Gene therapy is at an inflection point. Recent successes in genetic medicine have paved the path for a broader second wave of therapies and laid the foundation for next-generation technologies. This comment summarizes recent advances and expectations for the near future.

1. last 5 years - a renaissance in gene and cell therapy –> first approved therapies after decades of efforts
2. approved
   1. oligonucleotide, cell therapies, in vivo gene therapies –> cancer, inherited blindness, NM disease
   2. others will build on it
   3. of particular interest to us: blood disorders e.g. beta thalassemia, sickle cell anemia
3. authors suggest a time-line
4. outstanding issues:
   1. immune response: gene delivery vectors, products of foreign transgenes – AAV based; how about others? 50% excluded
5. new developments:
   1. better DNA editing and repair
   2. RNA editing
6. stil many unknowns: 6K of 20K human genes function unknown
   1. epigenetic regulator function not well known but clearly important
      1. CRISPR (CTX001) targets distal gene regulatory element rather than underlying genetic mutation
7. limit of regulatory models for gene therapy treatment

Gene therapy is arguably the most exciting area of biotechnology at this moment - both due to recent progress and because of the possibilities on the horizon. Unprecedented levels of control over nucleic acid delivery, modulation of the immune system, and precise manipulation of the human genome – technologies not imaginable ten years ago – will certainly unlock new areas of medicine over the next ten years. At the same time, this nascent glimpse of a new world of technical capabilities has inspired whole new areas of research, such as synthetic biology, cell reprogramming, and high-throughput functional genomics, which will undoubtedly continue to reshape the face of biomedical research.

• luxturna - for blindness - how does it work
• CRISPR

Bulaklak, K., Gersbach, C.A. The once and future gene therapy. Nat Commun 11, 5820 (2020). https://doi.org/10.1038/s41467-020-19505-2