Researchers Review Novel Huntington’s Disease Targets and Therapeutic Approaches

Over the last few decades, there has been an increasing number of clinical trials focused on the search of new therapeutic strategies to manage Huntington’s Disease (HD), an incurable neurodegenerative disease characterized by motor, cognitive and psychiatric problems. However, there have been few advances, and research is now focusing on disease-modifying compounds that can slow or even stop the disease progression. In a new review, University of Cambridge researchers discuss the shift from symptomatic therapies to mechanism-based medicines and summarize the currently in-development new therapies, either at early stage or in clinical trials.

The review paper, titled “Novel targets for Huntington’s disease: future prospects,” is published in Degenerative Neurological and Neuromuscular Disease.

HD is caused by a known genetic mutation, the CAG repeat (polyglutamine) expansion, in the huntingtin (HTT) gene, leading to the formation of a mutated form of the protein. The loss of the functional huntingtin protein affects axonal transport, essential for synaptic formation, and leads to mitochondrial dysfunction and neuronal damage. The prevalence of the disease is increasing which, besides causing suffering in patients, also leads to an increase in the economic burden associated with the disease. Such factors highlight the urgent need for new therapeutic options, both disease-modifying and symptomatic.

The now deeper and evolving understanding of the disease has led researchers to focus on the development of mechanistic-based drugs. Disease-modifying therapies can be divided into two approaches, targeting processes related to cell death caused by mutant Htt or lowering the level of mHtt in the brain. The review focuses on novel drug targets that are now beyond the point of early clinical trials but have not been developed beyond a Phase II study. The study summarizes ongoing and currently recruiting clinical trials along with completed clinical trials.

Among disease-modifying therapies, in which the ultimate goal is to delay disease onset and potentially prevent its manifestation, there are potential drugs targeting modulation of transcription, since transcriptional regulation is abnormal in HD. However, such drugs, including sodium phenylbutyrate and selisistat (SEN0014196), have not yet been proven to be effective, so this therapeutic strategy still needs to be validated. Targeting the immune / glial activation has also been investigated as a potential therapeutic strategy. Among drug therapies applying this model, there is immunomodulator laquinimod and the SemA4D inhibitor VX15/2503, drugs with different mechanisms of action and both in Phase II clinical trials testing their safety, tolerability, and efficacy, the results of which are expected in 2017. Other therapeutic strategies with drugs currently in clinical trials include inhibitors of mediators of cell death, Huntingtin-lowering approaches and cell transplantation and regeneration.

“While research into treatments to help patients in the premanifest or early stages of the disease is promising, there is still a distinct lack of research going into providing more effective treatments to help patients with disease in the more advanced stages,” the researchers conclude, highlighting the limited number of patients and burden of trial protocols on more advanced patients as the main obstacles to the development of new and more effective therapies.