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Drug summary: Cystamine is a drug that is thought to inhibit transglutaminase (TGase), an enzyme involved in the formation of huntingtin protein aggregates. Studies of cystamine in mouse models of HD have shown that cystamine improves physical symptoms, and decreases nerve cell death. Raptor Pharmaceuticals conducted phase II clinical trials from 2010-2015 to determine whether cysteamine – a form of cystamine – can benefit people with HD.

Problem: Protein Aggregation^

Research suggests that one problem in HD is protein aggregation: copies of the mutant huntingtin protein stick to each other and form clumps. These clumps, called protein aggregates or neuronal inclusions (NIs), are thought to cause some of the problems of HD by interfering with the many important processes that occur in neurons, as described in more detail here. While there is some debate over the exact role of protein aggregates – with some scientists speculating that aggregates are helpful, as they isolate mutant huntingtin protein and prevent it from doing further harm – some studies have shown that decreasing the number of protein aggregates might improve HD in animal models.

These protein aggregates are formed in part through the action of the enzyme transglutaminase (TGase), which links mutant huntingtin together. While scientists are still unsure whether protein aggregates are harmful or helpful, evidence about TGase is more clear: TGase seems to make HD worse. TGase levels are higher in the brains of HD patients. Scientists have genetically engineered some HD mice so that they lack the TGase gene, and therefore don’t have TGase. These mice live longer, lose less weight, have healthier brains, and have a later onset of motor symptoms (Bailey and Johnson 2006). Therefore, scientists are studying the effects of cystamine, a molecule that reduces TGase activity.

How can cystamine help treat HD?^

Cystamine is a competitive inhibitor: it blocks the region of TGase that allows the enzyme to hold onto copies of the mutant huntingtin protein and link them together. So in theory, cystamine should prevent TGase from forming protein aggregates.

Cystamine may also have other properties that could help treat HD. It may also help prevent early cell death by interacting with another type of enzyme, called a caspase. There are many different types of caspases, but they all contribute to early cell death in HD by playing a role in the cascade leading to apoptosis, or programmed cell death. (For more information on caspases and apoptosis, click here.). Cystamine inhibits caspase 3 in cells, and therefore might reduce apoptosis.

Cystamine may also promote brain health through other paths. Cystamine is thought to be an antioxidant, relieving the harmful effects caused by oxidative stress. (For more information on antioxidant treatments, click here.). It also increases levels of brain-derived neurotrophic factor (BDNF), a chemical in the brain that promotes neuron health (Borrell-Pages et al., 2006).


So in these ways – and possibly others – cystamine might reverse some of the problems caused by HD.

Research on cystamine^

Karpuj, et al. (2002) investigated how treating mouse models of HD with cystamine injections affected their physical symptoms and nerve cells. The researchers began treating the mice after seven weeks of age, when symptoms of HD had already begun to appear. Treatment was evaluated by measuring the amount of TGase activity, looking for abnormal mouse movement, charting weight loss, and counting the number of protein aggregates in the nerve cells in the brain.

Following treatment, the mice showed signs of improvement: the tremors and abnormal movement became less prominent, survival was extended by 20 percent, and weight loss was not as severe. TGase is normally very active in the mouse model of HD, but it was greatly reduced by treatment with cystamine.

To the researchers’ surprise, however, cystamine treatment did not influence the appearance or number of NIs. Instead, the researchers found increased production of the protein products of certain genes. In the fruit fly, these genes are known to exert protective effects in nerve cells against toxicity that results from polyglutamine diseases similar to HD. (For more information on polyglutamine diseases, click here.) One of the protein products of these genes, known as HDJ1 in humans and Hsp40 in mice, was found in elevated concentrations after treatment with cystamine. The researchers hypothesized that elevated HDJ1/Hsp40 in HD brains might indicate that the level of this protein was increased in a failed attempt at recovery. Releasing high levels of HDJ1/Hsp40 is probably a response to the HD disease process that was initiated by the altered huntingtin protein.

Dedeoglu, et al. (2002) examined the effects of cystamine in a mouse model of HD on TGase activity, brain and body weight, and survival. The mice received the drug in two ways: 1) through injections; and, 2) orally, in their drinking water. Treatment began when the mice were in the womb – by injecting pregnant mothers or putting cystamine in their water – and continued after birth. About 80 out of 180 mice in the first group and 26 out of 56 mice in the second group were not treated but were used for comparison to mice receiving cystamine.

The effect on survival largely depended on the dose of cystamine. In the group where mice were injected with the drug, those given the lower doses lived longer. However, all of the mice given the highest dose died, probably because of drug toxicity. The mice that were given the drug in their water survived longer than the mice that were not given cystamine at all. Injection and oral administration of cystamine were found to help survival equally at the appropriate dosage.

Both treatments also improved body weight gain compared to untreated mice. (HD often causes weight loss, so improved weight gain is sometimes thought to be a beneficial result because it combats a symptom of HD.) Also, mice treated with cystamine lost much less brain weight compared to mice not receiving cystamine treatment, which implies that cystamine protects nerve cells from degenerating in HD mice.

In the mouse model of HD, TGase activity is usually much higher than in normal mice (because, as mentioned above, TGase helps form huntingtin protein aggregates). However, when the HD mice in this study were treated with cystamine, their TGase activity fell within the normal range of non-HD mice. This finding may explain why treated mice were found to have fewer huntingtin protein aggregates. This study, along with that conducted by Karpuj, et al. (who started cystamine therapy after HD symptoms were already present), suggests that cystamine may be able to prevent protein aggregation in people with HD if given before the onset of symptoms.

Clinical Trials^

These promising results in animal studies have led researchers to investigate whether cystamine can be used to treat HD.

Dubinsky and Gray (2006) conducted a phase I clinical trial on 9 patients with HD, and found that 20 mg/kg of cysteamine – another form of cystamine – is safe and tolerable in HD patients. This study set the stage for future, larger studies.

Raptor Pharmaceuticals conducted a phase II clinical trial, which began in October 2010 and announced results in late 2015. Eight clinical centers in France recruited patients who were treated with either cystamine or a placebo for 18 months. After that, there was an “open-label” phase in which all patients were treated with cystamine for another 18 months. In their press release from 2015, Raptor claimed that the “efficacy results from the CYST-HD study are clinically meaningful and suggest that RP103 may play an important role in the treatment of Huntington’s disease.” For more information about this study please click here.

The Food and Drug Administration (FDA), which regulates drugs in the US, gave Raptor an orphan drug designation for its formula for cysteamine in 2008. The orphan drug designation is a status sometimes given to drugs intended to treat rare medical conditions, and is meant to promote research in those areas by making it easier for that drug to pass through the approval process.

For further reading^

  1. Bailey CD, Johnson GV. The protective effects of cystamine in the R6/2 Huntington’s disease mouse involve mechanisms other than the inhibition of tissue transglutaminase. Neurobiol Aging. 2006 Jun;27(6):871-9. PubMed PMID: 15896882. This technical article discusses some ways that cystamine might fight HD.
  2. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. 2002. Nature Medicine 8: 143-149. Online.
    This article reports that cystamine treatment increased survival rates and decreased abnormal movements in a mouse model of HD. It is a scientific article of medium difficulty with several technical parts.
  3. Therapeutic effects of cystamine in a murine model of Huntington’s disease. 2002. The Journal of Neuroscience 22(20): 8942-8950. Online.
    This article presents the research findings of a study examining cystamine in a mouse model of HD. It is a scientific article of high difficulty.
  4. Cystamine inhibits caspase activity: implications for the treatment of polyglutamine disorders. 2003. Journal of Biological Chemistry 278(6): 3825-3830. Online.
    This is a highly technical article that presents the research findings of a study examining the effects of cystamine on caspases in HD cells.
  5. Dubinsky R, Gray C. CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington’s disease. Mov Disord. 2006 Apr;21(4):530-3. This is paper about the phase I clinical trial of cysteamine for the treatment of HD.

-K. Taub, 11/21/04, updated by M. Hedlin 8.10.11