How likely is it that CRISPR/CAS9 will be available as treatment to replace APOE4 with APOE3/2 in humans in vivo in the near future?
CRISPR/Cas9 is the great white hope of genetic medicine with huge potential. However, this is a field in which progress has been famously slow because of high difficulties in translating promising pre-clinical therapeutic strategies to effective treatments in humans.
In broad strokes, the answer is going to be "when CRISPR based therapies are ready for other conditions". The biggest barriers to getting CRISPR based therapeutics into the clinic will be:
- Safety - can we be sure that the changes we intend are made cleanly and without off-target effects?
- Delivery - how do we get the CRISPR construct into the cells it needs to be in to work?
- Efficacy - can we effect a change in sufficient cells to produce a clinical response?
As pointed out in the comments, there are still significant safety concerns about off-target effects. https://www.nature.com/articles/s41591-018-0050-6 reports significant toxicity with efficient recombination. Furthermore, there is an emerging body of evidence that there are pre-existing CRISPR/Cas9 immune responses which may cause clinical side-effects and/or limit efficiency of recombination (https://www.biorxiv.org/content/biorxiv/early/2018/01/05/243345.full.pdf).
Delivery of the construct may well be the most difficult aspect of therapy. There are diseases which can be treated with exogenous cells, for example T cells cells modified with CRISPR techniques and re-infused as in:
However, what if the target is present in somatic tissues such as APOE4 (which is what I assume you mean instead of APOA4) such as the liver? How do we effectively get the CRISPR/Cas9 construct into these cells in a non-toxic, efficient and targeted manner?
https://www.sciencedirect.com/science/article/pii/S0167779917303049?via%3Dihub provides a nice review of current delivery methods but concludes that one of the current outstanding questions is "Are any of the currently available delivery methods reliable enough for therapeutic use of Cas9 genome editing in humans?".
Finally, efficacy. For some diseases, such as sickle cell anaemia, it is thought that as little as a 10% conversion from the disease form of HbS to wild-type HbA would be sufficient for clinical improvement. For APOE4 however there is still a significant (~4x) risk for developing Alzheimer's disease over baseline in heterozygotes compared to a ~12x risk over baseline for homozygotes (https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-8-9). To achieve a reduction in risk to baseline would therefore likely require significantly more than 50% recombination rate. Furthermore, for an effect to be longstanding and, ideally, lifelong the stem cells which give rise to e.g. liver parenchyma would have to be altered.
Overall, CRISPR/Cas9 is a technology which has revolutionised biomedical science in the laboratory already. It seems certain that some form of CRISPR/Cas9 based therapies will be used clinically within the next ten years, however there are huge technical, safety and ethical barriers before it is a widely available treatment for a range of conditions.