Researchers at the Serono Genetics Institute have announced the identification of 80 genes involved in the inflammatory and neuro-degenerative pathways of multiple sclerosis (MS) forming a library of potential targets for future treatments of the disease.
Scientists at Serono's research centre in Paris studied data from 1,800 patients, half of whom had MS, and used Affymetrix's GeneChip technology to identify and register the genes involved in the inflammatory and neuro-degenerative pathways of the disease.
This large-scale association study was performed in French, Swedish and American populations, comprising a total of 900 people with MS and 900 healthy individuals. This represents only the first phase of Serono's MS Whole Genome Scan project. The next step is to scan over 500,000 SNPs (single nucleotide polymorphisms) in these populations. Serono hopes to complete the project by the end of 2006.
"For our 80 new genes, one of which we discovered earlier, we found them to be involved in the two different pathways that defined MS. They are inflammatory and neuro-degenerative. We also discovered genes that were active in novel pathways of the disease," said Professor Daniel Cohen, vice-president and worldwide head of genetics.
Among the genes confirmed in the inflammatory response of MS were ones that coded for the Human Leukocyte Antigen (HLA). HLA genes are central to the immune response and are involved in recognition of infectious agents (e.g. bacteria, viruses).
Two genes that were involved in the neuro-degenerative pathway included neuregulin (NRG1), which codes to allow protein to be secreted form glial cells. Experiments have shown this gene to have significant activity in experimental allergic encephalitis (EAE) - a model of MS.
Presenillin 2 was also shown to be involved in the neuro-degenerative pathway, wich has been pivotal in Alzheimers and its presence confirms the neuro-degenerative etiology in MS.
Cohen is hopeful that now a genetic basis has been formed the possibility of correlating genetics with possible environmental factors, which may act as triggers, could be Serono's next area of research.
"Although it is an option, the prospect of measuring the influence of environmental factors in a laboratory is extremely difficult. However, we are confident there is a mechanism there."
Dr Tim Wells, senior executive vice president research, Serono told DrugResearcher.com that the genetic differences in the types of multiple sclerosis would need to be mapped. Only then could environmental factors come into the equation.
MS is a highly unpredictable disease and mainly affects young adults. The economic costs of MS in terms of both lost productivity and direct and indirect healthcare costs are huge. Treating to delay disease progression can lesson this economic burden, as costs increase as the disease progresses.
The average cost per patient per year (1999 prices) in Germany was $29 727 (€34 169) with a cost to society of $3.57 billion (€4.10 billion). In the UK, the cost amounted to $26,935 (€30 960) per patient per year, with a total cost to society of $2.37 billion (€2.73 billion).
Professor Jan Hibbert, head of division of neurology at the Karolinska Institute, Stockholm, Sweden said: "The identification of proteins involved in the inflammatory and neurodegenerative pathways of MS will lead to potential new drug targets and therapeutics."
>Serono already produces Rebif, a treatment for MS, the disease that affects more than 1 million people worldwide and can cause blurred vision, weakness, poor muscle coordination and loss of memory and mental function.
Rebif (human interferon beta 1-a) has been shown to reduce the biological activity of MS. It has also been demonstrated that Rebif therapy given very early in the course of the disease can delay the patient's conversion to clinically definite MS.
Research suggests that the effects of interferon beta may be due to the drug's mode of action and ability to control the activity of the immune system and to inhibit certain intracellular messages (e.g cytokines). These cytokines, such as interferon gamma, are thought to be involved in the inflammation process that results in MS symptoms.
Other disease-modifying drugs currently available include Avonex and interferon beta-1b (Betaferon/Betaseron), as well as glatiramer acetate (Copaxone) and immunosupressants, such as mitoxantrone.
Glatiramer acetate is a synthetic drug that does not occur naturally in the body. It is a random polymer of four amino acids, supposed to mimic a component of human myelin.
MS is characterised by the destruction of the fatty sheath (myelin), which surrounds and insulates nerve fibres (axons) within the central nervous system (CNS). Myelin aids transmission of nerve impulses (sensory and motor messages) to and from the brain and throughout the body. In patients with MS, the axons lose part of their myelin sheathing through inflammation (a process known as demyelination). At first the impulses sent by axons are no longer transmitted properly, resulting in the symptoms of MS.
As well as disease-modifying drugs, symptomatic drugs reduce the severity of symptoms but have no effect on the natural course of MS. The disease continues to progress.
Corticosteroids are used to reduce inflammation in the central nervous system during a relapse, and to speed up recovery from that relapse. However, corticosteroids have many side effects and do not slow down the progression of the disease, so they are not recommended for continuous use in MS.
Immunosuppressants, such as mitoxantrone, are sometimes used in MS to suppress the actions of the immune system in patients with rapidly worsening MS.
The current understanding for the best treatment strategy for MS would involve the prevention of disease accumulation, while at the same time producing the least side effects. Thus disease modifying therapies, which are directed towards preventing irreversible damage to myelin and nerve fibres, should therefore be started as early as possible in the disease.
In this way, inflammatory activity and the frequency and severity of relapses (attacks) may be reduced and the progression of disability delayed. This, in turn, may give the patient a better long-term prognosis.