A new treatment ‘silences’ genes that contribute to Alzheimer’s disease. A single dose can reduce the level of a harmful protein by 90%, according to a study cited by the British publication The Sunday Times.
The paper also presents the case of a patient, Anne Warburton, who, shortly before her 60th birthday, began to relapse. “She would ask questions shortly after she had already asked them, especially first thing in the morning,” said her husband, Peter. “The brain just couldn’t hold the information for long.”
It was the first sign that Warburton had Alzheimer’s disease, a devastating condition that affects around 600,000 people in the UK alone. But the mother of two, now 68, laughs as Peter describes his repeated questions. “He was mad!” he said.
Alzheimer’s disease, the most common form of dementia, affects people in very different ways, but it hasn’t diminished Warburton’s sense of humor. Former Bedfordshire County Librarian said: “You have to make the most of life.” “I have an amazing sense of humor and it’s a gift from God. I think it helps a lot.”
He also has more reason to be delighted than most people with dementia. He is one of 20 people in the world – including just four in the UK – who are part of a trial for a radical new treatment for Alzheimer’s.
Acting like an electric light switch, the treatment reduces the intensity of the gene that produces the protein that causes Alzheimer’s.
Preliminary results of a first phase study of the drug, which was published quietly at a medical conference in Amsterdam last month, suggest that a single dose of the treatment – known for now only as ALN-APP – reduces the level of amyloid precursor protein by up to 90%. Even after six months, tests showed their levels were still an average of 65 percent lower. This protein building block clumps together in sticky toxic plaques that clog the brain and cause the memory loss associated with Alzheimer’s.
Scientists believe that if given early enough, the treatment, by stopping the process at its source, could prevent patients from developing Alzheimer’s symptoms.
The finding adds to the growing excitement in the dementia field after years of stagnation.
In the past 10 months, two landmark studies have shown for the preceding in Alzheimer’s that the root cause can be slowed down, reducing mental decline by between a quarter and a third. The drugs – Lecanemab and Donanemab – work by removing amyloid proteins from the brain.
But the new approach to gene silencing works in a radically different way. “Instead of removing the proteins, it’s about going upstream and stopping their production,” said Dr. Catherine Mummery, a consultant neurologist at University College London Hospitals, who is leading the UK part of the study.
“If you’re just cleaning the protein that’s already there, you have to always remove the damage while the pipeline is still open. But if you turn off the tap, you have a better chance of preventing further damage.”
The first results show that the drug is safe and show that a single dose reduces protein production. The team will expand the study by giving repeated doses to see if the levels can be reduced further. Mummery hopes to eventually give the treatment once every six to 12 months, much less often than Lecanemab and Donanemab, which are given every two to four weeks.
The treatment provides an injection in the lower back, directly into the cerebrospinal fluid that surrounds the spinal cord, allowing it to reach the brain, bypassing the blood-brain barrier.
Mummery stressed that there is still a long way to go before the proven treatment will be ready for use by the National Health Service (NHS). The research team has not yet begun to see if the drug slows cognitive decline. “A large phase two trial is needed to show whether or not there is a clinical benefit,” he said. Details for this will be announced later this year.
But he said that given the encouraging results already published this year for Lecanemab and Donanemab, in theory, ALN-APP should do the job. He said he would actually expect a more dramatic impact. “I think these drugs will have the greatest potential if they are given very early, before people have symptoms. Then you have a better chance of preventing symptoms, not to mention treating them once they have symptoms them.”
The difficult thing would be to identify these patients, but those with genetic Alzheimer’s or the Alzheimer’s gene are the ones most likely to benefit.
Mummery said that the early results, which show that side effects are minimal, also suggest that patients can avoid the risk of brain hemorrhage seen with other new treatments.
The gene suppression approach works using a revolutionary new technology called RNA interference. This blocks messenger RNA – or mRNA – the genetic code that carries instructions from DNA to the centers of our cells that make proteins. mRNA became more prominent during the pandemic when it was used in the Pfizer-BioNTech and Moderna Covid vaccines.
In these cases, synthetic mRNA was injected into the arm, which instructs the body’s cells to produce thousands of copies of the Covid spike protein so the immune system can recognize it. Instead, RNA interference blocks mRNA naturally produced by the body to prevent cells from producing toxic or excessive proteins, thereby stopping the development of disease.
This approach was found out in the 1990s by American geneticists Andrew Fire and Craig Mello, who received the Nobel Prize in 2006.
As of 2019, the American company Alnylam Pharmaceuticals has developed treatments for several diseases using this approach. These include amyloidosis, a rare condition in which a different toxic protein attacks various organs; acute hepatic porphyria, a genetic condition that affects the nervous system; and primary hyperoxaluria type 1, which causes large kidney stones.
Another treatment Numitinclisiran, bought by pharmaceutical giant Novartis and introduced to the NHS, lowers cholesterol as an alternative to statins. All of these treatments work by shutting down genes in the liver. But the new treatment is the first to shut down genes in the brain.
“This is the first RNA interference program for the nervous system,” said Akshay Vaishnaw, president of British-born Alnylam. It’s positive for patients and very exciting, not just for Alzheimer’s, but also for Huntington’s, Parkinson’s and motor neurone disease.”
Other disease areas, such as cardiology, could be next. There are “dozens, if not hundreds” of human genes that cause disease by producing excess or abnormal proteins, he added, all of which can be targeted.
Richard Oakley, associate director of research at the Alzheimer’s Society, said this discovery will have a lasting impact on the field. “This is great science,” he said. “It’s as cool as it gets. That’s the kind of thing that gets us all excited.”
He stressed that with only 20 patients treated in the first phase, there is still a long way to go, but he added: “This opens a whole new avenue for treatment.”
Gene suppression approaches could be used to stop the production of other proteins involved in dementia. This year, Mummery’s team used another gene-silencing treatment, called an antisense oligonucleotide, to reduce levels of tau — a “messy-causing” protein that also plays a role in Alzheimer’s. Oakley said that over time, even APOE4 — the inherited gene carried by one of the four people who increases the risk of Alzheimer’s — could be turned off.
“We’ve already seen how gene silencing has been used to treat other conditions,” he said. “Dementia is not something that cannot be treated; We are confident about this because research has cured and addressed major diseases with time, energy and effort. We will eventually cure dementia.”
This, if it happens, will be too late for Anne Warburton. Although he is in positive spirits, the symptoms have already begun to make themselves felt. He suffers from what doctors describe as “mild to moderate” Alzheimer’s. He can still enjoy gardening, socializing and spending time with family and friends. But gradually the symptoms get worse. “It means forgetting appointments, forgetting things he promised to do, losing things every day,” said Peter, 69, who runs an economic consulting firm.
The couple do not know if Warburton was given the active drug; six of the 20 participants received a placebo, while the other 14 received the genuine treatment. But for the multi-dose phase of the study, which is about to begin, there will be no placebo, so all participants will get the real drug.
“When we decided to participate, they made it very clear to us that we were making a gift to the medical and scientific community,” said Peter. “It should not be expected that we get anything personal from this. But obviously we are only human, hopefully this drug will give Anne a better cognitive result.”