An amazing report of gene editing in living patients with symptomatic Transthyretin Amyloidosis (ATTR amyloidosis) appeared in NEJM Aug 5 .And yes, it seemed to “work,” at least decreasing blood levels of the amyloid TTR protein in ~14 days, with no serious adverse events. This was very experimental, and NOT a drug approval trial! No clinical effectiveness data were presented.
Based on CRISPR-Cas9 molecular biology, the proprietary IV product, containing targeting RNA and Cas9 RNA, was given to four adults in England, and two in New Zealand. Whether the patients will ever get better from their condition (which affects peripheral nerves and the heart) or have long term effects (off-target mutagenesis is a worry) will have to await longer term clinical followup.
ATTR amyloidosis is different from Alzheimer’s dementia, and the “amyloid” is different; the first is made in the liver, causing an abnormal accumulation of the TTR protein, while in Alzheimer’s disease beta-amyloid is presumably made by brain cells, in accumulations known as “plaques.” There are many kinds of amyloids, all abnormal accumulations of proteins, including what most people probably mean when they mention amyloidosis, light chain AL amyloid, made in blood cells, that can affect the heart and kidneys.
Gene editing in animal embryos, then human embryos has been followed by controversy and ethical issues. Dr. Lisa Rosenbaum wrote a “Medicine and Society” piece recently about CRISPR ethics.
So, might this be an approach to Alzheimer’s amyloid? The FDA expert Advisory Committee on aducanumab together wrote a NEJM Perspective July 28 about the very controversial aducanumab approval process, along with scientific issues about the amyloid cascade hypothesis in dementia, and with using beta-amyloid change as a surrogate endpoint.
Unlike ATTR amyloidosis, where a single gene might be modifed by CRISPR-Cas9, the Alzheimer’s dementia that affects the vast majority does not seem to be single gene problem. Still, there are the PSEN mutations in certain kindreds, and maybe there’s something in Down Syndrome, that might be interesting targets for the reported proprietary approach.
Of course families don’t want just “proof of concept,” as important as that is, or surrogate endpoints, they want to see evidence of recovery, or at least halting of progression, that even Aduhelm doesn’t seem to promise.