Posted by „Short road to discovery, winding road to use”
Josef Pitha
I assume that many of you remember the “story” of Dr. Sylvain Lesné, the recognized neuroscientist, author of the controversial Nature publication in 2006 titled: ‘A specific amyloid-beta-protein assembly in the brain impairs memory”. This paper soon became a commonly accepted and acknowledged guideline for investigators working on the pathomechanism of Alzhemier’s disease. (Lesné’s paper with 9725! citations)
Years later – as these findings could not be reproduced by other scientists – the paper was revisited, investigated and suspected to contain manipulated images used for demonstration that amyloid assembly plays a crucial role in Alzheimer’s pathogenesis. Lesné’s highly cited paper has in the meantime been retracted by Nature.
The September 2024 issue of Science published an article titled “Picture Imperfect”, dealing with the story that a prominent, internationally renowned scientist reported results of his misconducted studies in a number of earlier publications on Alzhemier’s disease and Parkinsonism. (Ref.1)
Dr. Eliezer Masliah, the head of the Division of Neuroscience at the National Institute on Aging, author of many seminal and highly cited (over 16,500 citations!) scientific papers over the past 20-25 years, became suspected that many of his papers contain manipulated, doctored images. In September 2024, National Institutes of Health has found clear evidence of research misconduct against Eliezer Masliah, and the Institute communicated: “Following an investigation, the National Institutes of Health (NIH) has made findings of research misconduct against Eliezer Masliah, M.D., due to falsification and/or fabrication involving re-use and relabel of figure panels representing different experimental results in two publications. NIH will notify the two journals of its findings so that appropriate action can be taken.”
NIH first began reviewing misconduct allegations against Masliah already in May 2023, the agency said, beginning an investigation phase in Dec. 2023 that just concluded on Sept. 15 this year. The misconduct findings, involve figures being re-used and re-labeled between two papers representing different experimental conditions, according to the NIH.
These all are image manipulations, cutting and pasting Western blots in order to demonstrate and corroborate the results, authors want to communicate, and also of re-using images and parts of images over and over, even when they should have been produced from different experiments at different times. (It was communicated that between 1997-2023, altogether 133 papers published by Masliah contain suspect images.)
The impact of these publications is well illustrated by the fact that some promising drug candidates were taken over and developed by Pharmaceutical Companies. Some of the challenged research includes work on drug candidates that are currently in clinical trials or are already in use, including treatments for Parkinson’s and Alzheimer’s disease, according to Science’s publication.
Four of fundamental papers by Masliah deal with a drug, prasinezumab with manipulated images, unfortunately. This drug is a humanized monoclonal antibody, targeting alpha-synuclein for Parkinson disease, co-developed by Prothena and Roche companies. Prothena and Roche reported that prasinezumab was found to have no benefit. Given the difficulty of neurodegeneration therapies, it is hard to say if that negative result is an innocent, honest failure of a great idea, or whether based on data which are just not real. There is also a proposed drug for Alzheimer’s therapy, called cerebrolysine, a peptide mixture derived from porcine brain tissue. An Austrian Pharma company (Ever) has run some small trials on it in human patients and distributes this drug in several countries, while cerebrolysine is not approved in the USA or the EU.
A third drug candidate, an experimental small-molecule, minzasolmin is supposed to prevent misfolding of alpha-synuclein and Masliah and co-workers published the original papers that make the case for its effects, they also had doctored images. To develop minzasolmin, Masliah co-founded a company, Neuropore in a partnership with the Beligan UCB Pharma. (Minzasolmin is currently in Phase II trials.)
Figure 1. How many papers need to be scrutinized, yet? (Source Ref. 1)
On Sept. 12, this year the United States Department of Health and Human Services finalized new guidelines for research misconduct investigations conducted by recipients of Public Health Services funding. The new rules clarify the requirements of misconduct investigations, give institutions 90 days to investigate claims instead of 60 and outline an appeals process and potential administrative remedies to misconduct, according to a release. (Ref. 2)
Alzheimer’s and Parkinsonism and Cyclodextrins
Concerning the investigations on the interaction between cyclodextrins (CDs) and neurodegeneration, we have been experiencing an increasing number of papers dealing with cyclodextrin-assisted alleviation of symptoms of Alzheimer’s and Parkinsonism. As CycloLab’s database indicates, more than 180 papers have been so far dedicated to the neuroprotective effect of CDs including effect of CDs on Alzheimer’s and Parkinsonism. To the best of my knowledge among this large body of publications, very few can be found to report contradictory data compared to those by earlier investigations. So, cyclodextrins have been performing convincingly and reliably well in the field of neuroprotection, both in vitro and in vivo.
One of the first studies reported by Camilleri et al in 1994, dealt with the interaction of beta-CD with amyloid beta-A4 peptide. (Ref. 3)
Another pioneering work by Jens Danielsson et al communicated the results of structural background of interaction of Alzheimer Aβ(1−40) Peptide and beta-CD by using Combined PFG-NMR Diffusion and Induced Chemical Shifts. (Ref 4)
A dedicated mouse model was used to corroborate efficacy of HPBCD against Alzheimer’s disease by Flint Beal’s team and they reported on highly convincing in vitro/in vivo correlation on t he protective effect of HPBCD. (Ref. 5)
A Japanese team published on the interaction between beta-CD and Amyloid beta-peptide by NMR- and circular dichroism studies and detailed the mode of interaction of Alzheimer beta-amyloid peptide (12-28) with beta-cyclodextrin. (Ref. 6)
The seminal work of Knut Wittkowski on the suitability of alpha-cyclodextrins in neuroprotection represents a further promising way to approach Alzheimer’s. Recent regulatory and scientific developments suggest a novel oral formulation of HP-alpha-cyclodextrin as a safe (not ototoxic) and convenient (oral) drug candidate against Alzheimer’s disease. (Ref. 7) A Chinese group reported on the antioxidant and anti-Alzheimer’s disease activities of 1,8-cineole and its beta-CD inclusion complex. (Ref. 8)
Scientists at University of Debrecen reviewed the „beyond – excipient” function of different CDs and wrote that more and more data suggest, CDs can be also considered full-fledged API drug candidates, too. (Ref. 9)
A comprehensive overview on the medicinal action of cyclodextrins in neurodegenerative diseases was by Susana Braga with impressive list of relevant references. (Ref 10)
Finally, we have to mention here a paper that deals with conflicting actions of 2-hydroxypropyl-β-cyclodextrin, a reputed potent modifier of cholesterol efflux from cellular membrane and endo-lysosomal compartments on autophagy flux in vivo in brains of normal- and Alzheimer model mice. The findings reported provide in vivo evidence for lysosomal enhancing properties of HPBCD, but also a caution that prolonged interference with cellular membrane fusion/autophagosome maturation could have unwanted consequences, which might require careful optimization of dosage and dosing schedules. (Ref. 11)
References:
- Derek Lowe: Fraud, So Much Fraud, Science 27 Sept 2024. https://www.science.org/content/blog-post/fraud-so-much-fraud
- https://www.hhs.gov/about/news/2024/09/12/hhs-finalizes-rule-research-misconduct-foster-research-integrity.html)
- P Camilleri , N J Haskins, D R Howlett Cyclodextrins and Neurodegenerative diseases J Exp Med FEBS Lett . 2012 Dec 17;209(13):2501-13. doi: 10.1084/jem.20121239. Epub 2012 Dec 3.
- Jens Danielsson, Jüri Jarvet, Peter Damberg. Astrid Gräslund Two-Site Binding of β-Cyclodextrin to the Alzheimer Aβ(1−40) Peptide Measured with Combined PFG-NMR Diffusion and Induced Chemical Shifts †Biochemistry 2004, 43, 20, 6261–6269. https://doi.org/10.1021/bi036254p
- Jiaqi Yao, Daniel Ho, Noel Y Calingasan, Nina H Pipalia, Michael T Lin, M Flint Beal Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J Exp Med 2012 Dec 17;209(13):2501-13. doi: 10.1084/jem.20121239.
- Qin XR, Abe H, Nakanishi H. NMR and CD studies on the interaction of Alzheimer beta-amyloid peptide (12-28) with beta-cyclodextrin. Biochem Biophys Res Commun. 2002 Oct 4;297(4):1011-15. doi: 10.1016/s0006-291x(02)02337-9.
- Knut M. Wittkowski Alzheimers and Dementia Supplement: Drug Development December 2021 https://doi.org/10.1002/alz.057530
- XinTan, RuiXu, Ai-Pei Li, Dan Li,et al Antioxidant and anti-Alzheimer’s disease activities of 1,8-cineole and its cyclodextrin inclusion complex. Biomedicine & Pharmacotherapy 175, 2024, 116784. 10.1016/j.biopha.2024.116784
- Kovacs T, Nagy P, Panyi G, Szente L, Varga Z, Zakany F. Cyclodextrins: Only Pharmaceutical Excipients or Full-Fledged Drug Candidates? Pharmaceutics. 2022 Nov 22;14(12):2559. doi: 10.3390/pharmaceutics14122559.
- Susana Santos Braga Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases Biomolecule 2023,13(4), 666; https://doi.org/10.3390/biom13040666
- Dun-Sheng Yang et al Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice Hum Mol Genet .2017 Mar 1;26(5):843-859. doi: 10.1093/hmg/ddx001.