Friedreich ataxia is a rare, autosomal recessive neurogenerative disorder caused by mutations to the frataxin (FXN) gene resulting in loss of functional FXN protein. Applications of cutting-edge genetic and cellular therapies expand therapeutic options for patients with rare, genetic diseases including Friedreich ataxia. Multiple investigational techniques and strategies seek to permanently alter the disease course in patients with Friedreich ataxia, although no product has established definitive benefit. This review catalogs both the history and ongoing efforts of genetic and cellular therapies applied to Friedreich ataxia and its disease models, including therapeutic efficacy and adverse effects. We list the key limitations and cautions of such therapies, chiefly those of potential FXN overexpression toxicity, critical therapeutic windows, and adverse effects of these therapies applicable to any disease target. As gene and cellular therapy continue to diversify in design and strategy, Friedreich ataxia patients will likely have multiple therapeutic options in the future from both investigational therapies described here and future ones yet to be optimized.

Hematologic malignancies remain among the most challenging cancers to treat due to genetic heterogeneity, clonal evolution, and therapy resistance. Extracellular vesicles (EVs), particularly small EV (sEV)-enriched populations, have emerged as active mediators of disease biology, contributing to tumor progression, immune evasion, and chemoresistance through intercellular transfer of bioactive cargo. Recent advances in EV engineering have repositioned these vesicles as programmable delivery platforms capable of transporting nucleic acids, proteins, and chemotherapeutic agents with improved targeting potential. Preclinical studies across multiple hematologic models demonstrate that engineered EVs can induce immune activation, modulate oncogenic signaling pathways, and partially overcome drug resistance. However, these findings remain largely confined to experimental settings, with limited standardization of loading efficiency, biodistribution, and functional potency. Clinically, EV-based applications in hematology are still at an early stage, with most studies focused on biomarker discovery and supportive therapies rather than direct antitumor interventions. In parallel, theranostic EV platforms and liquid biopsy approaches offer promising opportunities for minimally invasive disease monitoring, although their clinical validation remains incomplete. Artificial intelligence (AI) further enhances this field by enabling advanced biomarker analysis and guiding cargo design and targeting strategies, yet its therapeutic applications are still largely exploratory. Despite key challenges, including vesicle heterogeneity, donor variability, suboptimal cargo loading, and manufacturing constraints, these limitations are primarily technical and may be addressed through standardization and engineering optimization. Collectively, EV-based systems represent a promising but still maturing platform with the potential to contribute to next-generation precision oncology in hematologic malignancies.

The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.

Multidimensional effects of genetic mechanisms in cancer occurrence, development and treatment.

Gene therapy in pediatric patients with spinal muscular atrophy in Kazakhstan: Challenges and achievements.

Genetic therapies offer long-awaited hope for patients with rare genetic diseases and are emerging as cancer treatment as well. While these innovations appear promising, they are also extremely expensive and raise concerns about how they fit into an already overburdened healthcare system. What are the societal implications when these treatments become available? And how can we guide their adoption in the Dutch healthcare system in an ethically responsible manner? We describe the emerging landscape of genetic therapies, and specifically examine the ethical concerns surrounding their implementation within the Dutch healthcare system. From this reflection, we seek to offer direction on how to approach these new biomedical developments in a way that preserves the fundamental values of solidarity and justice. This is particularly important, given how rapidly developments in this field are progressing.

Millions of people have taken Direct-to-Consumer (DTC) DNA ancestry tests to learn more about their ethnic ancestry and family history. A small but growing body of research has noted that these DTC DNA ancestry tests raise challenging ethical, psychosocial, and resource-related issues that have not been adequately considered nor discussed. One key issue concerns a "Not Parent Expected" (NPE) discovery, in which a user suddenly and unexpectedly learns from these tests that an assumed parent (typically the father) is not a biological parent. Such news can negatively affect mental health, self-identity, and family relationships. Given the limited research on this topic, we aimed to explore experts' views on the ethical, psychosocial and support-related aspects of DTC DNA ancestry testing, particularly for individuals who receive NPE news. We conducted a qualitative study. This involved semi-structured interviews with ten experts on DTC DNA ancestry testing, who had written about or actively researched these issues. The interviews were analysed using codebook thematic analysis. The analysis resulted in three overlapping themes. The first concerned insufficient support for the NPE population, despite the emergence of some relevant resources. The supports discussed included formal resources, such as genetic counselling and therapy, as well as informal resources, including online peer support. Both formal and informal resources were seen as having advantages and disadvantages. The second theme concerned the need for better consideration of informed consent before taking these tests. Many experts reported that standard consent procedures do not fully prepare consumers for the possibility of making an unexpected discovery such as an NPE event. They suggested that this information could be communicated more effectively, including using creative measures before consent is obtained. The third theme related to the testing companies' role and responsibility in relation to support for individuals learning NPE news. A few experts suggested that these companies bear some moral responsibility, even in the absence of a legal obligation, to provide or direct individuals to supportive resources. Together, these findings contribute to ongoing debates regarding DTC DNA ancestry testing by highlighting the need for greater support for those affected by NPE discoveries and clearer consideration of the responsibilities of testing companies.

Background Epidermolysis bullosa (EB) is a phenotypically and genetically heterogeneous group of rare skin disorders characterised by mucocutaneous fragility. It is currently incurable, and management primarily focuses on wound care. While the implementation of DNA- and RNA-based therapeutic approaches represent promising avenues for EB management, their enormous costs mean comprehensive cost evaluations are needed to facilitate their effective introduction into clinical practice. This scoping review aims to provide a comprehensive overview of the reported costs and time investments of EB. Summary We performed a systematic literature search of the databases MEDLINE, Embase, Web of Science, Scopus, CINAHL, PsycINFO and EconLit covering the period between 2010 and 2025. We included English full text articles on patients with genetic EB, from any country or study setting, that reported on cost categories including quantification of costs or time investments. Twenty-two studies from 15 countries, published between 2013 and 2024, were included. Total sample size was 3046 patients with EB. Most studies (77%) used questionnaires and/or interviews completed by patients or primary caregivers as the primary data-collection method. Of the included studies, 73% reported direct non-healthcare costs, 59% direct healthcare costs and 27% indirect costs. Regardless of main EB-type or age category, the annual mean total economic burden per patient ranged from €42K to €77K. Analysis of time investments revealed that patient's dressings are typically changed daily, with the patient or caregiver spending up to two hours each day on care. Key messages The economic burden of EB is substantial, but it remains challenging to draw definitive conclusions about their exact magnitude due to heterogeneity in reporting. Further clarification of the current economic burden of EB care is essential for the cost evaluations and introduction of high-cost genetic therapies.

This cross-sectional online survey study explores the landscape of medical training on genetic therapies, assessing the experience, expectations and attitudes of medical geneticists, other specialists, and medical trainees in Canada and USA. Among the 315 participants, only 17% reported being "very familiar" with genetic therapies, and 70% expressed dissatisfaction with current training in this area. Across all groups, there was a consistently low level of satisfaction with existing training on genetic therapies, coupled with a strong consensus that this topic should be better integrated into medical programs. Physicians with specialization in genetics reported the highest familiarity and the most experience in teaching about genetic therapies, covering a broader range of topics than other specialties. All specialties acknowledged the pivotal role of medical geneticists in advancing education on genetic therapies. Instead of each specialty designing their own fellowship programs independently, there was a clear preference to do so in collaboration with medical geneticists. Furthermore, most respondents advocated for the introduction of genetic therapy education earlier in medical training, during medical school and residency programs. Our study highlights a clear and pressing need for comprehensive, stage-specific education reform about genetic therapies. Medical geneticists are uniquely positioned to lead and support these educational efforts, ensuring the successful adoption of advanced genetic therapies in patient care.

The article investigates the crucial roles of oxidative stress and inflammation in the progression of Chronic Kidney Disease (CKD), a condition that poses an increasing global health burden. An imbalance between reactive oxygen species (ROS) and antioxidant defenses leads to mitochondrial damage, which subsequently triggers endothelial dysfunction and promotes kidney fibrosis. CKD symptoms are further exacerbated by inflammation, driven by uremic toxins and cytokine activity. The article highlights NF-κB and Nrf2 as key signaling pathways that regulate these networks. Additionally, it examines how cardiovascular disease, mineral-bone disorder, and cognitive decline emerge as clinical consequences of inflammatory and oxidative tissue damage. Therapeutic strategies for CKD are categorized into three main approaches: antioxidants and anti-inflammatory medications, SGLT2 inhibitors, and bardoxolone methyl. The article also emphasizes non-pharmacological interventions, including behavioral modifications, dietary adjustments, probiotic use, and modulation of the gut microbiota. Finally, it discusses emerging research on biomarker development, precision medicine techniques, and genetic therapies aimed at improving CKD detection, management, and treatment outcomes.

Rare diseases present urgent public health challenges requiring coordinated global efforts. This study analyzes China's orphan drug innovation landscape through patent applications (1995-2023) to identify R&D patterns and policy implications. We analyzed 323 Patent Cooperation Treaty applications from Chinese entities using IPC classification and bipartite network modeling. Data from World Intellectual Property Organization were retrieved via PatSnap, with diseases mapped to China's Rare Disease Catalogues (207 conditions). Network metrics quantified disease-technology linkages. Three key findings emerged: (1) Patent filings surged 58.2% (188 patents) during 2018-2023, coinciding with China's regulatory reforms; (2) Innovation concentrated in oncology/neurology (34.3% patents cover 2 diseases), with 66.2% of catalogued diseases lacking patents; (3) Dominant technologies are small molecules and genetic therapies. Network analysis revealed an R&D ecosystem without a single dominant entity, alongside robust collaborative ties between Chinese and U.S. organizations. China's orphan drug innovation is expanding rapidly but remains uneven, concentrated in specific diseases and technological platforms. Policy interventions are needed to address therapeutic neglect through tiered incentives, dedicated funding for neglected diseases, and global partnerships to accelerate equitable treatment access.

Nanomedicines for DNA and interference RNA co-delivery: Combined gene therapy for Fabry disease

Abstract Rationale Mutation-agnostic genetic therapies are urgently needed for cystic fibrosis (CF). Airway basal cells are ideal for CFTR editing because of their self-renewal and multi-lineage potential. Ferrets provide a relevant model due to their airway similarity to humans and recapitulation of CF physiology. Here, we established preclinical proof of concept using an ex vivo ferret model to test engraftment of ferret bronchial epithelial cells (FBECs) on injured trachea, then performed in vivo autologous FBEC transplantation in wild-type (WT) ferrets to assess feasibility of cell-based therapy, including colocalized epithelial function determination. Methods WT FBECs were obtained via bronchoscopy, cultured, and GFP-labeled through lentiviral transduction. For ex vivo studies, excised whole WT tracheae were split along the ventral surface, affixed to a gelatin matrix, and cultured in antimicrobial media following epithelial injury. GFP+ cells were seeded, and tissues were evaluated using histology and Ussing chamber analysis. For in vivo experiments, WT ferrets underwent bronchial brushing to isolate FBECs, which were expanded (>600 million cells), and confirmed to be > 80% GFP+ and 100% basal cells by flow cytometry prior to transplant. Six hours after airway injury with 2% polidocanol GFP+ FBECs were reintroduced into donor ferrets via bronchoscopic instillation. Results Three weeks post-transplant, ex vivo trachea confirmed durable GFP+ engraftment with ciliated, basal, and secretory cell differentiation by immunofluorescence (IF, n = 4). Ussing analysis showed CFTR-dependent functional recovery in GFP+ engrafted tissues compared with injury-only controls. Short-circuit current (Isc) responses to forskolin (ΔIsc: untreated 1060 ± 315.4; injury only 138.5 ± 116.7; injury + GFP+ 361 ± 57.5) and Inh/GlyH inhibition (−979 ± 496.4; −205 ± 237.6; −788.5 ± 137.1 respectively) indicated augmented CFTR activity approaching untreated controls. In in vivo experiments, WT ferrets (n = 2) tolerated autologous FBEC transplantation and remained healthy up to 21 days. Fluorescent microscopy of the transplanted trachea showed successful GFP+ cell engraftment and intact epithelium in > 70% of the trachea at 21 days. IF analysis of the explanted airways confirmed transplanted cells largely exhibited KRT5+ basal cell identity with early evidence of epithelial differentiation at day 7. Conclusion We established proof-of-concept for autologous FBEC transplantation in a ferret model, demonstrating successful engraftment, epithelial regeneration, and partial restoration of CFTR function. Functional ex vivo ferret trachea culture enables evaluation of cell-based airway repair and CF correction strategies. These findings support the feasibility of basal cell-based therapies for CF and provide a foundation for future studies using genetically corrected CF ferret airway cells. This abstract is funded by: CFF

Cystic fibrosis (CF) is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) anion channel. Since the initial characterization of CF in the early 20th century, advances in clinical management have reduced disease burden and increased longevity. These advances are amplified by the recent development of highly effective CFTR modulator therapies (HEMT) that provided remarkable clinical results in people with CF (pwCF). However, some pwCF do not benefit from HEMT due to several limiting factors. Genetic therapies have increasingly emerged as prospective, complementary treatments to HEMTs for those unable to benefit from HEMT. Genetic therapies have yet to be approved for clinical use in pwCF, but multiple clinical trials are in progress. In anticipation of future approval of one or more of these candidates, it is essential to identify and discuss how these genetic therapies might be used in early life, when many CF lesions originate, especially for those with severe mutations. In this multidisciplinary review, we discuss several pertinent factors such as CFTR localization and function, CF disease origins, emerging developments in genetic therapies, ethical considerations and other perspectives needed to guide future genetic therapies in early life.

Pediatric cardiomyopathy (PCM) comprises a genetically heterogeneous, high risk group of myocardial disorders and is a leading cause ofpediatric heart failure and transplantation. Genotype-phenotype correlations and outcome data remain limited, particularly in populations with high consanguinity. We conducted a retrospective cohort study of 53 children with cardiomyopathy classified as hypertrophic (HCM), dilated (DCM), left ventricular noncompaction (LVNC), or restrictive cardiomyopathy (RCM). We analyzed demographics, consanguinity, echocardiographic parameters, genetic testing results (available in 26/53 patients, 49.1%), device therapy, transplantation, and mortality. The cohort included 20 HCM (37.7%), 17 DCM (32.1%), 13LVNC (24.5%), and 3 RCM (5.7%) patients, with a median age at diagnosis of 6.5years (interquartile range [IQR] 2.0-10.0). Consanguinity was documented in 24of53patients (45.3%). A pathogenic or likely pathogenic (P/LP) variant was identified in 9 of 26 tested patients (34.6%), corresponding to 17.0% of the total cohort (9/53). When variants of uncertain significance (VUS) are included, 20of26tested patients (76.9%) harbored at least one rare variant; however, 11ofthese 20 findings (42.3% of tested patients) were VUS, which are not counted toward diagnostic yield and remain subject to reclassification. Baseline ejection fraction was markedly reduced in DCM (median 35%, IQR 28-37%), whereas HCM and RCM had preserved systolic function at diagnosis. During amedian follow up of 3.0 years, 15 patients (28.3%) underwent implantable cardioverter defibrillator implantation, 6 (11.3%) underwent heart transplantation, and 18(34.0%) died; mortality was highest in DCM (58.8%) and RCM (66.7%). Among the 26 of 53 patients who underwent genetic testing, PCM in this cohort showed a P/LP diagnostic yield of 34.6% (9/26) and substantial mortality, particularly in DCM and RCM phenotypes. High consanguinity was associated with a notable P/LP yield and a frequent VUS burden; whether consanguinity contributes to earlier or more severe disease requires confirmation in larger, prospective studies. These findings support offering comprehensive genetic testing to pediatric cardiomyopathy patients, especially in high consanguinity settings, to enable molecular diagnosis and structured family counseling. In this cohort, a substantial proportion of tested patients had P/LP variants, and many others carried VUS that will require ongoing re evaluation. Future prospective studies should assess how specific genetic findings, combined with imaging and functional parameters, can be incorporated into validated risk stratification and management algorithms. s.

More disease-modifying therapies for sickle cell disease: Are small molecules and drug repurposing the way forward?

Introduction. The (1;19)(q23;p13) translocation, which generates the TCF3::PBX1 fusion gene, is detected in 3–5% of patients with acute lymphoblastic leukemia (ALL). In cases of relapse, the disease often demonstrates aggressive and refractory behavior, including the development of extramedullary sites. Defining the optimal sequence and combination of therapeutic approaches in this genetic subgroup requires further investigation and standardization on the basis of accumulated clinical data. Aim: to describe the clinical patterns of ALL relapse in children with the (1;19)(q23;p13) translocation and to analyze outcomes according to relapse site and disease course. Materials and methods. We conducted a retrospective descriptive analysis of seven pediatric ALL relapse cases harboring the (1;19)(q23;p13) translocation. We analyzed the clinical manifestations of relapses, the sequence of salvage therapy, and outcomes at last follow-up. For a more detailed analysis, two cases with opposite outcomes were selected: one with a durable second remission and another with a progressive, incurable disease. Results. At the time of analysis, sustained remission was achieved in only 1 out of 7 patients. In 3 cases, treatment options were exhausted and these patients were transitioned to a palliative level of care. At the time of manuscript preparation, 2 patients were undergoing hematopoietic stem cell transplantation, and 1 patient was receiving maintenance therapy. Conclusion. This case series highlights the need for individualized management of relapsed ALL in this genetic subgroup, including targeted and cell therapies, local control strategies, and updating risk stratification models.

Genetic engineering experiments and therapies are constrained by the size of DNA integrations into human cell's genomes. Existing AAV, lentiviral, and non-viral methods rapidly decrease in integration efficiency beyond ~5kb of sequence. Through systematic evaluation of non-viral DNA template formats, we identified circular ssDNA and dsDNA as capable of mediating >5kb integrations. Large circular DNA delivery efficiency and its impacts on cell viability and payload expression could be significantly improved with small DNA "helper" plasmids, mRNA-encoded nucleases, and sequence design optimizations. Collectively, these modifications enabled ultra-large-up to 10 kb DNA-integrations at >20% efficiency in primary human T cells at the TRAC locus and at >60% efficiency in human iPSCs at the AAVS1 locus. Finally, we demonstrate that GMP clinical-manufactured T cells with ultra-large integrations are functional in vitro and in vivo. Overall, we identified optimal template architectures, delivery modes, and sequence design rules for ultra-large DNA integrations in both research and clinical settings to accelerate basic genetic research and next-generation cellular therapies.

The liver's anatomic position and immune specialization make it both a major target and a major filter for systemically delivered therapeutics. Because portal venous inflow exposes the liver early to gut-derived molecules and exogenous compounds, many intravenously administered agents, including gene-based medicines and their viral and non-viral delivery systems, preferentially enter and accumulate in hepatic tissue. This review synthesizes how core liver physiology and immunobiology influence the performance, safety, and clinical translation of genomic medicines in hepatology, and outlines near-term practice and research shifts likely to define a genomics-driven future in liver disease care. We review the hepatic microarchitecture relevant to therapeutic trafficking, including sinusoidal transit, the space of Disse, hepatocyte uptake, and hepatobiliary elimination, and highlight the gatekeeping roles of liver sinusoidal endothelial cells and Kupffer cells in clearing particulate material and shaping inflammatory signaling. We then discuss how these same features create both opportunities, such as efficient hepatic targeting, and constraints, including innate immune activation, vector clearance, and variable intrahepatic distribution, for DNA- and RNA-based platforms. Finally, we propose five actionable developments poised to move genomics from a niche tool to a routine component of hepatology practice: earlier genomic testing in unexplained liver disease, multidisciplinary hepatology genome rounds, a centralized liver-specific gene resource, genetics-aware clinical trial design, and expansion of genetic therapies. Integrating liver biology with genomic medicine is essential to improve diagnostic yield, personalize therapy, and accelerate translation of gene-based treatments while mitigating immunologic and delivery-related barriers.

This review examines the function of N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac) glycans in cancer diagnosis and treatment, specifically in their interaction with biodegradable polymeric nanoparticles. Glycans play a central role in cellular communication, immune response, and adhesion, with structural changes usually indicative of precancerous conditions, thus making them key to diagnostic and therapeutic innovations. Neu5Gc, a dietary non-human sialic acid found in red meat and other foods, becomes a part of cell membranes, evoking immune reactions through anti-Neu5Gc antibodies that promote chronic inflammation, tumour formation, and metastasis. In contrast, Neu5Ac is compatible with human physiology and holds promise in antiviral and genetic disease therapies. This review explores the uses of biodegradable polymeric nanoparticles, including those from natural polymers such as chitosan and alginate, in Neu5Gc targeting for cancer diagnosis, immunotherapy, and drug delivery. It emphasizes their biocompatibility, controlled release, and improved targeting of Neu5Gc-containing tumour antigens. The review also addresses developments in electrochemical biosensors for Neu5Gc detection and computational glycan modeling, highlighting their potential in personalized oncology. By emphasizing biodegradable polymer-based approaches, this research highlights their promise as novel agents for cancer treatment, necessitating continued investigation into glycan-polymer interactions to further improve therapeutic outcomes.