PZ-2891 Offers New Therapeutic Option for Pantothenate Kinase-Associated Neurodegeneration

PZ-2891 is a new and unique therapeutic agent that has shown to be able to penetrate the blood-brain barrier and increase coenzyme A (CoA) levels in mice, leading to increased weight, longer life span, as well as improving locomotor activity, based on results from a study by Sharma et al.

Pantothenate Kinase-associated Neurodegeneration (PKAN) is a life-threatening neurological disorder that has no available treatments. Patients with PKAN have a mutation in the human PANK2 gene, causing a deficiency in CoA, leading to neurodegenerative symptoms such as impaired balance, speech, vision, and cognition. In the past, investigators have used protected phosphopantothenates to bypass PANK in hopes of restoring CoA levels. However, their efforts were futile because the compounds could not penetrate the blood-brain barrier, and thus had no effect on CoA levels.

PZ-2891 is a new compound that was created to activate the alternate PANK isoforms and has been able to cross the blood-brain barrier to elevate brain CoA. Sharma et al, identify the mechanism of action of PZ-2891 along with its results in mice with CoA deficiency.

PZ-2891 is classified as a PANK modulator, and it works mainly by activating 2 other PANK isoforms to match the loss from PANK2 to elevate CoA levels. Pantothenate kinase is the rate-controlling step for CoA; by working as an orthosteric inhibitor at high concentrations and an allosteric activator at lower concentrations, PZ-2891 diminishes the feedback inhibition of PANK and increases CoA levels in cells and tissues.

In-vitro tests were done in human liver-derived cell lines. When these cells were treated with PZ-2891, CoA levels increased. In cells that had inactive PANK3, PZ-2891 did not work, signifying the need for catalytically active PANK3. A reduction in pantothenate in the cell culture also reduced CoA synthesis, but had no effect on the CoA content itself, leading investigators to conclude that PANK was the sole rate-controlling step in the pathway of CoA.

The effect that PZ-2891 can have on CoA levels were next tested in mice. Mice administered PZ-2891 were noted to require higher doses to increase CoA in the brain compared to the liver. To determine if PZ-2891 would be useful in PKAN, investigators chose mice who did not have active PANK2 to stimulate patients with mutation in the PANK2 gene.

In these mice, PZ-2891 increased CoA level to the same extent as mice with PANK2, signifying that the activation of PANK1 and PANK3 was enough to activate CoA biosynthesis. The clinical efficacy of PZ-2891 was also examined in mice with brain CoA deficiency. In mice treated with PZ-2891, weight gain was immediate, and these mice lived 3 times the median survival than mice that were untreated (150 days versus 52 days). Furthermore, PZ-2891 helped improve locomotor activity in mice with these severe growth and locomotor defects.

Although these results are only in mice, additional optimization may lead PZ-2891 into becoming a much-needed therapeutic option for patients with PKAN.

Reference

Sharma LK, Subramanian C, Yung M, et al. A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat Commun. 2018;9(1):4399. doi: 10.1038/s41467-018-06703-2..