Prof. Haruhisa Inoue (left) and Keiko Imamura
at press conference.

Professor and neurologist Haruhisa Inoue and his team at the Center for iPS Cell Research and Application (CiRA), Kyoto, Japan, have combined drug repositioning with induced pluripotent stem (iPS) cell technology to find a new candidate drug to combat amyotrophic lateral sclerosis (ALS). The study can be read in Science Translational Medicine.

Drug repositioning describes the use of a drug already approved to treat one disease for treatment on another. It is estimated that drug repositioning can cut the costs of drug discovery to one third, because it avoids exhaustive human tests that measure dosage levels and side effects.

ALS is a devastating disease that rapidly kills motor neurons. Patients normally live only a couple of years after diagnosis, and even the best drugs extend a lifetime just six months or so.

Moreover, ALS is a heterogeneous disease, meaning its cause is diverse. "Only 10% of ALS cases can be attributed to a genetic mutation," said Inoue, and even that 10% contains various mutant causes. This heterogeneity makes standard drug screening all the more difficult. Inoue therefore decided to conduct phenotypic screenings. "The one common phenotype in ALS is the death of motor neurons," he said.

iPS cells were made from the skin or blood cells of patients suffering from different causes of ALS. The lab then differentiated the iPS cells to motor neurons and conducted drug screenings. The screenings regularly found candidate drugs that targeted two particular enzymes. "Srk and c-Abl11 are enzymes that have been associated with various cancers," explains Inoue. "Several anti-cancer drugs inhibit their function."

"ALS motor neurons show an accumulation of protein misfolding. In healthy cells, proper autophagy would prevent the misfolding," he added. Treating the cells with one candidate drug, bosutinib, promoted autophagy and reduced the amount of misfolding. Tests in ALS mouse models showed that bosutinib could extend the lifetime of the mice, again by reducing the amount of protein misfolding. Bosutinib has been approved in multiple countries as an anti-cancer drug since 2013.

Drug repositioning not only offers a new way to treat diseases, it also provides new insights on the molecular mechanisms causing them. ALS is a poorly understood disease, which is one reason why effective treatments remain elusive. These findings give new targets to study how the disease develops. "Maybe inhibiting inhibitors of autophagy will improve outcomes," said Inoue.

Director of CiRA, Shinya Yamanaka, views these findings as another example of the power of iPS cell technology for medical innovation. "The combination of drug repositioning and patient iPS cells will significantly lower the cost of drug development. This will encourage more companies to invest in difficult diseases and bring new treatments to patients faster."

• doi: 10.1126/scitranslmed.aaf3962