CRISPR-Cas9 is now the most widely used gene editing technology in the world, successfully treating blood diseases, cancers and eye diseases.¹⁸ Several therapies have been approved for clinical use and many more are in trials. However, CRISPR’s ability to correct gene defects depends on making double-strand breaks that are repaired by cellular processes. It is increasingly accepted that such double strand breaks are dangerous,¹⁹ resulting in potential chromosomal rearrangements or loss.²⁰ Drugs in the pipeline will not be abandoned, but future therapies will rely on more efficient and accurate techniques.

Future Horizons:

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5-yearhorizon

Ex vivo and in vivo therapies advance

More large-scale stage III clinical trials for ex vivo therapies take place, with more therapeutics approved and commercially licensed.³² Patient data shows mid-stage results of CRISPR-based haemophilia and retinitis pigmentosa therapies now in trials.³³ ³⁴ Early-stage clinical trials of in vivo editing techniques, targeting easily accessible tissues such as the eye³⁵ or the liver, show results. In vivo therapies move to experimental clinics. CRISPR corrects for mitochondrial genetic disease in IVF procedures. Next-generation “one shot” genome editors in vivo show long-term safety data in clinical trials.³⁶ Duchenne muscular dystrophy trial uses base editing to get into major tissues.[37](

10-yearhorizon

Safer germline editing blurs boundaries between therapy and prevention

Inhalation and other new delivery methods move into the clinic. Epigenome editing has its first trials targeting chronic diseases. New non-viral delivery techniques reduce the need for large doses, reducing cost. Adenosine transversion editors expand the capabilities and applications of base editing.³⁸ Heritable gene editing begins to gain limited acceptance, although not everywhere, as a consequence of successful somatic techniques and preclinical safety data. Base and prime editing enable in vivo therapeutics, bringing costs of therapy down.

25-yearhorizon

Polygenic editing erodes boundaries between therapy and enhancement

In vitro derived gametes can be edited safely before implantation. Many forms of gene editing are mainstream. It becomes possible to engineer resistance to radiation , chemical warfare and infectious diseases by altering single genes, enabling military applications as well as casual space travel. We use gene technologies to correct, slow down or even reverse processes linked to premature ageing to increase healthspan. A sleep-shortening gene is the first popular enhancement. Up- and down-regulating some specific genetic elements enhances some aspects of cognition.

The two likeliest candidates are base and prime editing. Base editing is powerful against point mutations, which account for 80 per cent of human genetic diseases.²¹ It also enables mitochondrial gene editing which is harder to achieve with CRISPR.²² Prime editing is also more specific and accurate, and new research continues to enhance its efficiency.²³ Research is under way to replicate CRISPR successes in sickle-cell disease and beyond with base and prime editing.²⁴ ²⁵ ²⁶ Prime editing can target multiple genes at the same time.²⁷ ²⁸

Modified adeno-associated viruses (AAVs) can deliver gene editors, although the large quantities required can trigger dangerous immune responses. Efforts are under way to re-engineer AAV to be bigger and evade immune response. One alternative is more efficient lentiviral vectors or viruses engineered to make them preferentially infect specific cell types, for example neural cells or airway cells.²⁹

Non-viral delivery has become an increasingly viable alternative, thanks to rapid progress in the use of lipid nanoparticles and inorganic-nanoparticle-based delivery systems.³⁰ ³¹

Next-generation editors and delivery - Anticipation Scores

The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate:

The uncertainty related to future science breakthroughs in the field
The transformative effect anticipated breakthroughs may have on research and society
The scope for action in the present in relation to anticipated breakthroughs.

This chart represents a summary of their responses to each of these elements, which when combined, provide the Anticipation Potential for the topic. See methodology for more information.