麻豆传媒

Two clinical trials are now underway that offer the first tests of an intriguing but still not widely accepted theory of multiple sclerosis -- that its trigger lies within a part of the human genome that medical research has largely ignored.

Some researchers in Great Britain and Europe now believe that MS results from activation of "human endogenous retroviruses," or HERVs -- remnants of retroviruses that infected humans eons ago and became incorporated into the germline, such as that it is now part of the human genome.

This theory has prompted a group in the U.K. to begin a in about 25 MS patients, to see if the drug affects brain lesions seen in MRI scans. The trial is expected to conclude this August, with results potentially reported before the year is out.

Separately, a Swedish company called GeNeuro Innovation, founded by Swiss researcher Herve Perron, PhD, has developed a monoclonal antibody called GNbAC1 targeting a specific HERV element; next month at the American Academy of Neurology's annual meeting.

Background

When the first full , one of the biggest surprises was how much of the genome appeared to encode retroviral elements such as integrase and helicase enzymes. By one estimate, 8% of the entire genome was made up of such sequences.

At first, these were assumed to be nonfunctional. But that, under some circumstances, they can become activated to express proteins.

It has yet to be proven conclusively that these are pathogenic, as even the proponents of HERV theories of disease will admit. One of the leaders of the U.K. raltegravir trial, , of the Albion Street Centre in Sydney, Australia, told attendees at an MS conference last fall that current laboratory methods aren't currently able to provide such proof, at least not for MS.

But there is circumstantial evidence -- several laboratories have isolated HERV proteins from MS lesion samples, and Epstein-Barr virus (EBV), which has itself been a suspected environmental cause of MS, has been found to activate HERV expression in lab studies.

, of Barts and the London School of Medicine and Dentistry in London, who also helps lead the raltegravir trial with Gold, told 麻豆传媒 that all herpes viruses, of which EBV is one, can trigger HERV expression. But, he said, "EBV is particularly effective in activating HERVs."

Also, according to Gold, HERV expression has been linked to activation of both the innate and adaptive immune systems, providing a connection to the well-documented immunological and inflammatory features of MS.

Although the HERV theory doesn't explain everything about MS, such as the gender imbalance, Giovannoni said the conventional autoimmune paradigm has "lots of holes" too.

"It doesn't explain everything about MS, and as part of a causation theory it should explain everything. It doesn't explain the epidemiology very well, it doesn't explain the sex ratio, it doesn't explain some of the responses to certain therapies," he said.

"That's a clue that we don't know the whole story."

The HIV Connection

Perhaps the most significant piece of evidence for the HERV theory of MS is even more indirect: People with HIV appear to be at vastly reduced risk for MS.

What does HIV status have to do with HERVs or MS? Because nowadays, essentially everyone with HIV in developed countries where broad-based epidemiological research can be conducted is treated with antiretroviral drugs.

Gold is an HIV specialist -- the Albion Street Centre, which he directs, is Australia's largest HIV outpatient clinic. His "aha" moment came when an HIV-positive patient who also had MS came under his care. This patient was first diagnosed with HIV infection in 1985 but managed to avoid developing AIDS before the advent of highly active antiretroviral therapy (HAART) in 1996.

In a 2011 letter published in the , Gold and colleagues described what happened after HAART was begun in 1996:

"Within months of commencing HAART, all MS symptoms gradually improved. Within 2 years, his urinary incontinence was controlled to the extent that he stopped wearing pads and fecal incontinence resolved. He has had no MS relapses."

The disease was not completely eliminated, the researchers indicated, because gadolinium-enhanced MRI scans made in 2002 continued to show lesions consistent with MS, even though clinical symptoms had largely disappeared.

Large-scale epidemiological studies have supported the notion that anti-HIV therapy may suppress MS pathology. A Danish national registry study published in letter form last year in Epidemiology, comparing 5,018 HIV-positive patients with some 50,000 age- and sex-matched individuals from the general population, found that the rate of MS incidence was markedly lower in the HIV patients (3.1 versus 10.4 per 100,000). However, it was not statistically significant because only one HIV patient developed MS during the study period.

Gold and colleagues conducted a similar (but as yet unpublished) study using the much larger U.K. general practice database, which covers some 55 million Britons. At the European MS meeting where he spoke last fall, he reported on results from some 21,000 HIV-positive individuals and 6.7 million controls, followed for a mean of 7 years.

In addition to matching controls to HIV patients by age and sex, they were also matched by region within the country and by the week in which they first came into contact with the national health system.

The relative risk for MS in the HIV patients versus controls was 0.38 (95% CI 0.15-0.79, P=0.011), he reported. The relative risk was even lower, 0.22, when only MS diagnoses occurring more than 1 year after HIV diagnosis were counted (at which point HAART is presumably well established in British HIV patients).

The Clinical Trials

There is no animal model for HERVs in MS, and the ability to study HERVs even in cell culture is limited, Gold said. He argued that "their exact role will only be obtained following appropriate clinical trials. If we wait for the laboratory to give us the answer, we will all have been retired."

Raltegravir was chosen for the U.K. trial for several reasons. One is that it is an HIV integrase inhibitor. "The integrases across HERVs and HIV are quite conserved," Giovannoni said, so that it is likely to be more effective in suppressing HERV elements than other types of antiretroviral drugs. He said it was also unique among antiretrovirals in also showing some potency against members of the herpesvirus family (though only in vitro -- this effect hasn't been studied clinically).

And, its manufacturer was willing to support the small, short-term trial. Gold pointed out that no company that markets MS medications is active in HIV drug development, or vice versa. He and Giovannoni were able to persuade raltegravir's maker, Merck's European subsidiary, to fund the 25-patient study which includes just 3 months of drug treatment after a 3-month baseline observation period. Gold said a longer and larger study would have been preferable but it could not be arranged.

The GNbAC1 monoclonal antibody's sponsor GeNeuro appears to have more resources, with France's Institut Merieux as a major investor. It has already completed a phase I safety study with the agent in healthy volunteers; the results to be presented at the AAN meeting next month are from 10 MS patients.

According to the abstract, no safety problems were seen, and a larger efficacy study is warranted. However, GeNeuro has not said whether or when such a trial would be undertaken.

Caution Reigns

MS specialists in the U.S. contacted by 麻豆传媒 were unanimous in urging caution about HERV theory, although some were warmer to it than others.

Alessandro Serra, MD, of University Hospitals Case Medical Center in Cleveland, told 麻豆传媒 that "many studies" had supported the association between HERV-expressed proteins and MS.

However, these proteins also appear "in patients with other neurological conditions, and even in a proportion of healthy individuals," Serra said.

He said the debate in the community was over "whether HERVs are just bystanders within the normal immune response of MS patients, perhaps unable to handle these viruses, or whether they actually represent a key component of the pathogenic process of MS and even have a causative role."

Jerry Wolinsky, MD, of the University of Texas Health Science Center in Houston, pointed out that the search for MS triggers has been going on for decades and wound up in many blind alleys. Viruses have long been a popular suspect, but "thus far not fruitful."

With regard to retroviruses lurking within the human genome, "to my knowledge there has been no consistently recovered retrovirus sequence associated with brain or other tissues from patients with multiple sclerosis," Wolinsky said.

"That does not mean that one might not be afoot, but the technology is well enough developed that it would be unusual to expect that one will be found in the future, given the failure to do so even with application of modern tools."

Wolinsky added that the 2011 case report from Gold and colleagues, of the HIV/MS patient whose neurological symptoms resolved with HAART, did not persuade him. "The course of MS is very unpredictable," he said, and the disappearance of symptoms may simply have been "serendipitous."

Other experts were also supportive of research while agnostic or skeptical about the HERV theory. For example, Robert Bermel, MD, head of the Cleveland Clinic's Mellen Center for Multiple Sclerosis, told 麻豆传媒 that "It becomes difficult ... to separate the specific effect of antiretroviral therapy from the effect of altered immune status related to HIV, or from the natural tendency of MS disease activity to decline over time."

On the other hand, Anthony Reder, MD, of the University of Chicago, called the HERV theory "important" as well as plausible.

HERVs, he said, result from "hundreds of millions of years of battles with retroviruses. The residual DNA fragments do not produce complete viruses but DNA fragments and retrovirus proteins do leak out and are seen by the immune system."

Serra said he hoped that the two clinical trials wouldn't be taken as make-or-break for the HERV theory. "We need more rigorous models, especially animal models that have been lacking so far. I know there are groups that are looking into it."

In the meantime, everyone who spoke to 麻豆传媒 emphasized that it would be premature for physicians or patients to try antiretroviral drugs on their own as MS therapies. Giovannoni said that some patients have told him that they had succeeded in obtaining raltegravir.

"That's a little premature and we wouldn't recommend it," he said.

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