ProMIS Neurosciences presents preclinical data on PMN310, RACK1

ProMIS Neurosciences announced data supporting the receptor of activated C-kinase 1 as a potential target in ALS and frontotemporal lobar degeneration with TPD-43-immunoreactive pathology, and updated preclinical data from the Company’s lead candidate for AD, PMN310. The data were presented in poster presentations on April 23 at the 75th American Academy of Neurology Annual Meeting in Boston, MA. Title: Protection Against Toxic Amyloid-beta Oligomers by PMN310, a Monoclonal Antibody Rationally Designed for Greater Therapeutic Potency in Alzheimer’s Disease: Evidence suggests that soluble toxic amyloid-beta oligomers, rather than Abeta monomers or plaque, are a primary driver of synaptic dysfunction, neuronal loss and cognitive decline in AD patients. However, it is difficult to specifically target toxic oligomers since they are much less abundant than other forms of Abeta in the brain. In the poster presented, clinical activity of various Abeta antibodies was shown to correlate with the ability to avoid monomer competition and retain binding to AD brain toxic oligomers. ProMIS’ lead therapeutic candidate, PMN310, showed selective binding to oligomers and was the least impacted by monomer competition compared to other Abeta-directed antibodies. Additionally, PMN310’s lack of binding to Abeta plaque observed in preclinical studies may reduce the risk of brain edema and microhemorrhages associated with plaque-binding antibodies. PMN310 protected memory function in two rodent models of AD, supporting further evaluation of the candidate as a potential therapeutic option for the treatment or prevention of AD. Title: RACK1 Knockdown Is a Potential Therapeutic Target in ALS and FTLD-TDP: ProMIS has evaluated RACK1 as a potential target for ALS and FTLD-TDP. These neurodegenerative disorders are characterized by the formation of pathogenic aggregates of misfolded TAR DNA binding protein 43 inside neurons which have been observed to co-aggregate with misfolded RACK1, a ribosomal protein. In a cell system, the misfolded form of RACK1 was detected by ProMIS antibodies selective for this RACK1 isoform. The poster presented describes how RACK1 knockdown was able to reduce TDP-43 aggregation as well as alleviate the TDP-43-induced global suppression of translation in vitro. Knocking down RACK1 also reduced retinal and motor neuron neurodegeneration in D. melanogaster in vivo. These preclinical findings support misfolded RACK1 as a potential therapeutic target for TDP-43 proteinopathy in non-SOD1 and non-FUS ALS as well as FTLD-TDP.