Gene and Molecular Therapy

Gene and molecular therapy encompasses a suite of approaches that seek to correct or modulate cellular function by altering nucleic acids within living tissues. At its core, gene therapy introduces functional genetic material to compensate for defective genes or to endow cells with new capabilities, while molecular therapies often deploy short oligonucleotides, messenger RNAs or genome-editing enzymes to fine-tune gene expression. Viral vectors such as adeno-associated virus (AAV) and lentivirus exploit natural infection pathways to deliver therapeutic payloads, whereas non-viral carriers—including lipid nanoparticles, polymeric particles and exosomes—offer safer alternatives with reduced immunogenicity. Key strategies include gene replacement for monogenic disorders, gene silencing via RNA interference in dominant diseases or cancer, and precise editing of the genome using engineered nucleases (for example CRISPR–Cas9) to excise or repair pathogenic mutations. Advances in synthetic biology and delivery technologies have now enabled systemic administration, targeted local delivery and controlled transgene expression, opening the door to long-term cures for conditions previously deemed intractable.

Research from Nature Portfolio

Longitudinal studies in non-human primates have elucidated the fate of AAV vector genomes following high-dose hepatic administration. Initial robust expression is largely episomal but declines over three months, yielding a stable baseline driven in part by rare integrations across non-oncogenic loci. This two-phase model clarifies mechanisms of long-term transgene persistence and informs safety assessments for liver-directed gene therapy programmes. In parallel, the feasibility of bilateral gene therapy for inherited deafness was demonstrated in children with autosomal recessive DFNB9. A dual-serotype AAV carrying the OTOF gene was safely administered to both ears, restoring auditory brainstem response thresholds, speech perception and sound localisation by six months post-treatment without serious adverse events. These milestone studies underscore the maturing clinical readiness of AAV-based interventions for both systemic and sensory applications.

Gene and Molecular Therapy publication trend

The graph below shows the total number of articles in gene and molecular therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Transgene: A therapeutic gene introduced into a host cell to restore or confer a desired function.

Vector: A delivery vehicle, often viral or nanoparticle-based, engineered to transport nucleic acids into target cells.

Episomal: Refers to DNA that persists in the nucleus independently of chromosomal integration.

Insertional mutagenesis: A risk in integrating vector systems where insertion of foreign DNA disrupts host genes, potentially leading to oncogenesis.

Double-strand break (DSB): A bilateral cut in DNA introduced by genome-editing nucleases to trigger repair pathways for precise modification.

RNA interference (RNAi): A cellular mechanism in which small RNAs, such as siRNA or miRNA, guide sequence-specific mRNA degradation to silence gene expression.

Promoter: A DNA sequence upstream of a gene that regulates transcription initiation and can be engineered for tissue-specific or inducible expression.

Tropism: The intrinsic affinity of a viral or non-viral vector for particular cell types or tissues.

References

1. Gene Therapy.
2. Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration. Nature Biotechnology (2023).
3. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nature Medicine (2024).
4. Viral vector platforms within the gene therapy landscape. Signal Transduction and Targeted Therapy (2021).
5. Current Clinical Applications of In Vivo Gene Therapy with AAVs. Molecular Therapy (2020).
6. Human Immune Responses to Adeno-Associated Virus (AAV) Vectors. Frontiers in Immunology (2020).
7. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nature Communications (2018).