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
- Study finds malfunctioning microglia linked to several neurological disorderson August 11, 2020 at 11:09 pm
Researchers at Fudan University in Shanghai, China have developed three different techniques that successfully replace almost all malfunctioning microglia - each technique with its own advantage in ap ...
- Study focuses on genetic neurological disorders that develop in children over timeon August 11, 2020 at 11:07 pm
A team of researchers at Children's Hospital of Philadelphia (CHOP) affiliated with the CHOP Epilepsy Neurogenetics Initiative (ENGIN) further bridged the gap between genomic information and clinical ...
- Scientists replace malfunctioning 'vacuum cleaner' cells linked to neurological disorderson August 11, 2020 at 8:16 am
Malfunctioning microglia are associated with a range of neurological diseases. Replacing these immune cells when they are broken potentially opens up a new era for treating such disorders.
- Neurogene Announces FDA Orphan Drug Designation for CLN7 Batten Disease Gene Therapyon August 11, 2020 at 6:27 am
Neurogene Inc., a company founded with a mission to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, today announced that the U.S. Food and Drug A ...
- The genetic architecture of human brainstem structures and their involvement in common brain disorderson August 11, 2020 at 2:12 am
The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify ...
- McKee CTE staging scheme accurate in diagnosing severity, location of diseaseon August 10, 2020 at 5:02 pm
Since 2008, researchers at Boston University School of Medicine (BUSM) and VA Boston Healthcare System have studied Chronic Traumatic Encephalopathy (CTE), a progressive brain disease associated with ...
- CDC tells parents, docs to watch for rare, neurologic condition in children this fallon August 10, 2020 at 3:16 am
We got him in to see the doctors and they all were like, ‘this doesn’t look right.’” Joplin doctors sent the family to Children’s Mercy in Kansas City, where Billy Sticklen was quickly diagnosed with ...
- 55% of coronavirus patients still have neurological problems three months later: studyon August 8, 2020 at 8:13 am
Could the coronavirus lead to chronic illness? While lung scarring, heart and kidney damage may result from COVID-19, doctors and researchers are starting to clock the potential long-term impact of ...
- Oral Treatment OK'd for Rare Neurological Diseaseon August 7, 2020 at 1:46 pm
"Evrysdi is the first drug for this disease that can be taken orally, providing an important treatment option for patients with SMA, following the approval of the first treatment for this devastating ...
- Pricey rare disease drugs for Covid-19 & CDC warns against rare neurological diseaseon August 6, 2020 at 5:19 pm
Teladoc Health reaches agreement to buy Livongo in a $18.5 billion deal ‘We don’t actually have that answer yet’: WHO clarifies… ‘We don’t actually have that answer yet’: WHO clarifies comments on ...
via Google News and Bing News