4:12 PM
Nov 06, 2018
 |  BC Extra  |  Preclinical News

Hopkins study props up PARP inhibitors for Parkinson's

A study in mice showed the potential of repurposed PARP-1 inhibitors to reverse aggregate α-synuclein-induced neuronal cell death in Parkinson's disease.

PARP inhibitors Lynparza olaparib, Zejula niraparib, Talzenna talazoparib and Rubraca rucaparib are marketed or approved for cancers where PARP-1 is necessary for DNA repair. Earlier studies had shown that PARP-1 activation also led to progressive loss of dopaminergic neurons in PD. However, safety and tolerability concerns intrinsic with PARP inhibitors have previously weighed against clinical testing for PD, as chronic treatment would be necessary to treat the neurodegenerative disease.

In a paper published Nov. 1 in Science, researchers from the Johns Hopkins University School of Medicine injected α-synuclein fibrils into mouse neurons as a PD model, inducing PARP activation and neuron death in vitro and in mouse brains. In vitro, Talzenna, Rubraca and veliparib reversed the effect, and in vivo, veliparib decreased dopamine neuron loss and α-synuclein pathology.

The PARP inhibitors prevented PARP activation and cell death in vitro at concentrations as low as 10 nM, suggesting that low doses may be sufficient to achieve clinical benefit, which might alleviate some toxicity concerns.

Clovis Oncology Inc. (NASDAQ:CLVS) markets Rubraca for ovarian cancer.

AstraZeneca plc (NYSE:AZN; LSE:AZN) markets Lynparza to treat ovarian and breast cancer. Merck & Co. Inc. (NYSE:MRK) markets Zejula for ovarian cancer and Pfizer Inc. (NYSE:PFE) markets Talzenna for breast cancer.

AbbVie Inc. (NYSE:ABBV) is evaluating veliparib in Phase III testing for breast, lung and ovarian cancers; Phase II testing for liver and skin cancers; and Phase I testing for additional solid tumors and hematologic malignancies.

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