It used to be that kiddies growing up in climates without muchsunshine had to take their daily spoonful of cod liver oil to ward offrickets.
Those who didn't risked growing up with the bulging foreheads,knock knees, bow legs and distorted rib cages of rickets, due to adeficiency of vitamin D. Nowadays, kids can get their vitamin Dsupplement in chewable multivitamin tablets, trademarked afterjuvenile-friendly comic strip characters.
Exposure to sunlight, plus foods such as fortified milk, rich in fat-soluble vitamin D, have demoted rickets from a major childhooddisease in northern climes to a relative medical rarity.
Vitamin D works by mobilizing calcium and phosphorus to promotebone growth and bone health. It's synthesized in the skin by theaction of the sun's ultraviolet rays, then converted to active hormonalform as it traverses the liver and kidneys.
That conversion, explains biochemist Hector DeLuca, involves aseries of hydroxylations _ adding on of an oxygen-hydrogen radical_ so the molecules' receptors can recognize them. The amount ofthe resulting hormone, secreted by the kidney, DeLuca told BioWorldToday, "is regulated depending upon the body's need for calcium."
DeLuca chairs the department of biochemistry at the University ofWisconsin in Madison. He discovered vitamin D's hormonalmetabolite in 1970. It's called 1,25-dihydroxyvitamin D3, not to beconfused with the form found in multivitamin tablets.
Since then, the university has licensed his chemically synthesizedhormone to Roche Laboratories, of Nutley, N.J., and AbbottLaboratories, of Abbott Park, Ill. "Its main use in the U.S.," DeLucasaid, "is to treat renal osteodystrophy, the bone disease of kidneyfailure. In Japan, Australia, New Zealand and some Europeancountries, it's also approved as therapy for osteoporosis."
DeLuca's latest discovery, that the hormone may well be effective inpreventing, arresting, perhaps reversing, multiple sclerosis, representsa stretch. It's reported in the current Proceedings of the NationalAcademy of Sciences (PNAS) dated July 23, 1996, under the title:"1,25-dihydroxyvitamin D3 reversibly blocks the progression ofrelapsing encephalomyelitis, a model of multiple sclerosis."
EAE Mice Today; MS Patients Tomorrow?
Relapsing encephalomyelitis is better known as experimentalautoimmune encephalomyelitis (EAE), induced in mice to mimic thesymptology of multiple sclerosis (MS).
DeLuca and his co-authors described how he construed a possibleconnection of the vitamin D hormone to EAE, and hence to MS:
"We and others," he recalled, "found the receptor to the vitamin Dhormone in places that don't play a role in calcium metabolism. Sowe began to look for other possible functions of the hormone. One ofthese turned out to be the immune system."
It's the immune system, of course, that turns against EAE mice andMS people, by attacking and destroying the fatty myelin sheathing oftheir nerve axons. Certain myelin-targeting T lymphocytes spearheadthis onslaught.
"The vitamin D hormone," DeLuca continued, "seems to affect thecytokines, notably interleukins, interferons, tumor necrosis factor,that control these populations of T helper cells. And we were reallystunned at how effective the hormone is in preventing EAE, which isconsidered a pretty good model of MS."
He added: "Until we put it in man, and relieve the human disease, welike to be cautious. We're picturing this happening within the year."
After initial discussions with clinicians at the University ofWisconsin teaching hospital, DeLuca went on, "right now we aretalking with medical doctors who actually see MS patients, and tryingto arrange collaborations with medical groups that have largenumbers of them under treatment."
For clinical trials, he plans to employ analogues of 1,25-dihydroxyvitamin D3, rather than the hormone currently marketed forbone diseases. "These noncalcemic analogues," he explained, "aresafer, and at least as effective, as the native hormone. They won'traise blood calcium to high levels, which is the main side effect of thepharmaceutical product."
Recently approved interferon-beta for treating MS, DeLuca observed,has not yet developed "a lot of experience in patients, and itsmechanism of action remains undefined. This," he continued, "maynot apply to the vitamin D hormone, which has been in patients nowfor almost 25 years. So we know what to expect as side effects."
Hormone Analogues Slated For Clinical Trials
He observed, "If we're going to go to analogues, of course, we haveto do preliminary toxicity studies, and enough for an IND[investigational new drug application]."
As for efficacy of eventual trials in MS, "certainly we want expertswho can document that it is or is not effective. We're trying to comeup with a short-term test, such as magnetic resonance imaging, todecide if it's going to work. Then, longer term, where one wouldactually score the symptoms, to see if we can arrest the progression ofMS, or actually make the patients get better."
DeLuca's paper in PNAS sets forth how he got these promisingresults in EAE mice.
To bring on their disease, 24 animals received low-dose injections ofmyelin basic protein (MBP), the antigen targeted by the autoimmuneT helper 1 cells. Within 10 days, all 24 showed symptoms of EAE.These began (stage 1) with tails gone limp, followed (stage 2) by legweakness and clumsy gait, (stages 3 and 4) front and hind limbparalysis, and ultimately (stage 5) approaching death.
But pretreating the animals a day before injecting the EAE-inducingMBP antigen, PNAS reported, "completely prevented the appearanceof any disability whatsoever."
So much for prevention of onset. Next, progression: Individual micewith overt EAE symptoms got abdominal injections of the hormone,plus an oral ration of it in their chow. Control mice got mockinjections and no diet supplement.
The hormonal treatment staved off progression during a 40-dayobservation period. "On the other hand, the mock-treated [control]mice all became paralyzed with peak EAE severity scores of [stage]4." Similar controlled experiments showed that the EAE progressioncan be reversibly prevented.
From further preclinical EAE trials now ongoing, DeLuca concluded:"Yes, it looks like they get better, but how much better we can't yetreport." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.