Lindsay Burns

Lindsay H. Burns (born January 6, 1965[1]) is an American neuroscientist and rower who won a silver medal at the 1996 Summer Olympics.[2] She is presently the Senior Vice President of a pharmaceutical company Cassava Sciences based in Austin, Texas. The company largely relies on her research and one of her major works, the discovery and development of simufilam (a drug for Alzheimer's disease) has met with scientific controversies since 2021.[3][4][5] She graduated in neuroscience from Harvard University, Cambridge, Massachusetts, and earned her PhD from the University of Cambridge, England.

Lindsay Burns
Personal information
BornJanuary 6, 1965 (1965-01-06) (age 57)
Big Timber, Montana, U.S.
Medal record
Women's rowing
Representing  United States
Olympic Games
1996 Atlanta Lwt double sculls
World Rowing Championships
1987 Copenhagen Lwt four
1990 Tasmania Lwt double sculls
1991 Vienna Lwt double sculls
1994 Indianapolis Lwt double sculls

Biography

Burns was born in Big Timber, Montana. She studied neuroscience at Harvard University from 1983[6] and graduated with a BS degree in 1987.[1] She went to England for a PhD research at the University of Cambridge. Supervised by Barry Everitt and Trevor Robbins,[7][8] she obtained her doctoral degree on the thesis Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes in 1991.[9]

She worked as a research fellow in psychobiology at McLean Hospital in Belmont, Massachusetts.[6] She later joined Cassava Sciences and became its Senior Vice President in 2021.[10] She is married to Remi Barbier, the founder, Chief Executive Officer and president of the company.[11]

Rowing career

Burns started competitive rowing soon after joining Harvard.[6] In 1987, she rowed in the Radcliffe varsity crew and won the Eastern Association of Women's Rowing Colleges (EAWRC) championship that gave her the Ivy title and the EAWRC League title.[12] She was included the US rowing team from 1987 and remained till 1996. Having competed at six World Championships, she had won four medals such as gold in the four in 1987, silvers in the double in 1990-91, and a bronze in the double in 1994, all in the lightweight category. She also won a silver medal at the 1995 Pan American Games competing in the quad sculls (heavyweight) category.[2] She was an alternate rower at the 1996 Summer Olympics in Barcelona, Spain. But she did not make it to the competition.[1]

She teamed up with Teresa Bell at the 1996 Summer Olympics in Atlanta, Canada, and won the second prize (silver medal) in the Lightweight Double Sculls.[2] In 2006, she was inducted into the Harvard Sports Hall of Fame.[12]

Scientific works

Burns' first research was on the effect of neurokinin A on brain functions in rats. Her first paper in 1988, written with Ann E. Kelley, reported the how dopamine carried cell signal of neurokinin A to induce behavioral changes.[13] She continued her PhD research on the role of dopamine in nerve cells.[7][8][9] While working at McLean Hospital, she focussed on the nature of brain damages.[14] Her collaborative research involved transplantation of pig neural cells into rat brain as a possible treatment of Parkinson's or Huntington's disease.[15] Further research indicated possible use in humans.[16] She continued to study the effects of amphetamine,[17] and of ziconotide in a rat model of spinal cord ischemia.[18]

Cassava Sciences (as Pain Therapeutics) was established in 1998 with projects on the development of three drug candidates: Oxytrex, Remoxy and PTI-901.[19][20] Burns joined the company as the leading scientist.[5] In 2005, she published a series of papers on Oxytrex and related research (opioid antagonists) on prevention of drug dependence.[21][22][23][24]

Since 2006, Burns collaborated with Hoau-Yan Wang, an Associate Medical Professor at the City University of New York,[25] who had been investigating Alzheimer's disease.[26][27][28] She and Wang linked up the research on opioid antagonists with Alzheimer's that became the field of their most important contributions.[29][30][31]

Discovery of simufilam and research controversies

In 2008, Burns, Wang and Maya Frankfurt published an important discovery in PLOS One that opioid antagonists such as naloxone and naltrexone bind to a protein called filamin A (FLNA).[32] Burns and Wang gave further confirmation and the possible signalling mechanism of the molecular binding in the same journal the next year.[33] FLNA is a cytoplasmic protein that maintains normal cell shape and division. Their further studies revealed that FLNA has important implications in brain disease like Alzheimer's disease in which the protein is misfolded.[30][34]

In 2010, Burns and Wang announced the discovery of "a novel analgesic" which they named PTI-609 (PTI for Pain Therapeutics, Inc.) and claimed that the molecule binds to FLNA. They declared: "PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone."[35] In 2012, they published in The Journal of Neuroscience a related "a novel compound" PTI-125 as that similarly binds to FLNA.[34] In 2017, they reported in Neurobiology of Aging an experimental demonstration of PTI-125 binding to distorted FLNA restoring normal FLNA in Alzheimer mice.[36][37]

In 2018, the National Institutes of Health granted Pain Therapeutics $260,585 for the clinical trials of PTI-125 as an Alzheimer drug.[38][39] The company name was changed to Cassava Sciences, Inc.[40] The United States Adopted Names (USAN) gave the chemical name as simufilam in 2020.[41] The same year, results of the first initial clinical trials were announced as a failure.[11] Subsequent trials were reported as good results.[42] The last trials Phase III started in February 2021.[43]

David Bredt, a neuroscientists at Johnson & Johnson,[44] has become suspicious of the research methods and findings on FLNA binding and simufimal trials. As he examined the research papers he came to the conclusion, saying, "They [Burns and Wang's papers] were making statements that were incompatible with biology and with pharmacology," and such important discoveries deserved to "win five Nobel Prizes."[3] With Geoffrey Pitt, a cardiologist and a professor at Weill Cornell Medical College, they discussed the issue with Jordan A. Thomas of the law firm Labaton Sucharow.[45] In August 2021, Thomas submitted a citizen petition to the Food and Drug Administration expressing concerns of unreliable research and misuse of scientific data and requesting investigation into the Cassava Sciences works.[11] However, the FDA responded in that it could not investigate the case and had to reject the petition, saying:

We take the issues you raise seriously. Please note that your Petitions are being denied solely on the grounds that your requests are not the appropriate subject of a citizen petition. This response does not represent a decision by the Agency to take or refrain from taking any action relating to the subject matter of your Petitions.[46]

Other scientists also started to make public comments that the research on simufilam is unreliable. To the link between filamin A and Alzheimer's disease, Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, noted: "But in fact, all the evidence seems to be from this [Wang's] lab." Robert Howard, professor of psychiatry at the University College London, remarked on the lack of placebo and small sample size that making such research conclusion "at the very least is implausible." Thomas C. Südhof, Nobel laureate neuroscientist at Stanford University, also commented: "The overall conclusions with regard to Alzheimer’s disease make no sense to me whatsoever... [The findings of Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."[3] While the FDA did not take any action, PLOS One retracted five of Wang's papers in March 2022, two of which were published with Burns[47] that reported the original discovery of FLNA binding,[32][33] the retraction notes of which reads:

The data and comments provided did not resolve the concerns about the integrity and reliability of data presented in this article. In light of these issues, the PLOS ONE Editors retract this article. The authors [Hoau-Yan Wang and Lindsay Burns] did not agree with the retraction. HYW stands by the article’s findings.[48][49]

In January 2022, The Journal of Neuroscience issued an expression of concern on the 2017 paper,[34] saying that "[It] will await the outcome of that investigation [by the City University of New York] before taking further action.[50] In May 2022, Neurobiology of Aging also issued an expression of concern on the 2017 paper,[36] saying that it "will make a final decision as to appropriate corrective action once that inquiry has been concluded."[51]

References
  1. "Olympedia – Lindsay Burns". www.olympedia.org. Retrieved May 2, 2022.
  2. "Biography: Lindsay Burns". Olympics. International Olympic Committee. Retrieved May 2, 2022.
  3. Mandavilli, Apoorva (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved April 28, 2022.
  4. "Retractions of a Key Collaborator's Papers Set Up a Big April for Cassava Sciences". Seeking Alpha. March 31, 2022. Retrieved May 2, 2022.
  5. Singh, Vandana (April 19, 2022). "New York Times Report Fresh Allegations On Cassava's Simufilam Alzheimer's Trials, Shares Fall". Business Insider. Retrieved May 3, 2022.
  6. "Harvard at the Olympics". Harvard Magazine. Retrieved May 3, 2022.
  7. Burns, L; Robbins, T; Everitt, B (1993). "Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine". Behavioural Brain Research. 55 (2): 167–183. doi:10.1016/0166-4328(93)90113-5.
  8. Burns, Lindsay H.; Everitt, Barry J.; Kelley, Ann E.; Robbins, Trevor W. (1994). "Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement". Psychopharmacology. 115 (4): 516–528. doi:10.1007/BF02245576.
  9. Burns, Lindsay H. (1991). Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes (Ph.D. thesis). University of Cambridge. OCLC 556753196.
  10. "Lindsay H Burns, Cassava Sciences Inc: Profile and Biography". Bloomberg.com. Retrieved May 3, 2022.
  11. Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Retrieved April 29, 2022.
  12. "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.
  13. Burns, Lindsay H.; Kelley, Ann E. (1988). "Neurokinin-α injected into the ventral tegmental area elicits a dopamine-dependent behavioral activation in the rat". Pharmacology Biochemistry and Behavior. 31 (2): 255–263. doi:10.1016/0091-3057(88)90343-7.
  14. Burns, Lindsay H.; Annett, Lucy; Kelly, Ann E.; Everitt, Barry J.; Robbins, Trevor W. (1996). "Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: Implications for limbic—striatal interactions". Behavioral Neuroscience. 110 (1): 60–73. doi:10.1037/0735-7044.110.1.60. ISSN 1939-0084.
  15. Isacson, Ole; Deacon, Terrence W.; Pakzaban, Peyman; Galpern, Wendy R.; Dinsmore, Jonathan; Burns, Lindsay H. (1995). "Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres". Nature Medicine. 1 (11): 1189–1194. doi:10.1038/nm1195-1189.
  16. Galpern, Wendy R.; Burns, Lindsay H.; Deacon, Terrence W.; Dinsmore, Jonathan; Isacson, Ole (1996). "Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology". Experimental Neurology. 140 (1): 1–13. doi:10.1006/exnr.1996.0109.
  17. Parkinson, John A.; Olmstead, Mary C.; Burns, Lindsay H.; Robbins, Trevor W.; Everitt, Barry J. (1999). "Dissociation in Effects of Lesions of the Nucleus Accumbens Core and Shell on Appetitive Pavlovian Approach Behavior and the Potentiation of Conditioned Reinforcement and Locomotor Activity byd-Amphetamine". Journal of Neuroscience. 19 (6): 2401–2411. doi:10.1523/JNEUROSCI.19-06-02401.1999. PMC 6782569. PMID 10066290.
  18. Burns, Lindsay H.; Jin, Zhen; Bowersox, S.Scott (1999). "The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia". Journal of Vascular Surgery. 30 (2): 334–343. doi:10.1016/S0741-5214(99)70145-X.
  19. Jacobs, Tom (2005). "No pain, no gain?". Nature Biotechnology. 23 (8): 934–934. doi:10.1038/nbt0805-934.
  20. Wolfson, Wendy (2005). "Janus-Faced Drugs: The Double-Edged Synthetic Opiate Trade". Chemistry & Biology. 12 (10): 1055–1056. doi:10.1016/j.chembiol.2005.10.003.
  21. Chindalore, Vishala L.; Craven, Richard A.; Yu, K. Peony; Butera, Peter G.; Burns, Lindsay H.; Friedmann, Nadav (2005). "Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex". The Journal of Pain. 6 (6): 392–399. doi:10.1016/j.jpain.2005.01.356.
  22. Olmstead, Mary C.; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats". Psychopharmacology. 181 (3): 576–581. doi:10.1007/s00213-005-0022-7.
  23. Leri, Francesco; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats". Pharmacology Biochemistry and Behavior. 82 (2): 252–262. doi:10.1016/j.pbb.2005.08.008.
  24. Burns, Lindsay H.; Vanderah, Todd W.; Wang, Hoau-Yan (2009), Dean, Reginald L.; Bilsky, Edward J.; Negus, S. Stevens (eds.), "Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance", Opiate Receptors and Antagonists, Totowa, NJ: Humana Press, pp. 3–17, doi:10.1007/978-1-59745-197-0_1, ISBN 978-1-58829-881-2, retrieved May 3, 2022
  25. Wang, Hoau-Yan; Burns, Lindsay H. (2006). "Gβγ that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein". Journal of Neurobiology. 66 (12): 1302–1310. doi:10.1002/neu.20286.
  26. Wang, H. Y.; Lee, D. H.; Davis, C. B.; Shank, R. P. (2000). "Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors". Journal of Neurochemistry. 75 (3): 1155–1161. doi:10.1046/j.1471-4159.2000.0751155.x. PMID 10936198.
  27. Wang, Hoau-Yan; Lee, Daniel H.S.; D'Andrea, Michael R.; Peterson, Per A.; Shank, Richard P.; Reitz, Allen B. (2000). "β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity". Journal of Biological Chemistry. 275 (8): 5626–5632. doi:10.1074/jbc.275.8.5626. PMID 10681545.
  28. Gopalan (May 24, 2007). "Magnets to the rescue of Alzheimer's patients". Medindia. Retrieved May 3, 2022.
  29. Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W. (2008). "Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling". The Journal of Pain. 9 (8): 700–713. doi:10.1016/j.jpain.2008.03.005. PMC 5469510. PMID 18468954.
  30. Burns, Lindsay H.; Wang, Hoau-Yan (2017). "Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease". Neuroimmunology and Neuroinflammation. 4 (12): 263–271. doi:10.20517/2347-8659.2017.50. PMC 8294116. PMID 34295950.
  31. Wang, Hoau‐Yan; Pei, Zhe; Xu, Qiang; Brunelle, Lynn A; Burns, Lindsay H.; Thornton, George Ben (2021). "SavaDx, a novel plasma biomarker to detect Alzheimer's disease, confirms mechanism of action of simufilam". Alzheimer's & Dementia. 17 (S5): online. doi:10.1002/alz.054385.
  32. Wang, Hoau-Yan; Frankfurt, Maya; Burns, Lindsay H. (February 6, 2008). "High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence". PLOS One. 3 (2): e1554. doi:10.1371/journal.pone.0001554. PMC 2212716. PMID 18253501.
  33. Wang, Hoau-Yan; Burns, Lindsay H. (2009). "Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine". PLOS One. 4 (1): e4282. doi:10.1371/journal.pone.0004282. ISSN 1932-6203. PMC 2628740. PMID 19172190.
  34. Wang, H.-Y.; Bakshi, K.; Frankfurt, M.; Stucky, A.; Goberdhan, M.; Shah, S. M.; Burns, L. H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". Journal of Neuroscience. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492.
  35. Burns, Lindsay H.; Wang, Hoau-Yan. "PTI-609: A Novel Analgesic that Binds Filamin A to Control Opioid Signaling". Recent Patents on CNS Drug Discovery (Discontinued). 5 (3): 210–220. doi:10.2174/157488910793362386. PMID 20726836.
  36. Wang, Hoau-Yan; Lee, Kuo-Chieh; Pei, Zhe; Khan, Amber; Bakshi, Kalindi; Burns, Lindsay H. (2017). "PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis". Neurobiology of Aging. 55: 99–114. doi:10.1016/j.neurobiolaging.2017.03.016.
  37. Toniolo, Sofia; Sen, Arjune; Husain, Masud (2020). "Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer's Disease". International Journal of Molecular Sciences. 21 (23): 9318. doi:10.3390/ijms21239318. PMC 7730926. PMID 33297460.
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  39. Cassava Sciences, Inc. (September 7, 2021). "A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multiple Dose, Biomarker and Safety Study of PTI-125 in Mild-to-moderate Alzheimer's Disease Patients". National Institute on Aging (NIA).
  40. Schoen, Eric (March 27, 2019). "Pain Therapeutics Announces Name Change to Cassava Sciences, Inc". GlobeNewswire. Retrieved April 28, 2022.
  41. Inc, Cassava Sciences (August 24, 2020). "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN". GlobeNewswire News Room. Retrieved May 3, 2022.
  42. Wang, H.-Y.; Pei, Z.; Lee, K.-C.; Lopez-Brignoni, E.; Nikolov, B.; Crowley, C.A.; Marsman, M.R.; Barbier, R.; Friedmann, N.; Burns, L.H. (2020). "PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients". The Journal of Prevention of Alzheimer's Disease: 1–9. doi:10.14283/jpad.2020.6.
  43. Owusu, Tony (February 28, 2021). "Cassava Jumps on Plan for Phase 3 Trial of Alzheimer's Drug". TheStreet. Retrieved April 30, 2022.
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  49. "Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine". PLOS One. 17 (3): e0266629. 2022. doi:10.1371/journal.pone.0266629. PMC 8967007. PMID 35353864.
  50. "Expression of Concern: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". Journal of Neuroscience. 42 (3): 529–529. January 19, 2022. doi:10.1523/JNEUROSCI.2306-21.2021. ISSN 0270-6474. PMID 34921050.
  51. "Expression of Concern: Wang et al., (2017) PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol. Aging, 55:99-114". Neurobiology of Aging. 113: 152. 2022. doi:10.1016/j.neurobiolaging.2022.03.012.
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