New target could yield treatment for Alzheimer's, ALS and more

Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are two very different brain diseases with one common characteristic: They both cause a progressive loss of brain cells that scientists have so far failed to prevent. Now a team of academic and industry researchers led by Roche unit Genentech has discovered a protein that, when blocked, reverses a signaling pathway that causes neurodegeneration in these conditions.

The research, published in the journal Science Translational Medicine, has inspired a new experimental treatment for ALS that’s now entering clinical trials, but it could find even broader applications. "The most noteworthy result of this study is that manipulation of this single pathway was sufficient to ameliorate disease symptoms in diverse models of neurodegenerative disease," said the authors in an interview that was released along with the study.

The focus of their work is a protein called dual leucine zipper kinase (DLK), which regulates neurodegeneration in both AD and ALS. DLK activates another protein called c-Jun N-terminal kinase (JNK), which induces brain-cell death. The authors demonstrated that DLK/JNK signaling is elevated in both mice and people with AD and ALS, and that deleting the gene that makes DLK protected against neuron loss in mouse models of ALS.

The researchers then developed two drugs to inhibit DLK. They both reduced JLK signaling in mouse models of ALS, and one delayed progression of the disease by 10%.

Genentech has now launched a phase 1 study evaluating an oral DLK inhibitor called GDC-0134, in people with ALS. They plan to enroll 70 patients at 9 clinical trial sites. "As DLK is a kinase, it belongs to a very druggable target class," the authors said. DLK inhibition also holds promise in Alzheimer’s, they added. "Inhibiting the activity of DLK alone or perhaps in combination with other disease modifying treatments (including an anti-Abeta therapy for Alzheimer's disease) may protect neurons from dying and improve clinical outcomes."

As biotech watchers know all too well, the neurology field is littered with disappointments in drug development for ALS and Alzheimer’s. That has sparked a worldwide search for better drug targets, which are emerging at a rapid pace. Just last week, for example, a Yale team described a link they discovered between amyloid plaques in AD and the failure of lysosomes in the brain to dispose of cellular waste. Earlier this year, scientists at the Mayo Clinic outlined their discovery of an ALS-related protein called polyGP, which results from a genetic mutation that may be targetable with drugs.

Biotech companies are following the developments closely and pursuing promising leads. The Genentech researchers are so encouraged by their findings, in fact, that lead author Claire E. Le Pichon started a new lab at the National Institutes of Health to further explore the role of DLK in brain diseases.