Pharma Voice

Tackling Huntington's disease

Even though there is a lot of research going on various CNS disorders, the understanding of some neurodegenerative disorders like Huntington's disease is still not comprehensive, Deshmukh V D and Juvekar A R observe.

A great amount of research is being carried out on various CNS maladies like the Parkinson's disease, Alzheimer's disease and various other neurodegenerative disorders. Despite vast knowledge, there are still gaps in the understanding of the pathogenesis of some of these neurodegenerative disorders. One such disease, which represents the class called polyglutamine disorders, is the Huntington's disease (HD), also known as Huntington's chorea. It is an autosomal dominant polyglutamine neurodegenerative disorder; characterised by psychiatric, cognitive and motor symptoms.

The disease is highly disabling and progressive and death occurs within 15-20 years of onset. Currently, there is no effective therapy available that can slow or cure the disease. But there is symptomatic treatment for the motor and psychiatric functions. It was George Huntington's graphic description in a paper On Chorea that first gave this disease a major recognition.

About the disease

As of today, Huntington's disease is universal. The prevalence of the Huntington's disease in North America and Europe is 5-10 per 1,00,000.

A very high concentration of HD has been found in parts of Venezuela, where the prevalence is about 700 per 100,000. Although HD is prevalent in India, there are no official records of the statistics, which is further hampering research in India.

The mean age of patient's onset of movement disorder is 40 years. The age of onset of HD is also affected by the sex of the affected parent. In nine percent of the patients, symptoms are present before the age of 20. The age of onset is inversely related to the CAG repeat number; the greater the number of CAG repeats, the earlier the onset.

A triad of motor, cognitive and emotional abnormalities characterises HD. Death typically occurs 15-20 years after the symptoms first appear, but some patients die earlier, often from falls or suicide, while some patients survive for three or four decades.

The HD mutation was found in 1993 as an unstable expansion of the CAG (trinucleotide) repeat within the coding region of the gene "IT15". This gene on chromosome 4 (4p63), encodes the protein, Huntingtin (htt). The mutation in Huntingtin produces an expanded stretch of glutamine residues attached to its amino terminal. Expansions beyond a threshold of 36 CAG's cause the disease. Polyglutamine expansions occur in other types of neurodegenerative disorders including several types of spinocerrebellar ataxia (SCA), Machado Joseph Disease. Although disorders are caused by similar type of gene mutation, the type of neurons affected and the neuropathological lesions produced are quite distinct.

Pathogenesis

Huntington's disease and other CAG repeat diseases including spinal and bulbar atrophy (SABA), spinocerre-bellar ataxia have been controversial. There were implications of polyglutamine aggregation, possible amyloid formation, localisation in the cell nucleus and possible proteolytic processing. The manifestation of disease is due to the abnormal levels of neuro transmitters mostly GABA. However, the proposed mechanisms for the neuronal cell death include:

• The excitotoxic model
• Oxidative stress
• Impaired energy metabolism
• Programmed cell death (apoptosis)

The term excitotoxic was coined to describe excessive neuronal excitation by the transmitter glutamate, resulting in cell stress or death due to influx of sodium, calcium and water under physiological conditions.

A model for HD pathogenesis

HD pathogenesis begins with altered conformation of the protein containing the expanded polyglutamine repeat. Proteolysis generates a fragment that leads to toxicity through several pathways. Nuclear importation may lead to altered gene transcription with a detrimental effect on cell survival. Inclusions also form in the nucleus, but may not be a major cause of cell death. Huntington fragments may interfere with mitochondrial energy metabolism, either directly, or more likely indirectly, perhaps via altered gene transcription. Micro aggregation of the fragment may lead to caspase activation and the consequent initiation of cell death pathways. Fragments may be transported into neurites, interfering with cytoskeleton function. The diagnosis of HD is done by genetic testing methods like direct mutation analysis and family based linkage studies. Although the discovery of the HD gene has facilitated predictive testing, the disease remains without a cure, and no treatment is currently available to slow or alter the disease's progression.

Therefore, the availability of such testing continues to be associated with numerous emotional, practical, and ethical concerns. This highlights the necessity of appropriate genetic counselling and support.

Future approaches

The recent biochemical, cell and animal studies are beginning to suggest approaches for development of rationale therapeutics. The current therapeutics for HD is limited to symptomatic treaments, so any intervention that can stop or slow disease progression would be a major advance.

Gene therapy: Due to the problems related to the delivery of the neuroprotective agents into the CNS; currently, both viral and non-viral vectors are being developed to target agents into CNS. Efforts have also been made in the delivery of neural progenitor stem cells that are capable of giving rise to both neurons and glia.

Aggregation blockers: Two studies have reported efficacy in in-vivo models to inhibit aggregation. The first expressed anti-aggregation peptides in drosophila, model of a polyglutamine disease and found that the resulting decrease in aggregation is correlated with delayed neurodegeneration and reduced lethality. The second approach administered congo red in a mouse model of HD and reported a decrease in neuronal aggregates.

Proteolysis inhibitors: Inhibiting the cleavage of htt has been shown to eliminate the toxicity of mutant htt protein in-vitro. Inhibiting proteolytic enzyme caspase as a therapeutic approach for HD has been demonstrated in cell culture models and mouse models. Several pharmacological agents, for example, cystamine and minocycline with putative ability to inhibit caspase activation have shown a significant effect on mice transgenic for various forms of mutant htt.

Excito-toxicity inhibitors: A variety of agents that reduce oxidative stress or inhibit glutamate release or NMDAR activation have been tested in mice models of HD. Several have shown efficacy in delaying death or reducing striatal degeneration, including creatine (reduces activation of the mitochondrial permeability transition and enhances brain levels of phosphocreatine), a-lipoic acid and coenzyme Q10 (antioxidants), remacemide (NMDAR antagonist) and riluzole (inhibits glutamate release).

Mitochondrial enhancers: One of the most efficient mitochondrial enhancer under study, CoQ or coenzyme Q10 (ubiquinone) is the carrier of electrons from complexes I and II to complex III of the mitochondrial electron transport chain. Primary coenzyme Q 10 has been associated with neurodegeneration in HD. CoQ along with remacemide has been shown to decrease progression of neurodegeneration in a number of clinical trials.

Transplantation: Polyglutamine aggregation leads to the death of several neurons. Surgical strategies have been developed in which transplantation of embryonic stem cells replaces lost neurons in the striatum. Embryonic grafts placed in quinolinic-acid-treated animals' improved motor functions such as paw reaching. These studies suggest an exciting avenue for therapeutic intervention in severe cases.

Although there has been tremendous advancement in polyglutamine disorder research, the pathogenesis of disease still remains cryptic along with its complete cure. Development of transgenic mouse models has not only enlightened certain aspects of pathogenesis but is also serving as surrogate for screening newer therapeutics.

The current approach of therapeutics is restricted to symptomatic treatment. Therefore, any treatment that stops or slows the progression of the disease will be a major breakthrough. The current scenario also intensifies the need of considering the non-pharmacological and the social aspect of HD.

There is need of social organisations and public groups to give a helping hand to the patients and alleviate the social stigma caused by Huntington's disease.

(The authors are from the Department of Pharmacology and Physiology, MUICT)