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Review
. 2025 Jan 14;17(1):104.
doi: 10.3390/pharmaceutics17010104.

Plasmid Gene Therapy for Monogenic Disorders: Challenges and Perspectives

Marco A Luís  1   2   3 , Marcelo A D Goes  1   2   3 , Fátima Milhano Santos  1   2   4 , Joana Mesquita  1   2 , Paulo Tavares-Ratado  1   5   6 , Cândida Teixeira Tomaz  1   2   3
Affiliations
Review

Plasmid Gene Therapy for Monogenic Disorders: Challenges and Perspectives

Marco A Luís et al. Pharmaceutics. .

Abstract

Monogenic disorders are a group of human diseases caused by mutations in single genes. While some disease-altering treatments offer relief and slow the progression of certain conditions, the majority of monogenic disorders still lack effective therapies. In recent years, gene therapy has appeared as a promising approach for addressing genetic disorders. However, despite advancements in gene manipulation tools and delivery systems, several challenges remain unresolved, including inefficient delivery, lack of sustained expression, immunogenicity, toxicity, capacity limitations, genomic integration risks, and limited tissue specificity. This review provides an overview of the plasmid-based gene therapy techniques and delivery methods currently employed for monogenic diseases, highlighting the challenges they face and exploring potential strategies to overcome these barriers.

Keywords: gene therapy; monogenic diseases; non-viral vector; pDNA.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
In vivo and ex vivo applications in gene therapy, with the three possible genetic manipulations (gene silencing, gene edition, and gene addition) used in both in vivo and ex vivo therapies.
Figure 2
Figure 2
Schematics of gene manipulation tools and delivery systems. Viral and non-viral gene delivery systems (abbreviations: SLNP—solid lipid nanoparticle; PLNP—polymeric lipid nanoparticle; INP—inorganic nanoparticle; ND—nanodiamond; GNR—gold nanorod; GND—gold nanodiamond).
See this image and copyright information in PMC

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