Tag Archives: AZP2006

London calling, again

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Three more encouraging reports from the Neuro 2023 conference jointly sponsored by CurePSP and the PSP Association of the UK, held in London on October 19 and 20.

  • In a series of 48 people with corticobasal syndrome (CBS) during life who had brain autopsies, the underlying pathology was actually corticobasal degeneration (CBD) in 16 (33%), PSP in 14 (29%), Alzheimer’s disease in 6 (13%) and other conditions in the rest.  Similar results have been found many times before, but this study analyzed the neurologists’ office notes and found that actual CBD pathology was most likely in patients with gait freezing as one of the first symptoms.  Among those without early freezing, CBD was most common in those with no early speech problems and onset before age 66.  Those with PSP pathology tended to have had early speech difficulty and onset after age 61.  These observations could be useful to neurologists in separating CBD from PSP during life for purposes of prognostication and treatment trial enrollment. (Ikuko Aiba, et al., Higashinagoya National Hospital, Japan)
  • In 2018, the TRIM11 gene on chromosome 1 was identified as the location of a variant influencing the onset age of PSP, but the precise molecular mechanism underlying that effect remained unknown.  Now, researchers have teased out a single nucleotide variant in an intron (a section of the gene regulating the rate of manufacture of the protein it encodes rather than its amino acid sequence) of TRIM11.  They found that the protein encoded by TRIM11 tags abnormal tau for degradation by the 26S proteasome, which is one of the cell’s garbage disposal systems, and that the variant reduces the production of that protein. This means that somehow stimulating TRIM11’s expression (the rate at which it encodes its protein) could slow the spread of abnormal tau and the progression of PSP. (Sumi Bez et al, University College, London, UK)
  • The drug ezeprogind (previously called AZP2006) has shown favorable results in an early-phase test for safety in people with PSP.  The trial was too brief and small to establish efficacy, but the sponsor, Alzprotect of Loos, France, notes “very promising trends” in slowing progression of the disease.  The orally-administered drug works by reducing inflammation and by improving the action of the lysosomes, one of the cell’s garbage disposal mechanisms.  It will now enter a 120-patient efficacy trial using slowing of progression on the PSP Rating Scale after 12 months as its primary outcome measure.  Half of the 24 trial sites will be in the US and half in Europe.  A start date has not been announced. (Noelle Callizot, et al, Alzprotect, Loos, France)

Appetizer, entrée and dessert

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. . . and today, three news morsels:

First, sleep: Researchers at UCSF led by Jun Yeop Oh sought correlations between loss of specific areas of brain cells in the autopsies of 12 people with Alzheimer’s and 10 with PSP who during life had had detailed sleep studies.  They found relationships between several specific abnormalities of sleep with loss of neurons in two clusters of cells in the hypothalamus that use orexin and histamine, respectively, as their neurotransmitters.  A third area known to be related to sleep, the (dopamine-using) locus ceruleus in the midbrain, showed little or no such correlation.  The authors conclude that this line of inquiry “is crucial in designing the next generation of sleep medications [by boosting orexin or histamine] and even slowing down the progress of neurodegenerative disease through early interventions.”

Next, tau: A report from Michela Marcatti and colleagues at University of Texas Medical Branch in Galveston describes important differences between Alzheimer’s and PSP in the way their abnormal tau acts on the brain’s synapses.  They specifically looked at soluble oligomers – clumps of only a few tau molecules that remain soluble in the brain’s fluids, making them far more toxic than the larger, insoluble neurofibrillary tangles.  They found that in AD, tau oligomers displace beta-amyloid oligomers from the synapses after the initial disease stages, which may explain why treatments aimed at beta-amyloid have failed to date.  This bolsters our hopes AD and PSP could share a common treatment. The authors also suggest that the various tau oligomers’ different patterns of attack on the synapses might explain the different subtypes of PSP. 

Finally, a new drug: The oral drug AZP2006 is presently in a clinical trial for PSP in Europe. It acts by enhancing the effect of progranulin, a protein involved in multiple cell processes with potential relationships to neurodegeneration.  Researchers at Alzprotect, the French drug company sponsoring the trial, published the effects of AZP2006 in cultures of rat brain cells (neurons and microglia together) and in mice that had been genetically engineered to age quickly. It reduced abnormal tau phosphorylation and inflammation in the cultures and slowed the rate of cognitive decline in the mice.  It actually restored some of the animals’ lost cognitive abilities (!!), but we don’t know how long that benefit would last or if it resulted from rescue of sick cells or from some more ordinary drug action.