A new kind of antibody targets a feature shared by proteins thought to cause the most damage in Alzheimer’s disease,...

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 for major neurological diseases, led by researchers from NYU School of Medicine.

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  • In the paper, the authors suggest six reasons for why they think their approach will succeed where a great many others have failed. This is important to stress – the literature is replete with stories where the investigator thought they had discovered a tractable way to drug the plaques associated with neurodegenerative disorders only to discover that after a long and expensive clinical trial, their drug had no impact on disease progression.

    > The potential advantages are:

    > 1) a diminished risk of inducing auto-immune complications since the immunogen used has no sequence homology to any human peptide/protein (except to the protein expressed in the very rare patients with British amyloidosis)

    > 2) selective targeting of the β-sheet secondary structure found in toxic oligomers, thus avoiding interference with the multiple physiological functions of soluble Aβ, tau and α-synuclein

    > 3) reduced risk of inducing vasogenic edema/encephalitis related to direct clearance of fibrillar Aβ vascular deposits, since mainly oligomeric forms of Aβ and tau are being targeted

    > 4) concurrently targeting Aβ, tau and α-syn related pathologic conformers, addressing the mixed pathologies found in the majority of NDD patients49,50,51,52

    > 5) minimal risk of increasing toxic oligomer species as shown with some vaccination methods53

    > 6) possible therapeutic use in prion diseases with the potential to interfere with the spread of PrPRes.

    > No other reported methodologies to produce mAbs to oligomers published thus far, has this unique combination of properties. Hence we believe that our technological approach has the potential to develop tools for the detection, monitoring and treatment of multiple NDD.

    The major thrust of their argument seems to be 1) that their antibodies are more specific to the pathological oligomers, relative to non-pathological forms of the proteins as normally expressed by the cell and 2) that the approach can be broadly applied to multiple NDDs.

    Assuming this is true (not clear to me that it is), this is good – but dose limiting toxicity from on target/off pathology effects is not the driver of clinical failure in NDDs. Unfortunately, this doesn’t move the needle for me very much in terms of confidence that treatment with these antibodies will be better than any other form of targeting Abeta or similar plaque pathologies in other NDDs.

  • I still check the comments, but I’m happy to see this in /r/science rather than /r/Futurology

  • How do you sign up for a drug trial?

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  • As someone who is subbed here by default and causally browses the sub, would this possibly be beneficial for people who are Huntington’s Disease carriers? I understand HD is similar to those listed in the title. Thanks for reading.

  • Journal reference:

    Production of Monoclonal Antibodies to Pathologic β-sheet Oligomeric Conformers in Neurodegenerative Diseases

    Fernando Goñi, Mitchell Martá-Ariza, Daniel Peyser, Krystal Herline & Thomas Wisniewski

    Scientific Reports 7, Article number: 9881 (2017)


    Published online: 29 August 2017

    Link: https://www.nature.com/articles/s41598-017-10393-z


    > We describe a novel approach to produce conformational monoclonal antibodies selected to specifically react with the β-sheet secondary structure of pathological oligomeric conformers, characteristic of many neurodegenerative diseases. Contrary to past and current efforts, we utilize a mammalian non-self-antigen as an immunogen. The small, non-self peptide selected was covalently polymerized with glutaraldehyde until it reached a high β-sheet secondary structure content, and species between 10–100kDa that are immunogenic, stable and soluble (p13Bri). Inoculation of p13Bri in mice elicited antibodies to the peptide and the β-sheet secondary structure conformation. Hybridomas were produced and clones selected for their reactivity with at least two different oligomeric conformers from Alzheimer’s, Parkinson and/or Prion diseases. The resulting conformational monoclonals are able to detect pathological oligomeric forms in different human neurodegenerative diseases by ELISA, immunohistochemistry and immunoblots. This technological approach may be useful to develop tools for detection, monitoring and treatment of multiple misfolding disorders.

  • This should be of interest for a wide variety of diseases, not just neurodegenerative ones.

    Autocatalytic cycles involving amyloid-like structures have served as models for what might have preceded life itself ([for example](https://www.researchgate.net/profile/Ehud_Gazit/publication/7757479_A_model_for_the_role_of_short_self-assembled_peptides_in_the_very_early_stages_of_the_origin_of_life/links/00b49526fd61a9db09000000/A-model-for-the-role-of-short-self-assembled-peptides-in-the-very-early-stages-of-the-origin-of-life.pdf)), which may explain why it’s so prevalent despite being (apparently) harmful.

  • I see a problem with this strategy for targeting alpha-synuclein, which accumulates in Parkinson’s disease and Lewy body dementia. Alpha-synuclein initially accumulates inside neurons, where antibodies could not reach, and only become extracellular after the neuron dies.

  • All this is above and beyond my knowledge. I know first hand how similar and awful the diseases can be. I truly hope this becomes a successful program or approach to treating these diseases.

  • Wait so does this mean I won’t have to worry about Alzheimer’s when I’m old? That’s one of my greatest fears, tbh.

  • Is this study peer reviewed?

  • Holy fuck, my alma mater. Tom Wisniewski is quietly brilliant! This is a game changer – this is the proverbial need in the haystack! We have ***the*** monoclonal antibody; now, it’s as simple as moving into preclinical models, and then barring the unforeseen within a few years human trials! While the neurodegenerative nature of the disease can be slow (or fast for early onset AD), the clearing of plaques by an immune system primed, likely with some form of genetically modified autologous B-cell infusion, will be rapid! It certainly won’t reverse the symptomatology of /u/Jetsurge’s grandma, but it could halt the disease in its tracks. Very promising pre-preclinical work!

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