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Nature Communications2020ReviewNon-viral Gene Delivery

The once and future gene therapy

Karen Bulaklak And Charles A. GersbachDOI 10.1038/s41467-020-19505-2

Summary

Gene therapy is at an inflection point: recent approvals and clinical successes have validated the field, but broader application is still limited by immune responses to vectors, inefficient delivery outside the retina and liver, and regulatory frameworks that are poorly suited to personalized, potentially curative therapies. The comment summarizes recent advances and expectations for the near future. Approved therapies: Spinraza (2016), Exondys 51 (2016), Vyondys 53 (2019), Kymriah (2017), Yescarta (2017), Tescartus, Luxturna (2017), Zolgensma (2019). - First CRISPR disease-modifying efficacy: CTX001 for sickle cell.

Keywords

CRISPRNanoparticlesGene editingsiRNAViral vectorsT cellsLipid nanoparticle
Purpose: Gene therapy is at an inflection point: recent approvals and clinical successes have validated the field, but broader application is still limited by immune responses to vectors, inefficient delivery outside the retina and liver, and regulatory frameworks that are poorly suited to personalized, potentially curative therapies. The comment summarizes recent advances and expectations for the near future.
Hypothesis: As a Comment article, this work does not test a single hypothesis. Its central thesis is:

If recent successes in gene therapy are leveraged alongside next-generation technologies—engineered AAV capsids, non-viral nanoparticles, gene editing, base/prime editing, and epigenome editing—then gene therapy will expand from rare monogenic diseases to common diseases and personalized medicines, provided that immune barriers, delivery challenges, and regulatory obstacles are addressed.

Aims: Primary Aim: To summarize recent advances and near-future expectations for gene and cell therapy. - Secondary Aims: - To highlight approved therapies and clinical milestones that validate the field. - To discuss next-generation technologies, including gene editing, base editing, prime editing, and epigenome editing. - To identify key barriers: immune response to vectors, delivery outside retina/liver, and regulatory challenges for personalized therapies. - To emphasize the role of functional genomics and non-coding genome annotation in expanding therapeutic targets.
Delivery system:

Component: Viral vectors; Examples Discussed: AAV (in vivo gene transfer to retina, CNS, liver, skeletal muscle); lentiviral and retroviral vectors (ex vivo T cell and HSC modification)

Component: Non-viral vectors; Examples Discussed: Lipid nanoparticles, polymeric nanoparticles; nanoparticle-delivered siRNA (Onpattro); non-viral CRISPR delivery to liver (NTLA-2001)

Component: Payloads; Examples Discussed: Transgenes, oligonucleotides (Spinraza, Exondys 51, Vyondys 53), siRNA, CRISPR-Cas components, base editors, prime editors, epigenetic editors

Component: Ex vivo cell engineering; Examples Discussed: CAR-T cells (Kymriah, Yescarta, Tescartus), hematopoietic stem cells (sickle cell disease, beta thalassemia), iPSCs, NK cells, universal allogeneic cells

Component: In vivo targets; Examples Discussed: Retina (Luxturna, EDIT-101), CNS (Zolgensma), liver (hemophilia, ATTR amyloidosis, NTLA-2001), skeletal muscle (Duchenne muscular dystrophy)

Component: Gene editing systems; Examples Discussed: CRISPR-Cas nucleases, TALENs, ZFNs, base editors, prime editors, RNA-targeted editors, epigenome editors

Approach: This is a narrative Comment / Perspective synthesizing clinical and preclinical literature. No primary experimental data are presented. The article:
  • Reviews approved gene and cell therapies and their clinical indications.
  • Discusses ongoing and imminent clinical trials (CTX001, EDIT-101, NTLA-2001).
  • Highlights technological advances in vector engineering, nanoparticle delivery, and gene editing.
  • Identifies barriers and proposes future directions.
  • Includes two schematic figures: a timeline of gene therapy milestones and a diagram of ex vivo vs. in vivo strategies.
Key methods: As a Comment, there are no primary methods. The article synthesizes:
  • Clinical trial results for approved therapies and investigational candidates.
  • Regulatory milestones (FDA and EU approvals).
  • Technological developments in AAV engineering, nanoparticle delivery, and CRISPR-based editing.
  • Genomic and functional genomics data (ENCODE Consortium, unknown gene function).
  • Immune evasion strategies (modified AAV capsids, antibody-cleaving endopeptidases, immunosuppression, tolerogenic nanoparticles).
Key results: Approved therapies: Spinraza (2016), Exondys 51 (2016), Vyondys 53 (2019), Kymriah (2017), Yescarta (2017), Tescartus, Luxturna (2017), Zolgensma (2019). - First CRISPR disease-modifying efficacy: CTX001 for sickle cell disease and beta thalassemia demonstrated clinical efficacy in the past year. - First siRNA drug approval: Onpattro (patisiran) approved in 2018 for hereditary ATTR amyloidosis. - AAV immunity barrier: As many as 50% of patients are excluded from AAV-based therapies due to pre-existing immunity to viral capsids. - NIH investment: $190 million over six years committed to the Somatic Cell Genome Editing Consortium. - Unknown gene function: Function of ~6,000 of ~20,000 human genes is currently unknown. - Non-coding genome: 98% of the genome is non-coding DNA; it harbors epigenetic regulators responsible for >90% of susceptibility for common disease.
Interpretation: The authors conclude that gene therapy is arguably the most exciting area of biotechnology at this moment. Unprecedented control over nucleic acid delivery, immune modulation, and precise genome manipulation—technologies not imaginable ten years ago—will unlock new areas of medicine over the next decade. The rapid pace of innovation is outpacing regulatory models, and accommodating personalized therapies (including n-of-1 treatments) will be a major change in the field. Synthetic biology, cell reprogramming, and high-throughput functional genomics will continue to reshape biomedical research.
Limitations: Limitations inherent to the Comment:
  • No primary experimental data; it is a perspective/opinion piece.
  • No systematic search strategy or meta-analysis.
  • Quantitative claims are drawn from selected literature and clinical trials, not comprehensively reviewed.
  • Potential competing interests: C.A.G. is an advisor to and founder of gene therapy/genome editing companies; K.B. is an employee of Sarepta Therapeutics; both are inventors on related patents.

Limitations of the field highlighted by the authors:

  • Immune response: Pre-existing and adaptive immunity to AAV capsids limits patient eligibility and re-dosing.
  • Delivery challenges: Expanding beyond retina and liver to other tissues remains difficult.
  • Regulatory obstacles: Current models requiring large patient numbers are not applicable to curative therapies for single patients or very small populations.
  • Incomplete genome annotation: Most non-coding regulatory elements and many genes have unknown function.
  • Personalized therapy challenges: Universal cell therapies and n-of-1 therapies require new regulatory and manufacturing paradigms.
  • Safety and modeling: In vivo genome editing outside retina/liver still needs validated delivery, safety, and disease models.

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