Gene Therapy Offers HD Patients Relief From Some Symptoms

Tetrabenazine inhibits the transport of a molecule called vesicular monoamine transporter type 2 or VMAT2

Thomas Morrow, MD

Huntington’s disease (HD), named for George Huntington, MD, who lived from 1850 until 1916, is a neurodegenerative disease. It is an autosomal dominant disease and results from a defect of the Huntingtin gene located on chromosome 4, which codes for the Huntingtin protein.

(Yes, the disease name is spelled differently from the gene and protein.)

The disease causes a variety of symptoms but the most characteristic symptom is chorea — random, jerky, involuntary, and uncontrollable movements which initially manifest themselves as an unsteady gait, a general lack of coordination, and slurring of speech. As the disease progresses, it affects virtually all muscular dependent functions and leads to incomprehensible speech, difficulties chewing and swallowing, and abnormal facial features.

Accompanying the chorea are cognitive and psychiatric symptoms. The cognitive abilities most affected are the functions such as planning, cognitive flexibility, perception, abstract thinking, and memory impairments. Psychiatric symptoms may include depression, anxiety, aggression, compulsive behavior, and a variety of addictions including alcoholism, hypersexuality, and gambling.

Huntingtin protein

A normal Huntingtin gene contains a repeating series of the three nucleic acids, CAG, on one end. The trinucleotide CAG codes for the amino acid glutamine. Each additional trinucleotide CAG results in an additional glutamine being placed on the protein.

A normal gene can have up to 27 glutamine amino acids on its end. This chain is referred to as polyglutamine or polyQ.

Having more than 27 glutamine amino acids in a row is abnormal but patients do not appear to become symptomatic until the chain reaches 36 glutamines in a row, which causes symptoms in some people but not in others. With a chain of 40 or more, people exhibit the disease. As the number of repeats increases, the rate of progression to disease increases and the age of onset becomes earlier. However, the relationship between the length of the polyQ and age of onset is not linear or absolutely predictable.

The Huntingtin protein is necessary for development and survival, but the presence of a long chain of polyQ results in the inability of brain cells to metabolize and degrade this protein completely. This causes an accumulation of protein fragments. These protein fragments are thought to interfere with a number of cellular functions and eventually cause cell death. Cell death occurs primarily in the striatum of the brain, an area critical for muscular control signals. Other areas affected are the cortical areas of the frontal and temporal lobes.

In the past, HD was typically diagnosed in the second or third decade of life for those with a high polyQ and in the fourth or fifth decade for the more moderate lengths of polyQ. The disease causes continued deterioration for an additional 15 to 20 years until death. A pathological diagnosis is established by a neurological exam or evidence of cell loss in the areas of the brain listed above as seen by CT or MRI.

Genetic testing can determine the number of CAG repeats. This test is not to be taken lightly. It must be accompanied by significant counseling, as there is no cure for HD.

Currently there are symptomatic therapies that are used off-label to control the emotional and psychiatric components of the disease. In mid-September, a new drug was approved by the FDA for treatment of the chorea, the first drug officially approved with an indication specific to HD. The drug, whose generic name is tetrabenazine and brand name is Xenazine, was developed by Cambridge Laboratories and will be marketed by Ovation Pharmaceuticals. It should be available late this fall. The price has not been announced.

Tetrabenazine causes depletion of monoamines and is given orally. The precise mechanism by which tetrabenazine decreases chorea is unknown but is thought to be related to its effect as a reversible depletory of dopamine, serotonin, norepinephrine, and histamine from nerve terminals. The agent inhibits a transport molecule called vesicular monoamine transporter type 2 (VMAT2).

Clinical studies

Clinical study 1 consisted of a randomized, double-blind, placebo-controlled multicenter trial conducted in ambulatory patients with the diagnosis of HD. Results from this study demonstrated a decline by five units in the total chorea score as measured at week 9 and 12 (averaged) in those on active drug as compared to a 1.5-unit decrease in the placebo group. Incidentally, the total chorea score in subjects receiving active drug returned to the pre-treatment baseline within one week of discontinuing the drug. Of note is that measures of functional capacity and cognition showed no difference between active drug and placebo.

Study 2 was performed in patients who had been treated with open-label tetrabenazine for at least two months (with a mean duration of two years). Eighteen patients were randomized to receive active drug (n=12) at the same dose or placebo (n=6). The treatment effect was similar to the results in Study 1.


Tetrabenazine has several boxed warnings. It can increase the risk of depression and suicidal thoughts and behavior in patients with HD.

A potentially fatal symptom complex which has been called neuroleptic malignant syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission, including tetrabenazine. NMS consists of hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Laboratory abnormalities may include creatinine phosphokinase elevations, myoglobinuria, rhabdomyolysis, and acute renal failure. If diagnosed, treatment consists of immediate discontinuation of tetrabenazine, intensive treatment of symptoms and concomitant treatment of any other serious medical problems that are present.

Managed care implications

The prevalence of HD varies greatly according to ethnicity and location. A health plan may expect to see about 10 symptomatic patients for every 100,000 people in its plan.

This drug offers a significant opportunity to health plans to assist in the management of these patients through a joint effort with the treating physician. Since the price has not been determined, budget impact is unknown at this time.

As the first drug approved specifically for the treatment of HD, this drug demonstrates a continued advancement, albeit one that took more than 130 years to achieve, again showing the promise of Tomorrow’s Medicine.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 23 years of managed care experience at the payer or health plan level.

The author is a director in the value-based health department at Genentech Inc. During the last three years, before taking the Genentech position, he received honoraria or other financial benefits from: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth. The views expressed in Tomorrow’s Medicine are the author’s alone.

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