PARP Inhibitor Tested in Cancer Patients Might Treat ALS, Study Suggests

Medicines used for ovarian and breast cancer, called PARP inhibitors, might be repurposed to treat people with amyotrophic lateral sclerosis (ALS), a study in cells suggests.

This suggestion came from researchers’ work with veliparib (ABT-888), an investigational PARP inhibitor, that found it effectively reduced TDP-43 aggregates — a hallmark of ALS — in lab-grown cells, and prevented neuronal death in primary cultures of rat spinal cord.

The study, “Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis,” was published in the journal Acta Neuropathologica Communications.

Aggregates of the TDP-43 protein are a hallmark of ALS, appearing in more than 95% of patients. TDP-43, however, is not the sole component of these aggregates, and studies have shown that other proteins, including those involved in stress response, may also be found within these aggregates.

Stress response proteins are seen as potential players in ALS. Their manipulation in cell and mouse models of ALS has been shown to reduce signs of the disease. But whether they are a consequence of the disease are an active participants in ALS remains to be addressed.

PARPs are enzymes involved in stress response that participate in signaling pathways by adding polymers, called PAR, onto target proteins. Researchers had previously shown that PAR could increase the accumulation of TDP-43 in cells, causing ALS-associated features in cell models of the disease.

Researchers here examined the role of the two most important PARPs — PARP1 and PARP2 — in cell and animal models of ALS.

Looking at spinal cord tissue from 27 ALS patients (median age, 59) and from 16 people without any neurological disorders, they found that PAR was elevated in the nucleus of motor neurons (nerve cells) from most ALS patients (89%), and in 19% of those without ALS.

The research team then induced TDP-43 accumulation in the cytoplasm of cells cultured in the lab under conditions that caused stress to the cells. They also induced TDP-43 buildup by genetically engineering the cells and subjecting them to stress.

In both cases, treatment with veliparib reduced TDP-43 buildup significantly, compared to cells not given such treatment.

Veliparib is a molecule that blocks the activity of PARPs, and has or is being investigated in clinical studies for lung, breast, and ovarian cancers, although not always with success. Other PARP inhibitors, like Lynparza (olaparib) and Zejula (niraparib), are approved for certain cancer indications.

Researchers also cultured motor neurons from rats in the laboratory and induced excessive production of TDP-43 to promote aggregate formation. The approach caused neurons to die, but veliparib use significantly lessened nerve cell death in these cultures.

“Our study implicates the activation of PARP-1/2 in the motor neuron nuclei of the ALS spinal cord. We show that treatment with Veliparib, a PARP-1/2 inhibitor, reduces stress-induced accumulation of TDP-43 in the cytoplasm of mammalian cells,” investigators wrote.

While the mechanisms that link PARP activity and TDP-43 in ALS remain to be addressed, the findings suggest that veliparib, and possibly other PARP inhibitors already on the market, could be studied as therapeutic approaches for ALS.

“We suggest that the PARP superfamily is an area that should be explored further in ALS therapeutics,” the researchers concluded.