Before the year is out, scientists expect to begin injecting a newtherapeutic under the skins of 25 to 30 patients withrelapsing/remitting multiple sclerosis (MS).

The Phase I trial will test the safety of a modified molecule aimed atthe defective myelin basic protein, which causes the chronicautoimmune disease. The altered peptide reversed MS-like paralysisin mice suffering from a neurological disease that closely mimics MS_ not just its symptoms, but the presumed mechanism of theneurodegenerative ailment.

There is no cure for MS, which afflicts between 250,000 and 350,000Americans, and more than 1.1 million people throughout the world.Twice as many women as men get the disease, which is usuallydiagnosed between 20 and 40 years of age.

MS occurs when some of the immune system's T cells, whichnormally patrol the body for pathogens and tumors, turn traitor andattack the myelin sheath that insulates nerve cells. This leads to thelong drawn-out chronic disability, with creeping paralysis cripplinglocomotion and other bodily functions, eventually breathing itself.

But like a cat toying with a mouse, MS often alternates theseprogressing symptoms over the years with periods of remission, inwhich the paralysis recedes, only to relapse more severely.

Mice don't contract multiple sclerosis, but they can model it in thelaboratory by incurring a strikingly similar autoimmune malady,experimental allergic encepha-lomyelitis.

"Encephalomyelitis is the best model we have to test experimentaltherapeutic approaches to MS," neuroimmunologist Stefan Brocketold BioWorld Today. "Both are inflammatory diseases of the centralnervous system. Both show reactivity of T cells and B cells againstthe main components of myelin basic protein. And the infiltrates thatlead to demyelination in both diseases have similar composition."

He added: "Besides these similarities, there's a major differencebetween MS and encephalomyelitis. MS is obviously a much longer,more chronic, disease than we can mimic in the mouse model."

Brocke is lead author of an article in today's Nature titled "Treatmentof encephalomyelitis with a peptide analogue of myelin basic protein[MBP]." Its senior author is Stanford University neuroscientistLawrence Steinman Their paper reports results of a three-yearresearch project at Stanford to beat the rogue T cells at their game ofdenuding MBP, by camouflaging that target protein's key antigen.

"What we altered," Brocke told BioWorld Today, "is the protein thatis the target of T cells, both in MS and encephalomyelitis."

He and his co-authors scouted out a small segment of the 300-plusamino acids in MBP's chain. They fixed on a 13-moiety stretch thatseemed particularly antigenic to a particular T-cell clone. "It was trialand error," Brocke recalled. "What we did was make systematicsubstitutions of alanine for phenylalanine all over that immuno-dominant peptide we were examining."

In in vivo animal trials, the most promising altered peptide turned upat residue 96. "Then," Brocke continued, "we looked for ways totreat a single attack of paralysis in mice with encephalomyelitis."Droopy tails and dragging limbs are the hallmarks of this paralyticMS surrogate in rodents.

Paralysis Receded _ Permanently

First, the Stanford group injected those MBP-hungry T cells intonormal, healthy mice. The animals duly came down withencephalomyelitis disease. But then, Brocke said, "when challengedwith the altered MBP peptide ligand, in soluble form, the paralysisreceded, and didn't come back. The persistence of the remission wasabsolute."

He explained the mechanism of this effect by recalling that onemission of T cells is to summon up inflammatory cytokines. "Firstamong them," he said, "is TNF-a, which correlates with MS lesionsand the encephalitogeneity of mouse T-cell clones." In his treatedmice, "TNF was clearly reduced."

At the other extreme, a different cytokine, interleukin-4 (IL-4),"which might be beneficial in the disease, was reduced to a lesserextent inside the lesion, as measured by polymerase chain reaction."IL-4, he observed, is reputed to be an immunosuppressive cytokine,but emphasized that "in vivo, there is not a lot known about it."

Stanford University has patents pending on Brocke's altered peptideligands, said co-author Paul Conlon, director of immunology atNeurocrine Biosciences Inc., of San Diego. He added, "Neurocrine isexclusive licensee from Stanford of those patents. They cover theseanalogs as well as related ones."

The company will submit an investigational new drug (IND)application to the FDA this year, Conlon told BioWorld Today, "andwe contemplate initiating Phase I safety trials within the year in theU.S. These studies are contemplated to take approximately six to ninemonths."

The impending trial will be trying "an analog similar to one describedin Nature by Brocke and Steinman, but not identical," Conlon said.

Altered Peptide Strategists Eye Other Targets

Stanford's Steinman, who is also Neurocrine's chiefneuroimmunologist, said, "This is the first time a complexautoimmune process has been completely shut down with a specificimmunomodulator peptide, which targets only a small percentage ofthe disease-specific cells."

Brocke explained this bystander effect: "When we target with analtered peptide ligand the cell that contributes to the disease, it canalso have a beneficial effect on other cells, which have a differentepitope [antigenic hot spot]. So that's more than just targeting a fewneighboring cells; it really targets maybe the whole infiltrate, eventhough we basically have an analog that only a few cells are reactiveto."

Neurocrine's president and CEO, Gary Lyons, foresees "that thisapproach can be used in many intractable autoimmune diseases,including diabetes, rheumatoid arthritis and uveitis." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.