Gene and cell therapy of human genetic diseases: Recent advances and future directions

Abstract

Disruptions in normal development and the emergence of health conditions often result from the malfunction of vital genes in the human body. Decades of scientific research have focused on techniques to modify or substitute defective genes with healthy alternatives, marking a new era in disease treatment, prevention and cure. Recent strides in science and technology have reshaped our understanding of disorders, medication development and treatment recommendations, with human gene and cell therapy at the forefront of this transformative shift. Its primary objective is the modification of genes or adjustment of cell behaviour for therapeutic purposes. In this review, we focus on the latest advances in gene and cell therapy for treating human genetic diseases, with a particular emphasis on FDA and EMA-approved therapies and the evolving landscape of genome editing. We examine the current state of innovative gene editing technologies, particularly the CRISPR-Cas systems. As we explore the progress, ethical considerations and prospects of these innovations, we gain insight into their potential to revolutionize the treatment of genetic diseases, along with a discussion of the challenges associated with their regulatory pathways. This review traces the origins and evolution of these therapies, from conceptual ideas to practical clinical applications, marking a significant milestone in the field of medical science.

Keywords: CRISPR/Cas9; cell therapy; gene editing; gene therapy; viral vectors.

FIGURE 1

Ex vivo and in vivo somatic gene and cell therapy strategies. This figure illustrates two primary approaches to gene therapy: In vivo and ex vivo. In the in vivo gene therapy (left panel) strategy, a therapeutic gene is first inserted into a suitable vector either viral or non‐viral, most commonly employing Adeno‐associated viral (AAV) vectors. The vector, loaded with the therapeutic gene, is then introduced into the patient's body either via local injection or systemic infusion. The vector serves as a vehicle to deliver the therapeutic gene to the target cells within the patient's body. Ex vivo gene therapy (right panel) commences with the extraction of stem cells or other target cells from the patient's body. These isolated cells are then subjected to gene modification, often utilizing LVs. The therapeutic gene is introduced into the isolated cells outside the patient's body. After successful gene transfer, these modified cells are expanded and subsequently reintroduced into the patient. Representatives of commercially available gene therapy drugs are shown at the bottom.

FIGURE 2

Current status of gene and cell therapy (As provided by The Journal of Gene Medicine Clinical Trial Website). Medical indications targeted by gene therapy clinical trials (A). This chart showcases the distribution of medical indications that gene therapy clinical trials aim to address. Various conditions, such as monogenic disorders, cancer, cardiovascular diseases, neurodegenerative disorders and others, are being targeted for potential therapeutic interventions through gene therapy research and trials. Clinical phases in gene therapy clinical trials (B). This chart displays the segmentation of gene therapy clinical trials based on their respective clinical phases. The phases include Phase I, Phase I‐II, Phase II, Phase II‐III, Phase III, Phase IV, and single subject. Each phase represents a distinct stage of testing, ranging from early safety assessments to large‐scale efficacy studies and regulatory approval. Vectors employed in gene transfer for gene therapy clinical trials (C). This chart illustrates the distribution of vector types utilized for gene transfer in various gene therapy clinical trials. Different vector platforms, such as viral vectors (adenovirus, adeno‐associated virus, lentivirus, retrovirus) and non‐viral vectors (nanoparticles), have been employed to deliver therapeutic genes.

FIGURE 3

Types of viral vector platforms and their inherent traits employed for genetic transfer., The table lists diverse vector types (adenovirus, adeno‐associated virus, lentivirus, and retrovirus) utilized in clinical and preclinical investigations in terms of expression longevity, transduction ability, packaging capacity, and immunogenic response.

FIGURE 4

Genome editing molecules, DNA repair mechanisms, and altered genomic outcomes. Engineered nucleases allow deliberate induction of site‐specific double‐stranded DNA breaks within cellular genomes. Examples include ZFNs, TALENs and Cas9, known as sequence‐specific DNA cleaving tools for genome manipulation. In genome editing processes, natural repair pathways of cells are harnessed for the mending of double‐stranded DNA breaks. The non‐homologous end joining (NHEJ) pathway often yields indel mutations at the repaired DNA break site. The homology‐directed repair (HDR) pathway employs a nucleic acid template for precise repair. In the context of genome‐editing endeavours, investigators can provide a repair template with homologous regions flanking the DNA break, guiding the HDR pathway to generate specific sequence alterations or insertions at the desired genomic locus.