A new kind of antibody targets a feature shared by proteins thought to cause the most damage in Alzheimer’s disease, Parkinson’s disease, and related conditions, creating potential for a unified treatment approach.
This is the finding of a study led by researchers from NYU School of Medicine and published online August 29 in Scientific Reports.
The new study is based on decades of work arguing that the contribution to disease of key proteins—amyloid beta and tau in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, and prion proteins in conditions like mad cow disease—is driven by certain, toxic forms dominated by a common structure: bundles of “beta sheets” in clumped proteins.
In tissues from autopsied patients with these diseases and in live mice, experiments demonstrated how the study antibodies target and remove only these toxic forms, say the authors, and without triggering the immune toxicity that has frustrated treatment development efforts to date.
“In an atmosphere where countless treatments have failed in clinical trials over the last 15 years, the fact that our approach continues to be effective in rigorous tests should be of interest to our peers and the industry, even if it runs contrary to conventional thinking,” says corresponding author Fernando Goni, PhD, research associate professor in the Department of Neurology at NYU Langone Health.
“While we still have a number of milestones to reach before this work is ready for clinical testing, our results suggest that these antibodies may halt key pathological mechanisms across several neurological diseases and regardless of disease stage,” says corresponding author Thomas Wisniewski, MD, director of NYU Langone’s Center for Cognitive Neurology, Silberstein Alzheimer’s Institute, and Alzheimer’s Disease Center.
New Approach to Antibody Design
The study focuses on proteins that form important structures in the brain. The instant they form as chains of amino acids, proteins fold into complex shapes needed to do their jobs. Unfortunately, proteins can also “misfold” for countless reasons, such as genetic abnormalities, toxins, age-associated cell processes, and inflammation that eventually cause the diseases addressed by the current study. Cells and tissues die as misshapen proteins stop working and build up, but the field has struggled to pinpoint which of these shifting forms to target as the key drivers of disease.
Many research efforts, including the current study, seek to design antibodies shaped to attach to and remove the right targets. Past and ongoing attempts have targeted the initial, short chains of amino acids that serve as basic, repeating structural units, or monomers, of each misfolded protein. Still others targeted end-stage fibrils, each made of thousands of monomers, which accumulate in plaques and tangles that tissues cannot eliminate. Neither approach has yielded an effective therapy.
In that light, Dr. Goni, Dr. Wisniewski, and colleagues designed their antibodies to target instead the “oligomers” formed as several misfolded monomers associate and acquire the “beta-sheet” shape, but before they are large enough to fibrilize. These intermediate forms may be uniquely toxic, say many in the field, because, unlike fibrils, they can dissolve, move in and out of cells, and from one cell to another. This mobility may explain the “prion-like” progression seen in misfolding diseases where abnormal proteins cause normal ones to misfold in a domino effect that damages nerve cells and their connections in the brain.
Importantly, growing toxic oligomers of amyloid beta, tau, alpha synuclein, and prion protein become increasingly dominated by the twisted strands of amino acids called beta sheets, which have spatial arrangements that let the strands stack up.
To design new kinds of antibodies, the research team zeroed in on a small 13-amino acid peptide, derived from the extremely rare genetic disease called British amyloidosis, but not present in the rest of the human population. They converted it into a larger, stable oligomer with more than 90 percent “beta-sheet” structure—the p13Bri immunogen—that could be “seen” by the mammalian immune system, and that could trigger a specific antibody response to solve problems encountered with standard approaches. By immunizing mice with p13Bri at high doses, they forced the production of extremely rare antibodies against beta sheets in toxic oligomers.
The researchers say that their rare antibodies, activated by a protein fragment seen only in a rare disease, have almost zero chance of triggering unwanted immune responses to normal proteins with similar sequences (autotoxicity), the downfall of many previous attempts. Finally, the team screened their lead antibodies against tissues taken from the brains of human patients with Alzheimer’s disease, Parkinson’s disease, and prion diseases. Only the six monoclonal antibodies that reacted to toxic oligomers from at least two misfolded proteins from two diseases were selected for further study.
“This publication details the first system for making antibodies that truly target only toxic oligomers of misfolded proteins dominated by beta sheets across several diseases, and without regard to the amino acid makeup of each misfolded protein’s monomer,” says Dr. Goni.
The Latest on: Neurological diseases
Daughter's artistic tribute honors father lost to Parkinson's disease
on May 22, 2019 at 6:39 pm
neurological research programs and support patients like her dad.Tap the video player above for the full story. Sofia Swoope used memories of her father, who died of Parkinson's disease in April 2018, ... […]
Summit charts a course to uncover the origins of genetic diseases
on May 21, 2019 at 7:18 pm
In contrast, internal genetic factors can be responsible for the onset and progression of diseases ranging from degenerative neurological disorders to some cancers. A team led by Ivaylo Ivanov of ... […]
Abeona Therapeutics Announces FDA Clearance of Investigational New Drug Application for ABO-202 Gene Therapy in CLN1 Disease
on May 21, 2019 at 7:00 am
“ABO-202 is a promising AAV9 gene therapy that extended survival and improved neurological function in the animal model of CLN1 disease. Importantly, the combined intravenous and intrathecal ... […]
Novel combination therapy treats neurological disorders
on May 18, 2019 at 10:53 pm
A novel pharmaceutical therapy for neurological disorders including stroke and Alzheimer’s disease has been introduced by BGN Technologies, the technology-transfer company of Ben-Gurion University ... […]
Automatic Diagnosis System for Neurological Diseases Using Deep Learning Developed
on May 18, 2019 at 5:35 pm
Osaka University and The University of Tokyo scientists have developed MNet, an automated diagnostic system for neurological diseases using magnetoencephalography (MEG). Their research results were ... […]
Innovator Finalist: Dr. Anthony Stringer works to expand cognitive rehabilitation treatments
on May 17, 2019 at 3:45 am
Stringer’s research focuses on cognitive rehabilitation outcomes following traumatic brain injury, stroke, epilepsy, and other neurological conditions. The ongoing expansion of the patients he is able ... […]
Lifetime Achievement: DeLong's discoveries revolutionized understanding of Parkinson's disease
on May 17, 2019 at 3:45 am
During a career spanning nearly 50 years, the neurologist made discoveries that revolutionized the understanding of Parkinson's disease and led to major breakthroughs in treatments for Parkinson’s and ... […]
Researchers develop automatic diagnosis system for neurological diseases using MEG
on May 16, 2019 at 11:41 pm
A team of researchers from Osaka University and The University of Tokyo developed MNet, an automatic diagnosis system for neurological diseases using magnetoencephalography (MEG), demonstrating the ... […]
Automatic neurological disease diagnosis using deep learning
on May 16, 2019 at 10:24 am
A team of researchers has developed MNet, an automatic diagnosis system for neurological diseases using magnetoencephalography (MEG), demonstrating the possibility of making automatic neurological ... […]
Abbott Partners With NIH On BRAIN Initiative to Advance Research for Neurological Disorders
on May 14, 2019 at 9:50 pm
- Partnership with NIH aims to increase understanding and accelerate the application of neurostimulation therapies - The BRAIN Initiative brings together the brightest minds across disciplines to ... […]
via Google News and Bing News