bims-curels Biomed News
on Leigh syndrome
Issue of 2024–11–24
fourteen papers selected by
Cure Mito Foundation
  1. Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia.
  2. Dual-localization signals enhance mitochondrial targeted presentation of engineered proteins.
  3. The rare reason for massive lactic aciduria and mitochondrial disorders: combined oxidative phosphorylation deficiency type 23 (COXPD23).
  4. Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial.
  5. Childhood Blindness: A Rare Case of Leber Hereditary Optic Neuropathy in a 16-Year-Old Egyptian Patient.
  6. Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
  7. VACCINE SAFETY IN CHILDREN WITH GENETICALLY CONFIRMED MITOCHONDRIAL DISEASE.
  8. WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: a case report.
  9. Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients.
  10. Medical Genetics for the Undiagnosed and Rare Patient: "Chasing Zebras".
  11. Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders.
  12. Difficult decisions and possible choices: Rare diseases, genetic inheritance and reproduction of the family.
  13. The Impact of Patient Access to Electronic Health Records on Health Care Engagement: Systematic Review.
  14. Advancements in Gene Therapy for Human Disease: Trend of Current Clinical Trials.
  1. BMC Genomics. 2024 Nov 22. 25(1): 1133
    Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia.
    Latifa Chkioua, Yessine Amri, Chayma Sahli, Tawfik Nasri, Mohamed Omar Miladi, Taieb Massoud, Sandrine Laradi, Mohamed Ghorbel, Hassen Ben Abdennebi.
       BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) rare disease due to the pathogenic variant of the NADH dehydrogenase enzyme. LHON is characterized by a sudden central vision loss due to focal degeneration of the retinal ganglion cell layer and optic nerve. Symptoms usually appear between the age of 18 and 35 years. Some individuals present the mtDNA mutations but not presented the LHON clinical features. The heteroplasmic or homoplasmic character of the mutations among patients explains why they develop the disease or not even though they carry the pathogenic variant.
    METHODS: This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital, Sousse, Tunisia. Screening for the common mutations in Mt-ND1 gene (m.3460G > A), Mt-ND4 gene (m.11778G > A) and Mt-ND6 gene (m.14484T > C) was performed in five Tunisian families by standard RFLP PCR, followed by direct sequencing of the entire of these genes. Indeed, bioinformatics tools were used to predict the potential functional impact of the identified mutations on the Human mitochondrial respiratory complex I protein.
    RESULTS: one novel p.L601M (m.1413 C > A) and four previously reported mutations were identified in this study including: rs199476112G > A (m.11778G > A); rs202227543G > A (m.14258G > A); rs1603224763 (m.14510 dup) and NC_012920.1: m.3244G > C. In this present report, only one patient was found carrying the primary point mutation (m. 11778G > A). The ophthalmologic findings showing major fundus changes included hyperemic optic discs; disc pseudo-oedema and microangiopathy leading to optic disc atrophy. The analyses of the stability of protein upon identified mutations using DynaMut tool server demonstrated that these variations induce a rigidification in the region where they are located.
    CONCLUSION: This is the first Tunisian report of mtDNA mutations identified in Tunisia causing the LHON. The main factors involved in the pathophysiological mechanisms of this disease are genetic, epigenetic, hormonal and environmental influences.
    Keywords:  Leber hereditary optic neuropathy; Mitochondrial DNA; Mutations; Pathophysiological mechanisms
    DOI:  https://doi.org/10.1186/s12864-024-11060-0
  2. Yi Chuan. 2024 Nov;46(11): 937-946
    Dual-localization signals enhance mitochondrial targeted presentation of engineered proteins.
    Bing-Qian Zhou, Shang-Pu Li, Xu Wang, Xiang-Yu Meng, Jing-Rong Deng, Jin-Liang Xing, Jian-Gang Wang, Kun Xu.
      Effective delivery of engineered proteins into mitochondria is of great significance for developing efficient mitochondrial DNA editing tools and realizing accurate treatment of mitochondrial diseases. Here, the candidate genes, eGFP and Cas9, were engineered with different mitochondrial localization signal (MLS) sequences introduced at their up- or/and down-streams. The corresponding expression vectors for the engineered proteins were constructed respectively, and HEK293T cells were transfected with these vectors. The fluorescence colocalization and Western blotting assays were used to analyze the mitochondrial targeting presentation effect of different engineered proteins. The results demonstrated that the daul-MLS modification of the eGFP and Cas9 proteins significantly improved the efficiency of mitochondrial targeted presentation, compared with the engineered proteins with single MLS added. Hence, it is speculated that dual MLS strategy can enhance the mitochondrial targeting of engineered proteins, which lays a theoretical foundation for the future development of efficient mitochondrial DNA editing tools.
    Keywords:  mitochondrial diseases; mitochondrial localization signal; mitochondrial targeting; mtDNA editing; protein engineering
    DOI:  https://doi.org/10.16288/j.yczz.24-171
  3. Z Geburtshilfe Neonatol. 2024 Nov 22.
    The rare reason for massive lactic aciduria and mitochondrial disorders: combined oxidative phosphorylation deficiency type 23 (COXPD23).
    Halil Tuna Akar, Hasan Akduman, Abdülkerim Kolkıran, Elifcan Taşadelen, Nur Aycan.
      Mitochondrial respiratory chain dysfunction and impaired oxidative phosphorylation are rare but significant causes of mitochondrial diseases in children, presenting with diverse clinical features. Combined oxidative phosphorylation deficiency type 23 (COXPD23), an autosomal recessive disorder due to GTPBP3 gene mutations, typically manifests as lactic acidosis, hypertrophic cardiomyopathy, and encephalopathy. This case report describes a male infant born at 35 weeks gestation, who exhibited severe lactic aciduria and hypotonia but no cardiomyopathy, which is atypical for COXPD23. Genetic analysis revealed a novel homozygous missense variant in the GTPBP3 gene. Despite intensive metabolic and supportive treatments, the patient's condition worsened, leading to death on the 23rd day. This case emphasizes the need to consider mitochondrial cytopathies in neonates with persistent metabolic acidosis and hyperlactatemia and highlights the importance of early genetic screening for accurate diagnosis and management.
    DOI:  https://doi.org/10.1055/a-2465-3661
  4. Orphanet J Rare Dis. 2024 Nov 21. 19(1): 431
    Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial.
    MMPOWER-3 Trial Investigators
       BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those subjects who responded to treatment, to build a more precise Phase 3 trial design for further investigation in likely responders.
    RESULTS: Subjects with mtDNA pathogenic variants or single large-scale mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants. Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant, in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome variants showed a significant change in the elamipretide group subjects who had chronic progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus - 8.0 ± 10.7 m for the placebo group; p = 0.0024). Pharmacokinetic (exposure-response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement.
    CONCLUSIONS: Post hoc analyses indicated that elamipretide had a beneficial effect in PMM patients with mtDNA replisome disorders, underscoring the importance of considering specific genetic subtypes in PMM clinical trials. These data serve as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been designed as described in this paper to determine the efficacy of elamipretide in patients with mtDNA maintenance-related disorders.
    CLASSIFICATION OF EVIDENCE: Class I CLINICALTRIALS.
    GOV IDENTIFIER: NCT03323749.
    Keywords:  Elamipretide; Mitochondria; MtDNA maintenance; MtDNA multiple deletions; PMM; Replisome
    DOI:  https://doi.org/10.1186/s13023-024-03421-5
  5. Cureus. 2024 Oct;16(10): e71619
    Childhood Blindness: A Rare Case of Leber Hereditary Optic Neuropathy in a 16-Year-Old Egyptian Patient.
    Abdulla I Abuhamaid, Ghufran S Alsaffar, Zainab H Madan, Yahya Wahba.
      Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial genetic disorder that is rarely encountered in daily clinical practice. It presents by an acute or subacute onset and a progressive course of painless, bilateral, sequential severe loss of vision, mostly seen in young males. Mutations in the mitochondrial DNA in these patients lead to dysfunction at complex I of the respiratory chain, causing a selective degeneration of the retinal ganglion cells and predisposition toward the development of the clinical symptoms. LHON can mimic other ophthalmological disorders, making it a commonly misdiagnosed and mismanaged disease. Management of LHON remains mainly supportive, as a definitive cure for this condition is yet to be developed. In this case report we describe the disease progression encountered in a 16-year-old Egyptian male patient diagnosed with LHON, highlight the difficulties encountered in diagnosing and managing this case, and review the literature on LHON.
    Keywords:  childhood blindness; incomplete penetrance; leber hereditary optic neuropathy; lhon; maternal inheritance; mitochondrial dna mutation; mtdna
    DOI:  https://doi.org/10.7759/cureus.71619
  6. EMBO Mol Med. 2024 Nov 20.
    Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
    Lindsey Van Haute, Petra Páleníková, Jia Xin Tang, Pavel A Nash, Mariella T Simon, Angela Pyle, Monika Oláhová, Christopher A Powell, Pedro Rebelo-Guiomar, Alexander Stover, Michael Champion, Charulata Deshpande, Emma L Baple, Karen L Stals, Sian Ellard, Olivia Anselem, Clémence Molac, Giulia Petrilli, Laurence Loeuillet, Sarah Grotto, Tania Attie-Bitach, Jose E Abdenur, Robert W Taylor, Michal Minczuk.
      Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.
    Keywords:  Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA
    DOI:  https://doi.org/10.1038/s44321-024-00172-5
  7. Immunol Lett. 2024 Nov 16. pii: S0165-2478(24)00120-2. [Epub ahead of print] 106946
    VACCINE SAFETY IN CHILDREN WITH GENETICALLY CONFIRMED MITOCHONDRIAL DISEASE.
    Annemarie de Vreugd, Franz A Zimmermann, Katja Steinbrücker, Maaike C de Vries, Lonneke de Boer, Mirian Ch Janssen, Martina Huemer, Saskia B Wortmann.
      We here explore adverse events following immunization (AEFI) in children with mitochondrial disease (MD) recruited from two expertise centers in Austria (SALK) and The Netherlands (RUMC). Parents completed a questionnaire on the type of immunizations received and AEFI in a post-vaccination exposure period of seven days. 95 individuals were invited to this study, of whom 30 (median age 13.4 years) participated. Together these individuals had received 376 immunizations with a median of 12 vaccinations each. In 316 of 376 (84%) vaccinations no AEFI occurred, 22 patients (73%) never experienced any AEFI. Eight patients experienced 76 AEFI after 60 vaccinations, these were mild (redness (n=9) /pain at injection site (n=21), fever (n=44), gastrointestinal complaints (n= 2)). None had a metabolic deterioration or seizures, no patient was admitted to the hospital. Although our data is limited by the small sample size, this may aid in discussing responsible immunization decisions with parents.
    Keywords:  adverse effect; adverse events following immunization (AEFI); epilepsy; immunization; metabolic deterioration; seizure; side effect; vaccination
    DOI:  https://doi.org/10.1016/j.imlet.2024.106946
  8. Eur J Hum Genet. 2024 Nov 22.
    WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: a case report.
    Giulia Ferrera, Kevork Derderian, Rossella Izzo, Barbara Gnutti, Andrea Legati, Giovanna Zorzi, Eleonora Lamantea, Arcangela Iuso, Anna Ardissone.
      Pathogenic WDR45 variants cause neurodevelopmental disorders (NDDs) including β-propeller protein-associated neurodegeneration (BPAN), characterized by developmental delay (DD), ataxia and extrapyramidal signs. Our patient, initially presenting at 22 months with DD, now, aged 7, shows intellectual disability, ataxia and rigidity. MRI findings were suggestive of Leigh syndrome, a mitochondrial disorder (MD) phenotype, with no brain iron accumulation. Reduced activity of respiratory chain complex I (cI) and complex II (cII) was identified in muscle and fibroblasts, and a cII reduction in muscle only; however, a primary MD was excluded. Exome sequencing revealed a de novo pathogenic WDR45 variant. Autophagic flux analysis showed a mildly reduced p62 response, with normal autophagy progression. This is the first report linking WDR45 to cI assembly and activity, indicating mitochondrial dysfunction as a potential pathophysiological BPAN mechanism. We recommend considering WDR45-related NDDs when diagnosing early-onset NDDs, particularly Leigh-like encephalopathies with cI deficiency, even without brain iron accumulation.
    DOI:  https://doi.org/10.1038/s41431-024-01745-1
  9. Iran J Allergy Asthma Immunol. 2024 Jul 27. 23(4): 374-392
    Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients.
    Milad Shokuhi Nia, Dormohammad Kordi Tamandani, Mohammad Kazem Momeni, Zakaria Bameri.
      Mitochondrial missense mutations and pathogenic variants have been implicated in the pathogenesis of COVID-19. This study evaluated the role of mitochondrial DNA (mtDNA) mutations and changes in gene expression in the progression of COVID-19 and their correlation with clinical characteristics. Next-generation sequencing with high throughput was used to identify mtDNA mutations in 30 COVID-19 patients compared to 20 healthy controls. The potential impact of identified mutations on protein structure and stability was predicted using bioinformatic tools. Quantitative real-time polymerase chain reaction was employed to assess the expression levels of mtDNA-encoded genes involved in oxidative phosphorylation in COVID-19 patients and healthy controls. Correlations between gene expression levels, clinical parameters, including leukocyte, lymphocyte, neutrophil, and platelet count, as well as creatinine, alanine transaminase (ALT), aspartate transaminase (AST), and blood urea nitrogen (BUN) levels, and disease severity were analyzed. We found 8 different mtDNA mutations in ND1, ND5, CO3, ATP6, and CYB genes, which were predicted to alter amino acids and decrease protein stability. Two missense unique mutations, C9555T in CO3 and A12418T in ND5 were identified and correlated with Complexes I and IV, respectively. This downregulation was correlated with age, elevated levels of leukocytes, lymphocytes, neutrophils, platelets, creatinine, ALT, AST, and BUN, as well as disease severity. These findings suggest that mtDNA mutations and altered expression of oxidative phosphorylation genes contribute to mitochondrial dysfunction in COVID-19. Targeting mitochondrial dysfunction may represent a promising therapeutic strategy for COVID-19 treatment.
    Keywords:  COVID-19; Mitochondria; Mitochondrial DNA; Mutation; Oxidative stress
    DOI:  https://doi.org/10.18502/ijaai.v23i4.16212
  10. Mo Med. 2024 Jul-Aug;121(4):121(4): 284-288
    Medical Genetics for the Undiagnosed and Rare Patient: "Chasing Zebras".
    Kathleen Sisco, Michelle Oliva.
      The world of genetic testing continues to evolve as new technologies provide insight into previously unchartered territories. Access to genetic testing, especially for complex medical patients, could potentially improve the lives of thousands of individuals with undiagnosed conditions. Barriers to testing include financial and physical limitations, along with the emotional and social fortitude that is at times needed for vulnerable populations to agree to testing and participation in research. As healthcare providers, it is imperative that we adopt a wholistic approach to care so that we can arm our patients with the necessary resources to navigate their medical journey.
  11. NPJ Digit Med. 2024 Nov 21. 7(1): 333
    Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders.
    Fangyi Chen, Priyanka Ahimaz, Quan M Nguyen, Rachel Lewis, Wendy K Chung, Casey N Ta, Katherine M Szigety, Sarah E Sheppard, Ian M Campbell, Kai Wang, Chunhua Weng, Cong Liu.
      Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease. Recognizing the difficulty in navigating these options, we developed a machine learning model trained on 1005 patient records from Columbia University Irving Medical Center to recommend appropriate genetic tests based on the phenotype information. The model achieved a remarkable performance with an AUROC of 0.823 and AUPRC of 0.918, aligning closely with decisions made by genetic specialists, and demonstrated strong generalizability (AUROC:0.77, AUPRC: 0.816) in an external cohort, indicating its potential value for general pediatricians to expedite rare disease diagnosis by enhancing genetic test ordering.
    DOI:  https://doi.org/10.1038/s41746-024-01331-1
  12. Soc Sci Med. 2024 Nov 18. pii: S0277-9536(24)00834-7. [Epub ahead of print]363 117380
    Difficult decisions and possible choices: Rare diseases, genetic inheritance and reproduction of the family.
    Waleska Aureliano.
      This article sets out to explore the dilemmas present in the reproductive practices of people affected by rare hereditary diseases, focusing on the use of diagnostic tests and the practice of genetic counselling in Brazil. The development of technologies capable of mapping 'genetic flaws' prior to conception or in prenatal consultations has led researchers to consider how these technologies may be shaping contemporary subjectivities related to kinship and guiding reproductive decisions based on knowledge of our 'genetic heritage.' Genetic counselling has emerged in this setting as a modality of health knowledge and information capable of assisting people, especially women, in their reproductive choices. In Brazil, access to these technologies and their use has proven to be unequal and heterogeneous. I argue that the idea of 'choice' that permeates genetic counselling needs to be problematized by considering the social, cultural, economic, affective and moral frameworks in which women are inserted and that inform and/or determine their reproductive decisions. Based on this premise, I analyse how families 'at risk' of rare hereditary diseases deal with the idea of 'genetic inheritance' in relation to the 'wish to have children', and the impasses surrounding the idea of 'informed choice' when we evaluate this rhetoric in the context of the shortfalls in access to healthcare and the limits to reproductive justice in Brazil.
    DOI:  https://doi.org/10.1016/j.socscimed.2024.117380
  13. J Med Internet Res. 2024 Nov 20. 26 e56473
    The Impact of Patient Access to Electronic Health Records on Health Care Engagement: Systematic Review.
    Dalia Alomar, Maryam Almashmoum, Iliada Eleftheriou, Pauline Whelan, John Ainsworth.
       BACKGROUND: Health information technologies, including electronic health records (EHRs), have revolutionized health care delivery. These technologies promise to enhance the efficiency and quality of care through improved patient health information management. Despite the transformative potential of EHRs, the extent to which patient access contributes to increased engagement with health care services within different clinical setting remains a distinct and underexplored facet.
    OBJECTIVE: This systematic review aims to investigate the impact of patient access to EHRs on health care engagement. Specifically, we seek to determine whether providing patients with access to their EHRs contributes to improved engagement with health care services.
    METHODS: A comprehensive systematic review search was conducted across various international databases, including Ovid MEDLINE, Embase, PsycINFO, and CINAHL, to identify relevant studies published from January 1, 2010, to November 15, 2023. The search on these databases was conducted using a combination of keywords and Medical Subject Heading terms related to patient access to electronic health records, patient engagement, and health care services. Studies were included if they assessed the impact of patient access to EHRs on health care engagement and provided evidence (quantitative or qualitative) for that. The guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 statement were followed for study selection, data extraction, and quality assessment. The included studies were assessed for quality using the Mixed Methods Appraisal Tool, and the results were reported using a narrative synthesis.
    RESULTS: The initial search from the databases yielded 1737 studies, to which, after scanning their reference lists, we added 10 studies. Of these 1747 studies, 18 (1.03%) met the inclusion criteria for the final review. The synthesized evidence from these studies revealed a positive relationship between patient access to EHRs and health care engagement, addressing 6 categories of health care engagement dimensions and outcomes, including treatment adherence and self-management, patient involvement and empowerment, health care communication and relationship, patient satisfaction and health outcomes, use of health care resources, and usability concerns and barriers.
    CONCLUSIONS: The findings suggested a positive association between patient access to EHRs and health care engagement. The implications of these findings for health care providers, policy makers, and patients should be considered, highlighting the potential benefits and challenges associated with implementing and promoting patient access to EHRs. Further research directions have been proposed to deepen our understanding of this dynamic relationship.
    Keywords:  electronic health records; empowerment; health care engagement; health care services; patient experience; patient satisfaction; personal health record; systematic review
    DOI:  https://doi.org/10.2196/56473
  14. Eur J Pharmacol. 2024 Nov 18. pii: S0014-2999(24)00833-1. [Epub ahead of print] 177143
    Advancements in Gene Therapy for Human Disease: Trend of Current Clinical Trials.
    Mahda Delshad, Zeinab Davoodi-Moghaddam, Melika Khademi, Atieh Pourbagheri-Sigaroodi, Mohammad Reza Zali, Davood Bashash.
      In an era of rapid scientific advancement, gene therapy has emerged as a groundbreaking approach with the potential to revolutionize the treatment of a myriad of diseases and medical conditions. The trend of current clinical trials suggests that there is growing interest and investment in exploring gene therapy as a viable treatment option. In 2023, a significant milestone was achieved with the approval of seven gene therapies by the Food and Drug Administration (FDA). Projections indicate that between 10 and 20 gene therapies could receive annual FDA approval by 2025. In this review, we conducted a comprehensive analysis of registered clinical trials on Clinicaltrials.gov to determine the progression status of gene therapies. Upon extraction of the data, we conducted a comprehensive analysis of the 2809 included studies. This involved a systematic approach, commencing with an overview, followed by a detailed examination of gene therapy strategies employed in various malignant and non-malignant disorders. Additionally, the study will cover the types of vectors utilized in current trials. Lastly, a meticulous review of 105 phase III-IV clinical trials was conducted to identify potential therapies demonstrating promise. We trust that the comprehensive overview provided will serve as a solid foundation for forthcoming research and study designs, ultimately contributing to the progression of gene therapy and its practical application within healthcare settings. Also, we anticipate that such inquiries will bolster the formulation of practical policies and guidelines for pharmaceutical companies engaged in gene therapy research and development.
    Keywords:  CRISPR-Cas; gene editing; gene therapy; genetic disorders; vectors
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177143
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