Advances in Gene Therapy of Human Diseases

Topic Information

Dear colleagues,

Gene therapy has made remarkable progress in recent years, offering promising treatment options for a wide range of diseases. Innovative therapeutic developments have shown highly encouraging results in treating many conditions, including inherited disorders, neurological diseases, certain types of cancer, cardiovascular diseases, autoimmune disorders, and rare genetic conditions. Novel therapeutic interventions including gene editing, gene addition, and RNA-based therapies have opened up new avenues for more effective, targeted treatments, bringing hope to patients with previously untreatable conditions.

In this Special Issue, we aim to cover the latest advancements in therapeutic strategies for a wide range of human diseases through original research articles and expert reviews. We will highlight approaches involving gene replacement, genome modification, nucleic acid-based therapies such as antisense oligonucleotides and miRNAs, RNA interference, and innovative delivery systems like viral vectors and nanoparticles.

Prof. Dr. Leonidas A. Phylactou
Dr. Andrie Koutsoulidou
Prof. Dr. Nicola Borbone
Dr. Monica Terracciano
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	4.5	7.8	2013	18.2 Days	CHF 2600	Submit
BioTech biotech	3.6	5.6	2012	20.7 Days	CHF 1800	Submit
Cells cells	6.0	11.4	2012	14.9 Days	CHF 2700	Submit
Current Issues in Molecular Biology cimb	4.1	5.0	1999	15.5 Days	CHF 2400	Submit
Genes genes	3.1	5.9	2010	13.3 Days	CHF 2600	Submit
International Journal of Molecular Sciences ijms	5.6	10.0	2000	17.5 Days	CHF 2900	Submit

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Published Papers (5 papers)

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All Biomedicines BioTech Genes IJMS CIMB Cells

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37 pages, 3375 KB  

Open AccessReview

Unveiling the Mysteries of CLEC3B: Physiological Roles, Pathological Impacts, and Research Gaps

by Le Li and Liang Guo

Cells 2026, 15(13), 1160; https://doi.org/10.3390/cells15131160 - 25 Jun 2026

Viewed by 225

Abstract

CLEC3B (C-type lectin domain family 3 member B), also known as tetranectin (TN), is a secreted trimeric protein containing a C-type lectin-like domain (CTLD). Located on chromosome 3p21.31. CLEC3B maintains organismal homeostasis through roles in immune regulation, angiogenesis, and musculoskeletal biology. Genetic studies [...] Read more.

CLEC3B (C-type lectin domain family 3 member B), also known as tetranectin (TN), is a secreted trimeric protein containing a C-type lectin-like domain (CTLD). Located on chromosome 3p21.31. CLEC3B maintains organismal homeostasis through roles in immune regulation, angiogenesis, and musculoskeletal biology. Genetic studies demonstrate that CLEC3B deficiency impairs tissue repair, bone mineralization, and fibrinolytic balance. Altered CLEC3B expression is linked to cardiovascular disease progression, autoimmune susceptibility, and cancer prognosis. This review synthesizes CLEC3B’s biological functions and evaluates its translational potential: circulating CLEC3B as a prognostic and diagnostic biomarker; tissue-resident CLEC3B as a predictive marker for therapeutic response; and CLEC3B-related pathways as candidate therapeutic targets for potential amenable to replacement or inhibition strategies. We identify critical research gaps to guide future investigations, including limited structural data, ambiguous glycan specificity, incomplete proteolytic network mapping, and lack of validated disease models. Collectively, these gaps currently preclude definitive therapeutic claims. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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11 pages, 1970 KB  

Open AccessArticle

Oligonucleotide Synthesis Errors Are a Source of Untoward Variation in HDR-Mediated Gene Editing

by Stacia K. Wyman, Zulema Romero, Seok-Jin Heo, Marian Navarrete, Netravathi Krishnappa, Donald B. Kohn, David I. K. Martin, Mark C. Walters and Dario Boffelli

Genes 2026, 17(7), 729; https://doi.org/10.3390/genes17070729 - 24 Jun 2026

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Abstract

Background/Objectives: Single-stranded oligonucleotides (ssODNs) are used as donor templates for therapeutic gene editing by CRISPR-Cas9 cleavage and homology-directed repair (HDR). Although ssODN sequence fidelity is critical to the safety and efficacy of editing, standard quality control methods cannot resolve individual nucleotide errors. Methods: [...] Read more.

Background/Objectives: Single-stranded oligonucleotides (ssODNs) are used as donor templates for therapeutic gene editing by CRISPR-Cas9 cleavage and homology-directed repair (HDR). Although ssODN sequence fidelity is critical to the safety and efficacy of editing, standard quality control methods cannot resolve individual nucleotide errors. Methods: We performed deep sequencing of ssODNs from three manufacturers and amplicons from edited hematopoietic stem/progenitor cells. Results: We find that synthesis errors are present in all ssODNs tested at rates that vary more than two-fold among manufacturers, at positions that are dependent on sequence context. These synthesis errors are propagated into the genome by HDR at frequencies proportional to their abundance in the ssODN. In our sickle cell mutation correction protocol, the most prevalent SNEs are predicted to produce benign β-globin variants, while the less frequent frameshift deletions are predicted to generate β-thalassemia-like alleles. Conclusions: Current quality control standards are insufficient to detect these errors, and deep sequencing of ssODNs should be incorporated into regulatory submissions for clinical gene editing programs. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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13 pages, 5839 KB  

Open AccessArticle

Systemic AAV-hGCDH Gene Therapy Alleviates Glutaric Acid Accumulation and Attenuates Chronic Brain Vacuolation in a Novel Mouse Model of Glutaric Aciduria Type I

by Su Jin Kim, Yu Hwa Nam, Eun Young Joo, Jisun Park, Saeyoung Park, Sung-Chul Jung and Dong-Kyu Jin

Int. J. Mol. Sci. 2026, 27(12), 5569; https://doi.org/10.3390/ijms27125569 - 20 Jun 2026

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Abstract

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, [...] Read more.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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21 pages, 1368 KB  

Open AccessReview

Enhancement of Therapeutic mRNA Translation in Cellular Stress Conditions

by Edyta Trepkowska-Mejer

Int. J. Mol. Sci. 2026, 27(11), 4663; https://doi.org/10.3390/ijms27114663 - 22 May 2026

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Abstract

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of [...] Read more.

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including “mRNA therapeutics,” “cellular stress,” “translation regulation,” “UTR engineering,” and “cap-independent translation.” Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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16 pages, 3084 KB  

Open AccessArticle

Precise CRISPR-Mediated Editing of the TGFBI R555W Mutation in Patient-Derived Peripheral Blood Mononuclear Cells

by Burak Dagdelen, Hilal Arikoglu, Dudu Erkoc-Kaya and Banu Bozkurt

Int. J. Mol. Sci. 2026, 27(5), 2418; https://doi.org/10.3390/ijms27052418 - 6 Mar 2026

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Abstract

Over 70 mutations in the transforming growth factor beta-induced (TGFBI) gene are associated with corneal dystrophies that impair vision. The R555W hotspot mutation is a major cause of granular corneal dystrophy type 1 (GCD1). Here, we evaluated the technical feasibility of [...] Read more.

Over 70 mutations in the transforming growth factor beta-induced (TGFBI) gene are associated with corneal dystrophies that impair vision. The R555W hotspot mutation is a major cause of granular corneal dystrophy type 1 (GCD1). Here, we evaluated the technical feasibility of CRISPR/Cas9-mediated editing of the R555W mutation in peripheral blood mononuclear cells (PBMCs) obtained from a patient with GCD1. Three single guide RNAs (sgRNA1–3) and matched single-stranded oligodeoxynucleotide donors (ssODN1–3) were designed and co-transfected into PBMCs. Transfected cells were enriched by flow cytometric sorting, with GFP-positive cells representing approximately 2–4% of the total electroporated population. Editing outcomes were initially screened using high-resolution melting (HRM) analysis, and the sgRNA3–ssODN3 combination identified as the most promising candidate was subsequently validated by next-generation sequencing (NGS). Sequencing revealed a homology-directed repair efficiency of 98.2% among GFP-positive sorted cells, demonstrating efficient and precise genome editing within the enriched population. Because PBMCs are not disease-relevant corneal epithelial cells and only genomic endpoints were assessed, the clinical applicability of this study is limited and the work should be considered a technical proof-of-concept. This framework supports optimization of CRISPR-based strategies prior to studies in biologically relevant corneal models. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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