Investigational Therapy Appears to Prevent Neuron Death, Improve Huntington’s Symptoms in Mice

A drug in clinical development by Takeda for schizophrenia, called TAK-063, was seen to reduce neuron death and improve symptoms in mice with Huntington’s disease. But the data needs to be confirmed in other animal models of Huntington’s, and it is too early to say if the drug would also benefit humans, researchers said.

The study, “TAK-063, a novel phosphodiesterase 10A inhibitor, protects from striatal neurodegeneration and ameliorates behavioral deficits in the R6/2 mouse model of Huntington’s disease,” was published in the Journal of Pharmacology and Experimental Therapeutics.

Scientists believe that the mutant huntingtin gene kills neurons in the striatum of the brain by blocking molecular signaling through a pathway employing the factors cAMP and cGMP. In medium spiny neurons — the neurons that die in Huntington’s — a protein called PDE10A (phosphodiesterase 10A) is responsible for breaking down these molecular messengers.

This  knowledge made researchers at Takeda Pharmaceutical suspect that a drug that blocks PDE10A could prevent neuron death in Huntington’s disease.

To test this idea, the research team used a mouse model of Huntington’s disease and treated it from a young age with the drug TAK-063 — a blocker of PDE10A. TAK-063 has just gone through a Phase 2 clinical trial (NCT02477020) for the treatment of schizophrenia.

The drug differs from earlier PDE10A blockers by more potently acting on one of the two medium spiny neuron pathways. Researchers believe that the so-called indirect pathway is more sensitive to neurodegeneration in Huntington’s disease than the direct pathway.

The two pathways are believed to have opposing roles in movement. This makes TAK-063 particularly suitable for Huntington’s, as it activates the indirect pathway more than the direct.

The team used two different doses of the compound; 0.5 mg per kg body weight and 5 mg per kg, and once the mice had reached an adult age, researchers explored the effects of the treatment on the brains and behavior of the mice.

Compared to control Huntington’s mice, the treatment increased levels of the brain growth factor BDNF, lowered the rate of neurodegeneration, and prevented seizures. Researchers also noted that it improved some movement symptoms, but it had no impact on coordination. It also did not improve the body weight of the mice.

Since Huntington’s disease causes cognitive difficulties in addition to movement problems, the team also assessed various learning and memory aspects. The treatment improved procedural learning — a type of learning not involving conscious processes — but could not improve problems with contextual memory.