14 May 2010

There may be a new glimmer of hope for patients with Huntington disease (HD). Recent research suggests that two drugs, one already approved in the U.S and Europe and one that seems to have successfully completed a European Phase 3 clinical trial, may slow progression of the disease. In the April 26 Molecular Neurodegeneration, researchers led by Ilya Bezprozvanny at the University of Texas Southwestern Medical Center at Dallas report that the approved drug tetrabenazine (TBZ) not only improves motor symptoms in mouse models of HD, but also protects neurons in the striatum, a region of the brain that helps control motor function. And if recent top-line data from the Phase 3 MermaiHD trial hold up, then a second drug, pridopidine, may do the same in humans. Both drugs work by reducing dopamine input into the striatum. “I think the results suggest that targeting dopaminergic signaling is potentially a disease-modifying strategy,” Bezprozvanny told ARF. Because of the neuroprotective effects, he believes the drugs should be given early in the disease. Currently, TBZ is given to HD patients to treat movement difficulties, or chorea, typically later in the disease. The full results of the MermaiHD trial have not yet been released.

TBZ’s history is unusual. An inhibitor of vesicular monoamine transporter 2 (VMAT2), a protein that loads synaptic vesicles with monoamine neurotransmitters such as dopamine and serotonin, the drug was initially developed by F. Hoffman-La Roche, Ltd. as a treatment for schizophrenia. TBZ didn’t pass muster for that indication, but Roche scientists noticed that the drug ameliorated motor problems in some patients. When one of the senior scientists on the project retired from the company, he was allowed to take the rights to the drug with him and began developing it for Huntington disease, according to Bezprozvanny. Cambridge Laboratories in the U.K., since acquired by Alliance Pharma Plc., Chippenham, U.K., sponsored the drug in clinical trials for HD, and TBZ was first approved for chorea associated with Huntington’s in Europe and then later in the U.S. Because TBZ had originally been developed for schizophrenia, no preclinical studies were carried out on HD mouse models until Bezprozvanny’s group became involved.

As first author Hongyu Wang and colleagues now report, the drug ameliorates motor problems in mice suffering from huntingtin toxicity. The researchers tested TBZ in YAC128 mice, which harbor a polyglutamine (polyQ)-expanded human huntingtin (htt) gene on a yeast artificial chromosome (see Slow et al., 2003). These animals produce human htt with a 128 polyQ stretch (the normal length in humans is less than 30); they have progressive motor symptoms and lose neurons in the striatum. Both these endpoints improved when Wang and colleagues began treatment before (at two months old) or after (at six months old) disease symptoms were apparent. Animals ate corn flour with placebo or 0.125 mg TBZ mixed in three times a week until they reached 12 months of age. In two tests of motor control, the accelerated rotarod and the beam walk, TBZ-treated HD mice performed better than YAC128 controls, though never as well as wild-type controls. Improvements were evident within four and three months for animals treated early and late, respectively, and persisted until the animals were sacrificed at 13 months old. The TBZ-treated YAC128 mice also had better gait compared to untreated littermates. The findings support earlier work from the same lab (see Tang et al., 2007). In addition, they demonstrate that starting treatment with TBZ early is protective, which could be germane to human therapy.

It may seem counterintuitive that a dopaminergic blocker would improve motor control, given dopamine’s key role in the striatum, a center for motor coordination. Loss of dopaminergic signaling from the substantia nigra (SN) to the striatum is linked to motor dysfunction in Parkinson disease (PD); VMAT2 itself is the target for new PET imaging ligands, where less VMAT2 in the striatum indicates PD. And yet, while L-dopa can compensate for loss of SN neurons in PD models and in humans, when given to YAC128 mice, the dopamine precursor actually hastens their demise, as Bezprozvanny previously showed (see Tang et al., 2007). “The striatum gets more dopamine than any part of the brain,” said Bezprozvanny. “The idea is that this innervation by dopaminergic neurons causes excitotoxicity, especially for neurons in HD,” he said. Based on his earlier paper, he proposes that high concentrations of dopamine and glutamate conspire to increase calcium influx in striatal neurons, setting off apoptotic cascades that lead to neuron loss. Wang and colleagues report that TBZ, given early or late, stanches striatal neuron loss in YAC128 mice. It does not fully protect, as there is still some neuron loss compared to wild-type animals.

Steven Hersch, director of the New England Center of Excellence for Huntington's Disease, Massachusetts General Hospital, Charlestown, agreed in a conversation with ARF that dopamine is a likely culprit in striatal neurodegeneration in HD. Indeed, earlier work from his lab showed that lesioning dopaminergic neurons can protect the striatum in HD model mice (see Stack et al., 2007). But Hersch cautioned that the striatum is only part of a much bigger picture. “The striatum is important, but it only captures part of the consequences of the disease. A lot of the functional disability and progressive decline is in the cortex and other areas of the brain,” Hersch said.

A case could be made for earlier treatment of Huntington’s patients based on the neuroprotective effect of TBZ. However, the drug has serious side effects, most notably an increased risk of suicide, which is likely due to its broad suppression of monoamine neurotransmitters, including serotonin. Bezprozvanny said that HD patients on TBZ are often given antidepressants. YAC128 animals on TBZ also show signs of depression, such as a disinterest in staying afloat when put through a forced swim test.

Because of the depressive action of TBZ, the more selective pridopidine (trade name Huntexil®), a dopamine D2 receptor modulator, may prove a better choice. The top-line data from the MermaiHD trial released by drug sponsor NeuroSearch on 3 February 2010 suggest that the drug improves motor symptoms in HD patients, as judged by scores in the modified motor score of the Unified Huntington’s Disease Rating Scale (see company press release). That data suggested that pridopidine might have a disease-modifying effect. Patients with longer htt polyglutamine-expansions usually decline faster than those with shorter repeats; this dichotomy disappeared in the treatment group, suggesting that the D2 blocker modifies disease progression in some people (see 8 March 2010 press release). Should that turn out to be true, pridopidine might be seen to slow decline in HD patients if given early enough.

For his part, Hersch considered it unlikely that these drugs, particularly TBZ, would be given to patients before symptoms emerge. “People without symptoms are healthy, so it would be hard to justify doing that,” he said. He did say that it might be possible to determine if the drugs affect disease progression in symptomatic patients by looking at post-marketing data. But overall, he thought the strategy of focusing on the striatum and neglecting other areas of the brain may turn out to be quite limiting. “I’d be more excited to work on something more global,” he said.—Tom Fagan

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References

Paper Citations

1. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003 Jul 1;12(13):1555-67. PubMed.
2. Tang TS, Chen X, Liu J, Bezprozvanny I. Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J Neurosci. 2007 Jul 25;27(30):7899-910. PubMed.
3. Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR, Yang L, Jenkins BG, Luthi-Carter R, Kowall NW, Hersch SM, Beal MF, Ferrante RJ. Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice. J Neurosci. 2007 Nov 21;27(47):12908-15. PubMed.

External Citations

1. MermaiHD
2. Alliance Pharma Plc.
3. NeuroSearch
4. company press release
5. press release

Further Reading

News

1. Drugs Slow Neurodegeneration in Fly Model of Huntington's 22 Nov 2002
2. In Mice, Huntingtin Defects Start in the Womb 5 Dec 2009