhancing antitumour efficacy but also on improving safety, accessibility, manufacturing efficiency, and equitable global implementation through evidence-based innovation.
