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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT: International Down Syndrome Day.

Down Syndrome and Alzheimer’s Disease.

Many scientists are not aware of the strong link existing between Down syndrome and Alzheimer’s disease. Down syndrome, also known as Trisomy 21, is a genetic defect caused by an error in cell division called “nondisjunction”. For centuries, and in all regions around the globe, people with Down syndrome have been described in the art and medical literature but it was not until 1866 that John Langdon Down, an English physician, published an accurate decription of a person with Down syndrome. The most common physical features of Down syndrome include: a flattened face, almond shaped eyes, a short neck, small ears, small hands and feet, a tongue that tends to stick out of the mouth, a single line across the palm of the hand, poor muscle tone, subjects short in height as children and adults, an IQ in the moderate low range and slower speaking children.  A century later, in 1959, a team of French scientists: Marie Gautier, Jérôme Lejeune and Raymond Turpin, identified Down syndrome as a chromosomal condition. Instead of the 46 chromosomes present in each cell, Marie Gautier and Jerôme Lejeune observed 47 chromosomes in the cells of individuals with Down syndrome. It was later determined that Down syndrome people had, in each cell in their body, three separate copies of chromosome 21 (Trisomy 21) instead of two. 95% of people with Down syndrome have a full extra copy of chromosome 21. A minority (3%) have a Translocation Down syndrome with a whole chromosome 21 present but attached to a different chromosome. Mosaic Down syndrome which affects about 2% of the population have some of their cells with three copies of chromosome 21 and other with the usual two copies.

Down syndrome is the most common chromosomal disorder and, in the US, each year 6,000 babies are born with this syndrome which represents 1 in every 700 babies born. Older mothers are more likely to have babies affected by Down syndrome which partially explains the increase of the current prevalence.

Chromosome 21 carries a gene that produces the amyloid beta precursor protein (APP), which is supposed to be an important target in the appearance of Alzheimer’ disease. From an early age people with Down syndrome are producing more of the beta amyloid protein than normal subjects. Down syndrome people are the largest population of genetic determined Alzheimer’s disease in the world with around 6 million people.

In a Neuroscience report from the World Economic Forum of May 2015, Elisabeth Head, Associate Professor at the University of Kentucky raised the question “Why studying Down syndrome could help us understand Alzheimer’s disease.” She indicated that the lifespan of people with Down syndrome had dramatically improved from 10 years in 1960 to 25 years in 1983 to close to 60 years today. It has been identified that virtually all people with Down syndrome over 40 years old develop Alzheimer’s disease. For people with Down syndrome beta amyloid plaques, neurofribillary tangles, and hippocampus atrophy detected by MRI have been identified in patients in their late 30’s. It might therefore be very useful to understand Alzheimer’s disease in people with Down syndrome. But to the best of our knowledge this was not the case and even worse. “If you look at all the Alzheimer’s disease clinical trials for the past 20 years, …, in every study one exclusion criteria says having Down syndrome” said Michael Raffii, Professor of Clinical Neurology at the University of Southern California’s Keck School of Medicine. Eisai’s and Biogen’s Adulhelm and Eisai’s Lequembi, two of the recent FDA approved drugs for the treatment of Alzheimer’s disease, have never been tested in a single patient with Down syndrome. Eli Lilly and Roche have explained that the strict cutoff of early-stage patients being 60 years old has excluded Down syndrome patients. “There is no one with Down syndrome at 65 years with early stage. That cutoff needs to be fixed in their studies” said Richard Fisher, chief scientific officer for LuMind, an advocacy group which connects the Down syndrome community with scientists and physicians. So far, no patients with Down syndrome have ever been enrolled in a late-stage clinical trial for Alzheimer’s disease. Advocacy groups, such as LuMind, are laying the groundwork for a better understanding by the community and help companies and authorities to lift the many hurdles and issues to enroll Down syndrome people in large placebo-controlled Alzheimer’s clinical trials or in a selected population trial with Down syndrome patients.

We are nevertheless aware of two European companies who are now investigating Down syndrome patients in dedicated clinical trials.

AC Immune, based in Lausanne (Switzerland), which has announced in May 2022 that ACI-24, an anti beta amyloid vaccine, was found to be safe and elicited immune response in a phase 1b clinical trial in adults with Down syndrome. “The data published in JAMA Neurology demonstrate that interventional clinical trials can be successfully conducted in individuals with Down syndrome,” said Michael Raffi. Establishing the adequate clinical endpoints and ensure the informed consent of patients was a lengthy and critical process chaired by a National Institutes of Health (NIH) working group. One key challenge is the current assessment scales used to diagnose patients with an already existing intellectual disability.

Aelis Farma, based in Bordeaux (France), which has announced on November 15, 2022, that the positive results from its safety trial with AEF0217, granted authorisation to start a trial in people with Down syndrome. AEF0217 is a Signaling Selective Cannabinoid 1 Receptor Inhibitor (CB1-SSi). Recent research has suggested that cognitive disorders linked to Trisomy 21 involve a hyperactivity of the CB1 receptor. AEF0217 is positioned as the first treatment for cognitive deficits by hyperactivity of the CB1 receptor, a condition unrelated with the overproduction of beta amyloid.

On World Down Syndrome Day (WDSD), 21 March, a global awareness day which has been officially obsverved by the United Nations since 2012, we are pleased to report that specific clinical trials for Down syndrome patients have finally been initiated.

Paris, March 21, 2023.

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