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LAUSANNE, Switzerland—Down syndrome, also known as trisomy 21, currently affects roughly one in 700 infants and an expected 6 million people worldwide. Individuals with Down syndrome present with physical and cognitive deficits, and have also been found to be predisposed to Alzheimer’s disease-like characteristics.
This is due to the fact that individuals with Down syndrome have an extra copy of chromosome 21, which contains the gene for APP, encoding the precursor protein of Abeta, which is one of the main characteristics of Alzheimer’s disease. As a result, people with Down syndrome are roughly three to five times more likely to develop characteristics reminiscent of Alzheimer’s disease than those without trisomy 21, and at a much younger age. More than 98 percent of individuals with Down syndrome over age 40 develop Alzheimer’s disease-like characteristics, with up to 80 percent developing associated dementia over the age of 60.
New work from AC Immune is hoping to treat these cognitive deficits caused by Down syndrome with the use of an anti-Abeta vaccine, ACI-24, which has seen promising preclinical results. Those results appeared in the paper “An anti-Abeta-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome,” which was published recently in PLOS ONE. The study included scientists from AC Immune, the Department of Neurology and Neurological Sciences at Stanford Medical School and the Department of Neurosciences at the University of California, San Diego School of Medicine.
ACI-24 is a liposomal therapeutic anti-Abeta vaccine candidate discovered with AC Immune's proprietary SupraAntigen technology platform. It is designed to stimulate the immune system to produce antibodies that specifically target the oligomeric and fibrillary Abeta proteins to both prevent beta amyloid plaque accumulation and enhance the clearance of plaques. Preclinical data showed significant activity in plaque reduction and memory restoration, in addition to a favorable safety profile.
“We see this work as both groundbreaking and as the next step in testing the idea that it will be possible to treat and eventually prevent Alzheimer’s disease in people with Down syndrome,” said Dr. William Mobley, executive director of the UC San Diego Down Syndrome Research and Treatment Center and co-author of the paper. “The findings from the publication suggest vaccination is a good strategy to combat the effects of the elevated Abeta level in adults with Down syndrome. We are delighted to participate in a public-private partnership with AC Immune, the Lumind LuMind Research Down Syndrome Foundation and the NIH to test the effect of an anti-Abeta vaccination.”
In this work, mouse models of Down syndrome were vaccinated with ACI-24 at 5 months of age and then examined for cognitive measures at 8 months, according to the paper's abstract. The authors reported that “Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments.”
In addition, the mice “showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.” The paper also noted that their results implied that “vaccination against Aβ can be used to address the impact of APP products in young and old mice.”
ACI-24 is now being evaluated in a Phase 1/2a clinical trial in patients with mild to moderate AD. AC Immune is also beginning recruitment for a clinical trial of ACI-24 targeting Alzheimer’s disease-like characteristics in individuals with Down syndrome. The Phase 1b trial will consist of a 12-month treatment period followed by a 12-month follow-up, and is being conducted in collaboration with the University of California, San Diego Down Syndrome Research and Treatment Center.
AC Immune is also advancing efforts in other neurodegenerative diseases, including Parkinson's disease. April saw the company announce a research and development collaboration with Biogen featuring a pair of radiopharmaceutical diagnostic programs in neurodegenerative diseases. AC Immune and Biogen will further research, develop and clinically validate an alpha-synuclein PET radioligand that can be used as an imaging biomarker for Parkinson’s disease and related synucleinopathies to enable the development of new disease-modifying therapies. In conjunction with this effort, the two companies will also advance a new research program to identify and develop novel PET radioligands for TDP-43, a recently identified target in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease).
The collaboration, which is slated for three years initially, will be primarily funded by Biogen. Both companies will share responsibilities for the R&D program, with AC Immune leading the chemistry and biology research for the alpha-synuclein PET tracer and the TDP-43 PET tracer program and Biogen taking point on scientific assessment and radiopharmaceutical development of the AC Immune compounds. AC Immune will retain its intellectual property and commercialization rights from the collaboration, and both companies will share the clinical program design.
The goal is to generate a clinically validated alpha-synuclein PET tracer as well as longitudinal data in Parkinson’s disease patients. An alpha-synuclein PET tracer could aid in diagnosing neurodegenerative diseases with alpha-synuclein pathology earlier and more accurately, and also enable the tracking of disease pathology over time alongside symptomatic endpoints. Biogen and AC Immune will also seek to identify and develop a TDP-43-PET tracer with potential for future therapeutic programs targeting neurodegenerative diseases such as ALS.