Itanapraced’s novel mechanism of action (via the AICD/FoxO3a axis), was recently acknowledged by the Expert Advisory Panel of the World Health Organization, charged with selecting the International Non-Proprietary Name.
Itanapraced represents the first (and thus far only) member of a novel class of pharmacological agents which binds to AICD, with implications for the treatment of several neuroinflammatory and neurodegenerative conditions. In collaboration with the University of Heidelberg using a combination of crystallographic and NMR techniques, CereSpir recently identified itanapraced’s binding site within AICD. The effect of itanapraced binding to AICD has also been elucidated, namely, to prevent AICD from translocating to the nucleus, and thus, diminishing its ability to modulate the expression of several genes. AICD interacts with FoxO3a, a critically important protein which is produced by one of the very few genes strongly associated with human longevity. A key function of FoxO3a in neurons is as part of the cell’s response to oxidative stress where low levels of stress are counterbalanced by FoxO3a’s ability to switch on the production of antioxidant enzymes at the nuclear transcriptional level. However, under conditions of acute or chronic oxidative stress, the initially beneficial effects of FoxO3a are lost when it translocates to the nucleus in association with AICD to co-promote expression of the pro-apoptotic factor Bim leading to cell death. The AICD-FoxO3a axis has also been shown to regulate an important gene called PTEN-induced putative kinase 1 (PINK1) regulating mitochondrial function. When this pathway is dysregulated, it causes the breakdown of mitochondria leading to even more damage from oxidative stress. Additionally, the AICD-FoxO3a interaction may serve to amplify the effects of AICD across multiple pathways such as repair mechanisms, metabolism, autophagy, the immune system and apoptosis.
Itanapraced for the treatment of PD
An important signal promoting translocation of AICD to the nucleus is the phosphorylation of a particular amino acid (Thr-668) contained within its structure. Various protein kinases have been shown to be able to phosphorylate at this position, especially kinases active under conditions of oxidative stress such c-jun N-terminal kinases (JNK) and leucine-repeat-rich kinase-2 (LRRK2) which is believed to play a central role in PD where it is either aberrantly expressed or its activity modified as in the rare gain-of-function LRRK2 mutants. Importantly LRRK2-mediated phosphorylation of Thr-668 has been shown to promote AICD nuclear activity and neurotoxicity in Parkinson’s disease suggesting that an inhibitor of AICD could prevent the loss of dopaminergic neurons and thus slow down or arrest the development of the disease. CereSpir is collaborating with a preeminent group of academic investigators led by Professor Eng King Tan (https://www.duke-nus.edu.sg/content/tan-eng-king) to test itanapraced in preclinical models of PD for its ability to prevent neuronal death. Preliminary beneficial effects of the compound have been observed. CereSpir anticipates initiating phase 2 trials in PD patients in 2019.
Itanapraced for the prevention or treatment of ai-TBI
Both APP and FoxO3a are rapidly upregulated in neurons and glial cells after TBI. Initially, thought to be neuroprotective through the release of the neurotrophic fragment of APP (known as sAPPα) and by induction of anti-oxidant enzymes by FoxO3a, the intensity of oxidative stress from a severe TBI, can conversely, promote neuroinflammation and cell death suggesting that an inhibitor of AICD could be beneficial in treating such patients and prevent the development/progression of ARDS-TBI. A recent study published in the journal Cellular Physiology and Biochemistry in December 2017, provided compelling data showing the ability of itanapraced to attenuate both neurotrauma and acute lung injury in vivo in a preclinical model of TBI. These striking ameliorative effects of itanapraced could be attributed, in significant part, to its effects on preventing the accumulation of hypertrophic microglia. CereSpir anticipates starting Phase 2 trials in 2019.