A new treatment ‘silences’ the gene that contributes to Alzheimer’s disease. A single dose can reduce the level of a dangerous 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 wasn’t able to retain the information for very 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 her repeated questions. “It was driving people crazy!” she says.
Alzheimer’s disease, the most common form of dementia, affects people in very different ways, but it hasn’t dampened Warburton’s sense of humor. “You have to make the most of life,” said the former Bedfordshire County Librarian. “I have an amazing sense of humor and that’s a godsend. I think it helps a lot.”
She also has more reasons than most people with dementia to be cheerful. She is one of 20 people in the world – including just four in the UK – who are part of a trial for a radical new gene-silencing treatment for Alzheimer’s.
Acting like an electric light switch, the treatment reduces the intensity of the gene that produces the proteins that cause Alzheimer’s.
Interim results of a phase one study of the drug, 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 levels were still an average of 65 percent lower. The building blocks of this protein clump 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 growing excitement in the dementia field after years of stagnation.
In the past 10 months, two landmark studies have shown for the first time in Alzheimer’s that the root cause can be slowed, reducing cognitive 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 up the proteins that are already there, you have to constantly remove the damage while the faucet is still open. But if you turn off the tap, you have a much better chance of preventing further damage.”
Initial results show the drug is safe and demonstrate that a single dose reduces protein production. The team will expand the study by giving repeated doses to see if levels can be reduced further. Mummery expects the treatment to eventually be given once every six to 12 months, much less often than Lecanemab and Donanemab, which are given every two to four weeks.
The treatment is given by an injection in the lower back, directly into the cerebrospinal fluid that surrounds the spinal cord, which allows it to reach the brain, bypassing the blood-brain barrier.
Mummery stressed that there is still a long way to go before the treatment is proven to be ready for use by the National Health Service (NHS). The research team has yet to begin looking at whether the drug slows cognitive decline. “A large phase two trial is needed to show whether or not there is a clinical benefit,” she said. Details for this will be announced later this year.
But she said that given the encouraging results already published this year for Lecanemab and Donanemab, in theory, ALN-APP should do the job. She said she 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.”
The tricky thing would be identifying these patients, but those with genetic Alzheimer’s or young-onset Alzheimer’s are the ones most likely to benefit.
Mummery said the early results, which show that side effects are minimal, also suggest that patients could avoid the risk of brain hemorrhages seen with other new treatments.
The gene suppression approach works by using a revolutionary new technology called RNA interference. This blocks messenger RNA – or mRNA – the genetic code that carries instructions from DNA to the protein-making centers of our cells. mRNA rose to prominence 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, instructing the body’s cells to produce thousands of copies of the Covid spike protein so that it could be recognized by the immune system. Instead, RNA interference blocks the body’s naturally produced mRNA to prevent cells from producing toxic or excessive proteins, thereby halting the development of disease.
This approach was discovered 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 been developing 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 serious kidney stones.
Another treatment Numitinclisiran, which has been bought by pharmaceutical giant Novartis and is being introduced to the NHS, lowers cholesterol as an alternative to statins. All of these treatments work by turning off genes in the liver. But the new treatment is the first to turn off genes in the brain.
Akshay Vaishnaw, the British-born chairman of Alnylam, said: “This is the first ever RNA interference program for the nervous system. It’s great for patients and it’s 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 excites us all.”
He stressed that with only 20 patients treated in the first phase, there is still a long way to go, but added: “This opens up a whole new avenue for treatment.”
The gene suppression approach 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 “tangle-causing” protein that also plays a role in Alzheimer’s. Oakley said that over time, even APOE4 — the inherited gene carried by one in four people that 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 an untreatable thing; we are confident about this because research has cured and addressed most major ailments 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 good spirits, the symptoms have already started to make themselves felt. She suffers from what doctors describe as “mild to moderate” Alzheimer’s. She can still enjoy gardening, socializing and spending time with family and friends. But gradually the symptoms worsen. “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 multiple-dose phase of the study, which is about to start, there will be no placebo, so all participants will get the real drug.
“When we decided to participate, we were made very clear that we were making a gift to the medical and scientific community,” said Peter. “There should be no expectation that we get anything personal from this. But obviously we’re only human, hopefully this drug will give Anne a better cognitive outcome.”
2023-08-06 13:13:25
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