PARP inhibitors show promise for treating ALS and other brain disorders

AstraZeneca’s Lynparza and Tesaro’s Zejula—part of an emerging class of cancer medicines known as PARP inhibitors—are on the market and being used to treat ovarian cancer with BRCA mutations. Now new research out of the University of Pennsylvania suggests this class of medicine could prove useful in treating some brain diseases, too.

PARP inhibitors prevent the misplacement of a specific protein that has been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration, the Penn team found. In so doing, it prevents the abnormal protein clumping that’s a hallmark of these and other brain diseases.

The harmful protein, called TDP-43, forms clumps when it is outside the cell nucleus. The protein binds with a molecule called poly(ADP-ribose) (PAR), and as time goes on, they form damaging brain structures known as stress granules. The Penn team found that PARP inhibitors preventPAR from being generated, which cuts down on TDP-43’s harmful effects, according to a statement.

The team made the discovery by testing PARP inhibitors on cultured cells. They observed a drop in the accumulation of TDP-43, they reported in the journal Molecular Cell.

"What excited me about pursuing this pathway was the promise of small molecules that attack the disease process of TDP-43," said lead author Leeanne McGurk, Ph.D., a research associate at Penn, in the statement.

There continues to be strong interest in new candidates to treat ALS, despite some disappointments in the field. In June, Flex Pharma pulled out of a phase 2 trial of its oral ALS candidate because of tolerability issues, for example. But not long after that, Biogen struck a $535 million deal with AliveGen to develop an ALS drug that targets myostatin, which regulates muscle function. And RNAi high-flyer Alnylam said recently it’s preparing to enter clinical trials of one or more drugs that target ALS.

Although no one is testing PARP inhibitors in neurodegenerative disorders quite yet, the new class of drugs is generating interest for its potential utility beyond ovarian cancer. In June, Pfizer wonpriority review from the FDA for its PARP inhibitor, talazoparib, in BRCA-mutated, HER2-negative breast cancer. Meanwhile, researchers at Yale are examining PARP inhibition in rare, inherited cancers, and a group in the U.K. discovered that the drug class might also be effective against hard-to-treat brain tumors.

The Penn researchers believe PARP inhibitors could easily be fine-tuned for use in brain disorders. "Given the lack of treatment options, we are excited by these experiments that help elucidate molecular events that could lead to new therapeutics," said team co-leader Nancy Bonini, Ph.D., a biology professor at the university.

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