Very upbeat piece on immunophilins in WSJ.....
A Chance Finding Spurs Race
To Develop Host of Nerve Drugs
By ROBERT LANGRETH
Staff Reporter of THE WALL STREET JOURNAL
Medical researchers have long dreamed of creating an elixir to rejuvenate damaged nerves,
restoring memory to Alzheimer's disease victims and movement to the paralyzed. But progress
has come grudgingly.
Now a chance finding may provide the greatest hope to date in the high-risk quest to restore
life to injured nerve and brain cells. Independent of one another, research teams at Johns
Hopkins University in Baltimore and Oregon Health Sciences University in Portland recently
made the surprising discovery that medicines originally developed to suppress the immune
system and fight organ-transplant rejection can also regrow nerves in the spine or brain
damaged by neurological diseases or accidents.
Now several companies, including Guilford
Pharmaceuticals Inc., Vertex Pharmaceuticals Inc. of
Cambridge, Mass., and Pfizer Inc., are racing to develop
experimental nerve drugs, called neuroimmunophilins, that
can be used to combat the largely untreatable symptoms of
illnesses such as Parkinson's disease, Alzheimer's disease and stroke. Guilford, working with
Amgen Inc., could begin human trials of a prototype drug based on the research, to be tested
in Parkinson's disease patients, within a year.
"This is compelling research," says Nicholas Saccomano, a director of brain research at
Pfizer's Groton, Conn., laboratory. "With leads for Alzheimer's disease drugs few and far
between, you'd have to be nuts not to look into this."
Drugs based on the serendipitous findings are still years off, and their success is far from
certain. After all, neurological disorders are among the most mysterious and intractable human
maladies. Several years ago, two tiny biotechnology companies, Cephalon Inc. and Regeneron
Pharmaceuticals Inc., raised hopes among patients and their families when they spent tens of
millions of dollars testing genetically engineered nerve drugs to treat patients with the lethal
disorder called ALS, or Lou Gehrig's disease. Cephalon is still seeking FDA approval for its
nerve-drug Myotrophin.
Those trials ultimately ended in disappointment because the drugs weren't very effective.
Scientists are also troubled because the new agents' nerve-reviving mechanism is still a
mystery, a fact that many drug companies don't like to hear when investing in new science.
Creating a Stir
But the new research is generating excitement among paralyzed patients and their families.
Susan Howley of the American Paralysis Association in Springfield, N.J., says the
neuroimmunophlins have caused a "stir" at scientific meetings and appear to be a "legitimate
area of inquiry."
The idea behind nerve-growth medications is simple and immensely appealing. Most
degenerative brain illnesses occur when important neurons die off over time or simply lose
their ability to transmit electrical signals to other cells. Researchers hope to develop drugs to
protect dying nerves or revive those that are impaired.
Almost all previous attempts to restore nerves have used genetically engineered versions of
naturally occurring proteins the body uses to spur neuron activity. While these so-called
growth factors work well in laboratory tests, their impact in human trials has been minimal.
One big problem is that previous drugs like the ones from Regeneron and Cephalon were
large, unwieldy molecules that easily disintegrated in the body and couldn't easily enter the
brain or spinal cord. Thus for most diseases they had to be injected directly into the brain or
spinal cord to work, a difficult and risky procedure that has deterred many companies from
even testing the drugs in humans.
The new nerve-growth agents, the neuroimmunophilins, have several advantages over the
older nerve drugs. They can be given orally, suggesting they will be able to slip easily from
the bloodstream into the brain. They also appear to target only damaged nerves while leaving
healthy ones intact, suggesting they may have far fewer side-effects.
If they work, "it would be an extraordinary change in the way neurological diseases are
treated," says Fred Gage, a nerve regeneration expert at the Salk Institute in La Jolla, Calif.
"You'd have something that didn't just treat symptoms but actually altered the course of the
disease."
Hunch Pays Off
The neuroimmunophilins were discovered four years ago by the laboratory of Solomon
Snyder, a noted brain scientist at Johns Hopkins, and other scientists in Oregon. They were
investigating the properties of FK-506, then an experimental drug for organ transplantation
(now sold as Tacrolimus by Fujisawa Pharmaceutical Co.). On a hunch, Dr. Snyder and his
colleagues decided to examine FK-506's effects on brain cells. To their surprise, they found
that brain cells contained 50 times more "receptors" for FK-506 than did immune system cells,
suggesting that FK-506 had a mysterious but powerful biological role in the brain.
Dr. Snyder's team was further surprised when test-tube experiments showed that the
transplant medicine stimulated the growth of many types of damaged brain cells. "Not only did
it work, but it was unbelievably potent," says Dr. Snyder.
Meanwhile, Bruce Gold, a young and then-unknown neuroscientist at Oregon Health Sciences
University, became curious about the properties of FK-506 after his brother was treated with
the drug following a liver transplant. He noticed vague reports in the medical literature that the
drug interacted chemically with molecules involved in nerve growth, and wondered if that
would affect nerve growth.
Not sure what would happen, he injected the compound into animals with crushed leg nerves.
The result "was absolutely surprising and unexpected," he says. "The nerves responded to the
drugs and the animals could walk again sooner than they would have otherwise." Further
laboratory animal experiments revealed that FK-506, in fact, could help partially regenerate
nerves in the spinal cord that are critical to motor control and don't normally regrow.
Who Knows Why
Neither research team is certain why the new agents make cells grow. The scientists guess they
work in a way analogous to hormones, spurring production of growth-boosting proteins and
other chemicals normally abundant only during the first years of life when expanding cell
growth is needed.
FK-506's immune-suppressing action and numerous side-effects, including increased cancer
risk, kidney dysfunction and hypertension, made it inappropriate for use in patients with
chronic diseases. So researchers at Guilford Pharmaceuticals, which Dr. Snyder co-founded in
1993, located the portion of FK-506 responsible for the nerve-stimulating effects and
produced a series of drug-like molecules mimicking it. In tests on animals given a Parkinson's
disease-like syndrome, the drugs appear to regrow damaged nerves and cure the major
symptoms of the disorder, Guilford officials say.
The success of Drs. Gold and Snyder is spurring interest from larger companies. Last year,
Amgen called the neuroimmunophilins a breakthrough in brain biology and licensed Guilford's
experimental drugs in a deal that will give Guilford $48.5 million in cash and stock. Amgen's
agreement could bring Guilford almost $400 million if the drugs eventually work. |
