Review Explores Investigations Into Immunomodulatory, Anti-Inflammatory Therapy in Huntington Disease

Huntington disease (HD), an autosomal-dominant neurodegenerative disease characterized by the selective loss of neurons in the striatum and cortex, leads to progressive motor dysfunction, cognitive decline, and behavioral symptoms. Current therapies target only the symptoms of HD, as there are no disease-modifying therapies available. However, several studies have suggested that inflammation plays a role in HD, and a recent review, published in Neural Regeneration Research, explored the anti-inflammatory and immunomodulatory agents that have been investigated as possible treatments for HD.

While the primary cause of HD is the mutant Huntingtin gene (mHTT) expression in neurons that leads to neuronal death, immune mechanisms may be activated by cell degeneration, releasing mediators that amplify neuronal toxicity and contribute to disease progression. Additionally, mHTT can promote cell-autonomous immune activation. Furthermore, microglia—resident myeloid cells with phagocytic activity—are activated in patients with HD, and produce pro-inflammatory cytokines that contribute to neuronal toxicity. Interestingly, immune activation and inflammation may be present years before the onset of major motor symptoms in patients with HD.

Nonsteroidal anti-inflammatory drugs have been evaluated in HD with mixed results, as has an antibiotic, minocycline, that has anti-inflammatory and anti-apoptotic properties. Laquinomod, a disease-modifying therapy approved to treat multiple sclerosis that has immunomodulatory and neuroprotective effects, is currently in a clinical trial in HD.

Other compounds with anti-inflammatory and immunomodulatory properties, such as the anti—tumor necrosis factor (anti-TNF) agent XPro1595 and anti–semaphorin 4D (anti-SEMA4D) molecule, have been used in pre-clinical settings; in a transgenic mouse model of HD, XPro1595 decreased TNF in the cortex and striatum, enhanced motor function, and reduced the burden of mHTT aggregates. Anti-SEMA4D improved neuropathological signs, cognitive deficits, and behavioral symptoms in mice.

Stem-cell therapy also shows promise; stem cells have immunomodulatory and anti-inflammatory properties that can decrease or control the inflammatory response in HD. Stem cells have provided functional recovery in pre-clinical models of HD, but further research is needed.

The review’s authors note that, while the immune system clearly has a role in HD, it is not yet clear whether immune changes in HD result from neurodegeneration or whether they represent an independent mechanism in the disease, and that the role of the immune system in different phases of HD is not yet well defined.

A significant challenge to addressing the immune system in HD is the length of a determined intervention in a clinical trial to confirm the disease-modifying potential of an investigational therapy; because HD progresses slowly, long and resource-intensive trials are needed.