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Ray D’Alonzo, Ph.D., is an Associate Director of Research and Development
at Procter & Gamble Pharmaceuticals where he has worked for 29 years and led
research programs in bone metabolism, infectious disease, respiratory
disease, arthritis, and nutrition. He has published scientific papers on a
wide variety of topics from the chemical composition of fats and oils to the
pharmacoeconomics of osteoporosis. Dr. D’Alonzo is the recipient of the
Chancellor’s Medal from the University of Massachusetts, Amherst, in part,
for his contributions to the development of new pharmaceutical agents. As
both a patient and scientist, he has made a personal effort to increase the
awareness of Chiari in the health care sector and to assist others afflicted
with the syndrome. He has published the story of his personal struggle
with Chiari in a book,
Contents Under Pressure,
with 100% of royalties going towards Chiari education, awareness, and
research programs.
February 20, 2006 -- Current medications used to treat Chiari are not
particularly effective. There are no disease modifying drugs for Chiari and
drugs used to treat symptoms are usually only modestly beneficial. There is
also a school of thought that drugs which mask the symptoms and pain of
Chiari could also do more harm than good by masking the progression of the
syndrome and delaying the need for surgery to relieve hindbrain compression.
I would like to address in this first article of my column what it would
take to discover and develop a breakthrough disease modifying drug for
Chiari.
However, before I discuss Chiari, I want to talk about what it took to find
a treatment for osteoporosis as lessons can be learned from that experience.
In 1984, I headed a research team looking for a new drug to treat
osteoporosis. At that time, osteoporosis was poorly understood. In many
countries/cultures, osteoporosis wasn’t even considered a disease. It was
considered a natural consequence of aging. Early diagnosis was a problem;
bone-scanning machines were not yet standardized and used almost exclusively
for research. Treatment options were also very limited. Parathyroid hormone,
or PTH, was known to stimulate bone formation but its use was limited
because it required frequent injections and was expensive. In some
countries, oral fluoride was used because fluoride increases bone density
quickly and dramatically; however, concern existed about the quality of new
bone tissue that it produced, and it was later shown in clinical studies
conducted in the late 1980’s and early 1990’s to actually increase fracture
risk.
My team focused on new agents that prevented the loss or resorption of bone
and discovered a novel potent bisphosphonate. We first synthesized the drug
in 1984 and evaluated it in animals for both efficacy and safety in 1985/86.
Clinical human studies were initiated in late 1987. After testing the
molecule in over 15,000 women and men, our data were submitted in 1998 to
the FDA requesting approval. Approval was granted in 2000 and today the drug
is prescribed to protect millions of women with annual worldwide sales
approaching nearly $ 2 billion.
Along the way, we had to overcome many challenges, working with hundreds of
academic investigators. We worked with instrument companies to develop
diagnostic tests. We helped form appropriate medical societies. We sponsored
hundreds of conferences and seminars to educate health care providers. The
research team, which I was appointed to lead in 1984 actually had been in
place since the late 1970’s; it took about 20 years to discover and develop
a drug for this major disease. We probably spent a billion dollars in the
process, and a couple of other drug companies followed our lead and spent
similar amounts of money.
Chiari today, is where osteoporosis was 25 years ago. A key difference,
however, is that Chiari is 100 times less prevalent than osteoporosis. As a
result, it is not on the radar screen of any drug company as a disease of
interest because the cost of discovering and developing a drug to
effectively treat it will not be readily recovered in sales.
Drug companies will continue to develop new drugs for other diseases that
will have application to Chiari for treating symptoms, like pain or
numbness; however, discovering a treatment that halts the progression of the
syndrome, or better, prevents the malformation in the first place is another
story.
To find a new effective treatment for Chiari, the pathogenesis of the
disease must be better understood. By pathogenesis I simply mean the origin
and development of the disease. I have spent the last couple of months
looking into what is known about the pathogenesis of Chiari. I have read
over 3000 medical paper titles, a couple hundred abstracts and about 30 full
papers. This may sound like a lot of papers but actually it isn’t. Searches
on diseases for which even a modest understanding exists will typically
yield hundreds of papers on pathogenesis. Relevant to the pathogenesis of
Chiari, there are two key questions: How or why does the malformation form
in the first place? And, what changes occur that bring on the emergence of
symptoms later in life? There is more in the medical literature germane to
the first question than the second.
There are a couple of theories on how the malformation forms during fetal
development but most of the literature converges on a theory involving
differential growth rates of the skull and hindbrain. Observations and
measurements on fetuses, infants, and young children support the theory that
the skull begins to grow first but does not grow to its full volume, forcing
the later growing hindbrain to grow downward and through the foramen magnum
(large opening at the base of the skull)1. It has been suggested
that in the more severe instance of Chiari II, this may be related to
differential pressures between the skull and spine; either as a result of a
defect in the unfolding or closure of the developing fetal tissue2.
Why such a defect occurs in the first place is unknown. Defects in
developing tissue can be caused by any number of mechanisms including
genetic miscoding, chemical/microbiological offenders, or dietary
deficiencies. Interestingly, animal models exist in which Chiari
malformations have been induced using the mumps virus, vitamin A
over-dosing, and surgical trauma. Basic academic research is needed to
determine why incomplete mesoderm closure during fetal development occurs.
If it is due to a chemical or biological offender, then a cure may be as
simple as removing the offender. If it is due to a dietary deficiency, then
a simple supplement may represent the solution. A genetic defect would
represent a more difficult challenge to find a cure.
Another approach is to find out what changes take place later in life to
trigger symptoms. Turning again to the literature, there are at least three
theories, but one in particular has been the focus of most of the research.
This theory holds that symptoms are a result of increased pressure to the
hind brain as a consequence of the malformation blocking the flow of
cerebrospinal fluid (CSF). This is the basis of using Cine MRI for diagnosis
as Cine MRI can determine if CSF flow is compromised at the foramen magnum3.
However, the malformation is present prior to the onset of symptoms and CSF
flow blockage. So, exactly what changes occur with respect to the
malformation? With the spinal cord and the cerebellar tonsils both occupying
the foramen magnum, little space exists for CSF drainage in the first place.
As a result, only a small change needs to take place to further restrict
that space and block CSF flow.
A few theories have been offered with respect to small anatomical changes
that choke off CSF flow at the foramen magnum; understanding these changes
in greater depth could unlock the secret to finding a breakthrough
treatment. The first has to due with the thickening of the dural band. The
dural band is a relatively thick band of tissue lining the dura around the
foramen magnum. It is often observed during surgery to be thickened,
fibrous, and even ossified (calcified like bone) in many patients.
Understanding why these changes in the dural band occur and then finding a
drug to inhibit them would be one approach to look for a treatment that
prevents the onset of symptoms- provided dural band-thickening is the
culprit.
The second has to do with the formation of intradural adhesions. Dissection
of such adhesions is often performed during decompression surgery as it is
believed that releasing these adhesions promotes CSF flow from the fourth
ventricle to the spinal canal. It is not understood, however, why these
adhesions form in the first place. One theory I have heard is that they may
form in a natural attempt by the body to stabilize the herniated tonsils
from the forces associated with the turning of the head. An understanding of
the role of adhesions in CSF blockage and the biochemistry which regulates
their generation and subsequent growth could lead to new ideas for
preventing their formation.
The third has to do with craniocervical junction compression or “settling”.
It is well known that we all lose height as we grow older. This is due to
the compression of spinal column discs over several decades of life. The
skull also settles to some extent on the spine over time as well. This
craniocervical settling may result in pushing the tonsils further down into
the spinal canal to cause CSF blockage and symptom onset. To what extent
this process may contribute to the progression of the syndrome could also be
further explored. However, since the average age at which symptoms emerge in
patients is only 25, this factor seems less likely.
It is important to realize that basic research to understand the
pathogenesis only represents the very first step. Discovering a new class of
drugs to intervene in the disease process would be the next major hurdle,
followed by an extensive search for a specific molecule that is not only
effective--but safe. If that weren’t enough of a challenge, there would
remain the challenge of screening and diagnosing people at risk before any
drug treatment could be effectively utilized. At present, most Chiari
patients are only diagnosed after prominent symptoms emerge, and it is not
practical nor within the financial means of the healthcare system to provide
MRI scans on everyone. Net, some affordable and effective means for
identifying patients with Chiari malformations who are at risk of developing
symptoms would be needed.
Regardless of the approach taken, a great deal of research (costing hundreds
of millions of dollars) will ultimately be needed to discover and develop a
truly new effective pharmacologic treatment for Chiari. The first step is to
gain a better understanding of the basic pathogenesis of Chiari as discussed
previously. Since the potential market for treating Chiari is too small to
attract the attention of traditional pharmaceutical companies, this first
research step is best taken by academic and government investigators. Once
the biological target for intervention is better understood, the quest for
discovering and developing novel therapeutic agents is likely to be taken up
by small entrepreneurial biotech companies, as these companies often enter
the pharmaceutical industry by conquering less prevalent diseases.
The potential to conquer Chiari clearly exists. Interest and awareness
amongst academic and government researchers must be increased as a first
step. This often initially occurs by non-profit organizations providing seed
funds for basic research. Success in basic research will attract larger
government grants and eventually small industry.
Non-profit organizations are highly dependant on those of us afflicted with
Chiari (and our friends and relatives) to provide support; this is true for
many other diseases. Our support can come in many ways, from simply
increasing awareness in others to making significant monetary donations. The
one thing we can not afford to do is to sit back and let Chiari conquer us.
-- Ray D'Alonzo, Ph.D.
1 Griffiths et al, Acta Radiol. 2004 Apr;45(2):236-42.
2 McLone and Naidich, AJNR Am J Neuroradiol. 1992 Mar-Apr;13(2):463-82.
3 Quigley et al, Radiology. 2004 Jul;232(1):229-36.
** If you
would like to share your comments, thoughts, or ideas with Ray,
please send them to dalonzo.rp@fuse.net.
Due to the volume and nature of email received, individual responses are not
possible. **
[Ed. Note: The opinions expressed above are solely those of the
author. They do not represent the opinions of the editor, publisher,
or this publication. Anyone with a medical problem is strongly
encouraged to seek professional medical care.]
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