Is the immune system involved in the progression of Huntington’s disease (HD)? And if so, can drugs that target the immune system help HD patients?
The answer to the first question is yes, however, the answer to the second question is unclear, according to a recent review from Gabriela Delevati Colpo, PhD and colleagues published in Neural Regeneration Research
HD is a neurodegenerative disease caused by an unstable CAG (cytosine-adenine-guanine) repeat expansion in the Huntingtin
gene that leads to the production of a mutant form of the huntingtin protein. The means by which the mutant huntingtin protein leads to neurotoxicity and the observed motor, behavoural, and psychological features that afflict adults with HD has not yet been determined, however, there is strong evidence that the immune system does play a factor in the pathophysiology of the condition.
For example, the severity of HD is correlated with the accumulation of microglia in the brain. Microglia activation is also present in HD patient prior to disease onset and produces many chemicals involved in the inflammatory process [e.g., tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)] that are also linked to HD.
As the authors note in their article, “immune activation and enhanced inflammation are important features of HD, being already present in pre-clinical stages of the disease, i.e
., years before the onset of motor symptoms. In this context, the study of immune-related mechanisms as potential therapeutic targets for HD is warranted.”
Current treatments for HD are focused on the symptoms. Xenazine (tetrabenazine) and Austedo (deutetrabenazine) are the only U.S. Food and Drug Administration (FDA)-approved therapies indicated for HD patients and they are to treat the chorea-like symptoms. Patients are also prescribed various antidepressants, antipsychotics, and mood stabilizers to manage the behavioral and psychologic problems that often appear in HD (e.g., aggression, irritability, impulsiveness, anxiety, depression and psychosis). None of these therapies target the underlying pathophysiology of HD and that is where the use of drugs that alter the immune system may be of value.
To date, however, the results with anti-inflammatory drugs for HD has been mixed.
The nonsteroidal anti-inflammatory drugs (NSAIDs) celecoxib and meloxicam showed some promise in an HD animal model while (Kalonia and Kumar, 2011) while acetylsalicylate and rofecoxib did not (Norflus et al., 2004). No human clinical trials testing NSAIDs in HD patients have begun.
Two immune modifying drugs that have been tested in humans are minocycline and laquinomod, the former of which is a tetracycline antibiotic with anti-inflammatory and anti-apoptotic activities. Animal studies have shown the drug to attenuate HD progression but the results in humans has been mixed. In one study, it was found that 24 months of taking the drug (100 mg) led to a stabilization of motor and physiological outcomes whereas a second study, using a larger dose (200 mg) did not.
Laquinomod is an immunomodulator being tested in a variety of neurological disorders, including multiple sclerosis (MS) and HD.
In animal models of HD, laquinomod displays neuroprotective effects and improves behavior and the drug is currently part of a phase 2 clinical trial
Colpo et al concluded their review with the caveat that while it seems apparent that the immune system is involved in the pathophysiology of HD, it is not clear how it is involved. The authors wrote “This is a largely unexplored area where studies addressing pathophysiological mechanisms, biomarkers and pharmacological targets can impact the clinical management of patients with HD in the real world.”
To read the article in its entirety, click here.
Colpo GD, Stimming EF, Rocha NP, Teixeira AL. Promises and pitfalls of immune-based strategies for Huntington's disease. Neural Regen Res.
2017;12(9):1422-1425. doi: 10.4103/1673-5374.215245.
To keep up with the latest Huntington's disease news, follow Rare Disease Report
, and Linkedin