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Cells
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Gene Therapy for Rare Diseases
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Gene Therapy for Rare Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 52913

Special Issue Editor

Prof. Dr. Cord Brakebusch

E-Mail Website
Guest Editor
Biotech Research & Innovation Centre, The University of Copenhagen, Copenhagen, Denmark
Interests: Rho GTPases; keratinocytes; mouse disease models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Each rare disease is infrequent, but since more than 7000 rare diseases exist, more than 300 million patients are suffering from rare diseases worldwide, making them an important unmet health problem. Most rare diseases are caused by mutations. Therefore, gene therapy is the only curative treatment possibility for patients with rare diseases. Stimulated by the development of CRISPR gene editing and improved viral vector technologies, many trials are currently ongoing to correct the defective genes of patients with rare diseases and improve their quality of life. On the other hand, many challenges still need to be overcome to make gene therapy a standard treatment option in the clinic. These challenges include the efficient targeting of relevant stem cells, the effectiveness of precise genome editing, and patient safety. The recent development of prime editing and base editing has further contributed to the excitement in the field and to the hope that a cure for many rare diseases is possible in the near future. This Special Issue will accept reviews and original research articles in the field of gene editing and rare diseases.

Prof. Dr. Cord Brakebusch
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene therapy
  • gene editing
  • rare diseases
  • CRISPR
  • viral vectors
  • base editing
  • prime editing

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 154 KB  
Editorial
Editorial for Special Issue on Gene Therapy of Rare Diseases
by Cord Brakebusch
Cells 2026, 15(6), 504; https://doi.org/10.3390/cells15060504 - 12 Mar 2026
Viewed by 331
Abstract
A rare disease is a condition that affects only a small portion of the population [...] Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)

Research

Jump to: Editorial, Review

25 pages, 13962 KB  
Article
Durable Global Correction of CNS and PNS and Lifespan Rescue in Murine Globoid Cell Leukodystrophy via AAV9-Mediated Monotherapy
by Dar-Shong Lin, Che-Sheng Ho, Yu-Wen Huang, Tsung-Han Lee, Zo-Darr Huang, Tuan-Jen Wang, Wern-Cherng Cheng and Sung-Fu Huang
Cells 2025, 14(24), 1942; https://doi.org/10.3390/cells14241942 - 8 Dec 2025
Viewed by 810
Abstract
Globoid cell leukodystrophy (GLD) is a devastating lysosomal storage disorder caused by galactocerebrosidase (GALC) deficiency, leading to cytotoxic psychosine accumulation, broad neuroinflammation, dysfunction of autophagy and ubiquitin-proteasome system, progressive demyelination in both the central (CNS) and peripheral nervous systems (PNS), and premature death. [...] Read more.
Globoid cell leukodystrophy (GLD) is a devastating lysosomal storage disorder caused by galactocerebrosidase (GALC) deficiency, leading to cytotoxic psychosine accumulation, broad neuroinflammation, dysfunction of autophagy and ubiquitin-proteasome system, progressive demyelination in both the central (CNS) and peripheral nervous systems (PNS), and premature death. Curative treatments are lacking, highlighting the urgent need for transformative approaches. Existing therapies have failed to achieve durable metabolic correction across neural compartments or sustained functional recovery. Here, we demonstrate that a single intracranial administration of high-titer AAV9-GALC targeting the thalamus and deep cerebellar nuclei achieves unprecedented and lifelong therapeutic efficacy in the Twitcher mouse model of GLD. This region-specific monotherapy achieved broad neuronal and glial transduction throughout the CNS and PNS, resulting in sustained supraphysiological GALC activity and complete normalization of psychosine levels. Treated mice exhibited preserved proteostasis, axonal architecture, and myelin integrity, inhibition of neuroinflammation, alongside restored motor function. Remarkably, treated mice attain lifespans approaching wild-type levels, far surpassing all previously reported interventions in this model, indicating a durable, possibly lifelong therapeutic effect. By achieving durable and comprehensive metabolic and structural correction across neural systems without repeated dosing, multi-route delivery, combinational therapy, hematopoietic stem cell transplantation, or high-dose systemic delivery, this study establishes CNS-directed AAV9 monotherapy as a clinically translatable and potentially lifelong therapeutic paradigm for GLD. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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Review

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48 pages, 1764 KB  
Review
Engineering Liver-Specific Promoters: A Comprehensive Review of Design, Mechanisms, and Clinical Applications in Gene Therapy
by Valentin Artemyev, Anastasiia Iu. Paremskaia, Amina A. Dzhioeva, Daria Mishina, Viktor Bogdanov, Julia Krupinova, Ali Mazloum, Sofya G. Feoktistova, Olga N. Mityaeva and Pavel Yu. Volchkov
Cells 2026, 15(1), 14; https://doi.org/10.3390/cells15010014 - 22 Dec 2025
Cited by 1 | Viewed by 2460
Abstract
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies [...] Read more.
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler–Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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20 pages, 2498 KB  
Review
CRISPR/Cas-Based Ex Vivo Gene Therapy and Lysosomal Storage Disorders: A Perspective Beyond Cas9
by Andrés Felipe Leal, Luis Eduardo Prieto and Harry Pachajoa
Cells 2025, 14(15), 1147; https://doi.org/10.3390/cells14151147 - 25 Jul 2025
Viewed by 3389
Abstract
Lysosomal storage disorders (LSDs) are inherited metabolic conditions characterized by lysosomal enzyme deficiencies leading to substrate accumulation. As genetic diseases, LSDs can be treated with gene therapies (GT), including the CRISPR/Cas systems. The CRISPR/Cas systems enable precise and programmable genome editing, leading to [...] Read more.
Lysosomal storage disorders (LSDs) are inherited metabolic conditions characterized by lysosomal enzyme deficiencies leading to substrate accumulation. As genetic diseases, LSDs can be treated with gene therapies (GT), including the CRISPR/Cas systems. The CRISPR/Cas systems enable precise and programmable genome editing, leading to targeted modifications at specific genomic loci. While the classical CRISPR/Cas9 system has been extensively used to generate LSD disease models and correct disease-associated genetic alterations through homologous recombination (HR), recently described Cas proteins as well as CRISPR/Cas9-derived strategies such as base editing, prime editing, and homology-independent targeted integration (HITI) offer a novel way to develop innovative treatments for LSDs. The direct administration of the CRISPR/Cas9 system remains the primary strategy evaluated in several LSDs; nevertheless, the ex vivo CRISPR/Cas9-based approach has been recently explored, primarily in central nervous system-affecting LSDs. Ex vivo approaches involve genetically modifying, in theory, any patient cells in the laboratory and reintroducing them into the patient to provide a therapeutic effect. This manuscript reviews the molecular aspects of the CRISPR/Cas technology and its implementation in ex vivo strategies for LSDs while discussing novel approaches beyond the classical CRISPR/Cas9 system. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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43 pages, 7604 KB  
Review
Prime Editing: Mechanistic Insights and DNA Repair Modulation
by Astrid Mentani, Marcello Maresca and Anna Shiriaeva
Cells 2025, 14(4), 277; https://doi.org/10.3390/cells14040277 - 13 Feb 2025
Cited by 5 | Viewed by 11263
Abstract
Prime editing is a genome editing technique that allows precise modifications of cellular DNA without relying on donor DNA templates. Recently, several different prime editor proteins have been published in the literature, relying on single- or double-strand breaks. When prime editing occurs, the [...] Read more.
Prime editing is a genome editing technique that allows precise modifications of cellular DNA without relying on donor DNA templates. Recently, several different prime editor proteins have been published in the literature, relying on single- or double-strand breaks. When prime editing occurs, the DNA undergoes one of several DNA repair pathways, and these processes can be modulated with the use of inhibitors. Firstly, this review provides an overview of several DNA repair mechanisms and their modulation by known inhibitors. In addition, we summarize different published prime editors and provide a comprehensive overview of associated DNA repair mechanisms. Finally, we discuss the delivery and safety aspects of prime editing. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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Graphical abstract

25 pages, 1031 KB  
Review
Synthetic Promoters in Gene Therapy: Design Approaches, Features and Applications
by Valentin Artemyev, Anna Gubaeva, Anastasiia Iu. Paremskaia, Amina A. Dzhioeva, Andrei Deviatkin, Sofya G. Feoktistova, Olga Mityaeva and Pavel Yu. Volchkov
Cells 2024, 13(23), 1963; https://doi.org/10.3390/cells13231963 - 27 Nov 2024
Cited by 18 | Viewed by 12514
Abstract
Gene therapy is a promising approach to the treatment of various inherited diseases, but its development is complicated by a number of limitations of the natural promoters used. The currently used strong ubiquitous natural promoters do not allow for the specificity of expression, [...] Read more.
Gene therapy is a promising approach to the treatment of various inherited diseases, but its development is complicated by a number of limitations of the natural promoters used. The currently used strong ubiquitous natural promoters do not allow for the specificity of expression, while natural tissue-specific promoters have lowactivity. These limitations of natural promoters can be addressed by creating new synthetic promoters that achieve high levels of tissue-specific target gene expression. This review discusses recent advances in the development of synthetic promoters that provide a more precise regulation of gene expression. Approaches to the design of synthetic promoters are reviewed, including manual design and bioinformatic methods using machine learning. Examples of successful applications of synthetic promoters in the therapy of hereditary diseases and cancer are presented, as well as prospects for their clinical use. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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14 pages, 1580 KB  
Review
Regulation of Precise DNA Repair by Nuclear Actin Polymerization: A Chance for Improving Gene Therapy?
by Xiubin He and Cord Brakebusch
Cells 2024, 13(13), 1093; https://doi.org/10.3390/cells13131093 - 24 Jun 2024
Cited by 5 | Viewed by 3003
Abstract
Although more difficult to detect than in the cytoplasm, it is now clear that actin polymerization occurs in the nucleus and that it plays a role in the specific processes of the nucleus such as transcription, replication, and DNA repair. A number of [...] Read more.
Although more difficult to detect than in the cytoplasm, it is now clear that actin polymerization occurs in the nucleus and that it plays a role in the specific processes of the nucleus such as transcription, replication, and DNA repair. A number of studies suggest that nuclear actin polymerization is promoting precise DNA repair by homologous recombination, which could potentially be of help for precise genome editing and gene therapy. This review summarizes the findings and describes the challenges and chances in the field. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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Figure 1

15 pages, 667 KB  
Review
Advancements in Hematopoietic Stem Cell Gene Therapy: A Journey of Progress for Viral Transduction
by Aurora Giommetti and Eleni Papanikolaou
Cells 2024, 13(12), 1039; https://doi.org/10.3390/cells13121039 - 15 Jun 2024
Cited by 12 | Viewed by 9340
Abstract
Hematopoietic stem cell (HSC) transduction has undergone remarkable advancements in recent years, revolutionizing the landscape of gene therapy specifically for inherited hematologic disorders. The evolution of viral vector-based transduction technologies, including retroviral and lentiviral vectors, has significantly enhanced the efficiency and specificity of [...] Read more.
Hematopoietic stem cell (HSC) transduction has undergone remarkable advancements in recent years, revolutionizing the landscape of gene therapy specifically for inherited hematologic disorders. The evolution of viral vector-based transduction technologies, including retroviral and lentiviral vectors, has significantly enhanced the efficiency and specificity of gene delivery to HSCs. Additionally, the emergence of small molecules acting as transduction enhancers has addressed critical barriers in HSC transduction, unlocking new possibilities for therapeutic intervention. Furthermore, the advent of gene editing technologies, notably CRISPR-Cas9, has empowered precise genome modification in HSCs, paving the way for targeted gene correction. These striking progresses have led to the clinical approval of medicinal products based on engineered HSCs with impressive therapeutic benefits for patients. This review provides a comprehensive overview of the collective progress in HSC transduction via viral vectors for gene therapy with a specific focus on transduction enhancers, highlighting the latest key developments, challenges, and future directions towards personalized and curative treatments. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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16 pages, 2723 KB  
Review
Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy
by Matilde Vale, Jan Prochazka and Radislav Sedlacek
Cells 2024, 13(11), 920; https://doi.org/10.3390/cells13110920 - 27 May 2024
Cited by 5 | Viewed by 8331
Abstract
Diamond–Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow’s ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a [...] Read more.
Diamond–Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow’s ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a ribosomopathy, with RPS19 being the most frequently mutated gene. Non-RP mutations, such as in GATA1, have also been identified. Current treatments include glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation (HSCT), with HSCT being the only curative option, albeit with challenges like donor availability and immunological complications. Gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, emerges as a promising alternative. This review explores the potential of gene therapy, focusing on lentiviral vectors and CRISPR/Cas9 technology in combination with non-integrating lentiviral vectors, as a curative solution for DBA. It highlights the transformative advancements in the treatment landscape of DBA, offering hope for individuals affected by this condition. Full article
(This article belongs to the Special Issue Gene Therapy for Rare Diseases)
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