A Holy Grail for ApoE4?

By Dale Bredesen, M.D., Chief Science Officer for Apollo Health

A bit over a decade ago, Dr. Ram Rao, our esteemed colleague here at Apollo Health, performed a fascinating and important series of experiments, in which he proved that ApoE4 — the very protein that is the most common genetic risk for Alzheimer’s — actually binds to DNA and affects over 1000 genes. Now, to understand what a paradigm shift this finding was, imagine seeing a submarine — but it’s not in the ocean; it’s motoring down the freeway. Unexpected, right? That’s the same sort of “What the heck?” moment Ram created with his remarkable finding.

But as we all got over the shock of seeing that biochemical submarine careening down the cellular freeway, we realized the dramatic implications of his discovery. Ram quickly found a drug candidate that reversed this DNA-binding effect, making ApoE4 act much more like ApoE3. Genetic research at Stanford found that a rare mutation in some people with ApoE4 completely abrogates their propensity to develop Alzheimer’s, and it has turned out that the drug candidate has a very similar mechanism.

Now our colleagues at UCLA in the Drug Discovery Lab (which we set up originally at the Buck Institute in 2007), led by Dr. Varghese John, have extended Ram’s finding through further development, designing a drug candidate that is orally bioavailable, potent, brain penetrating, and highly effective at restoring the DNA activity that is otherwise blocked by ApoE4. This represents something of a Holy Grail for those with ApoE4 — a drug candidate that could be taken for prevention as well as for treatment. To date, this candidate has shown no evidence of toxicity, and appears to be a superb prospect for human trials.

So what does it take for a promising new drug candidate that exerts an effect unlike any drug on the market, and addresses an important need, to be offered for compassionate use (also called expanded access)? There must be an IND (investigational new drug) granted, the drug must be in trial, the patient must be considered to have a life-threatening condition, and there must be no other approved drugs for the condition. Certainly, Alzheimer’s disease is a life-threatening condition, and the drugs available do not improve cognition, so once the new drug candidate, currently designated DDL-218, completes its pre-clinical testing and files an IND, I hope that it shall be considered for compassionate use. With the many millions of people who are ApoE4+ who either are symptomatic or at risk, I hope that this new candidate may ultimately prove to be helpful for many, especially when used as part of a personalized, precision medicine protocol. This combination of personalized protocols like ReCODE, combined with key, targeted pharmaceuticals like DDL-218, represents the future, and should help us to take the next step toward eradicating dementia.