X-Message-Number: 31295
Date: Tue, 23 Dec 2008 09:22:56 -0800 (PST)
From: 
Subject: antiaging drug trial for progeria


Premature Aging Disease: Gene Discovery To Clinical Trial Of Potential 
Treatment, All Done In Just 5 Years

ScienceDaily (Dec. 16, 2008) - One of the fastest translations of a basic 
research discovery into a promising clinical trial for an "untreatable" and 
fatal disorder will be discussed publicly for the first time by the key players 
in this remarkable research story, on Dec. 14, at the American Society for Cell 
Biology (ASCB)'s annual meeting in San Francisco.


The disease is Progeria, or Hutchinson-Gilford Progeria Syndrome (HGPS), a rare,
accelerated aging disease that afflicts children.

The discovery of the gene responsible for the disease five years ago led 
scientists to the experimental drug that is now being evaluated in 28 children 
with this "premature aging" disease.

Speaking at the special ASCB session will be the physician heading the clinical 
trial, the gene-hunter whose research team pinpointed the DNA mutation, and the 
cell biologist who conducted the basic research on the protein structures in the
cell nucleus that were subsequently found to be abnormal in HGPS.

Also on the panel will be the medical director of the Progeria Research 
Foundation who is both a scientist and the mother of a child with HGPS.

In addition to describing this bench-to-bedside story, the ASCB special 
symposium will spotlight new research suggesting that the basic cellular 
mechanism defective in children with HGPS may be at work in "normal" aging 
disorders, particularly in cardiovascular disease.

HGPS is estimated to affect about one child in 4 million. At birth, children 
with the disease appear normal. However, their growth soon slows, and children 
with HGPS begin to show signs of accelerated aging, such as hair loss, wrinkled 
skin, and loss of body fat. A 10-year-old child with HGPS typically looks like 
an 80-year-old adult.

HGPS' lethal damage occurs within the major blood vessels. The children develop 
premature cardiovascular disease, which typically leads to death from heart 
attack or stroke at about the age of 13. There currently are no treatments for 
the disease.
The study

The 28 children enrolled in the clinical trial range in age from 3 to 15 years 
old and come from 16 countries. The two and one-half year phase 2 clinical 
trial, which began in 2007, is evaluating the FTI drug lonafarnib. In clinical 
studies in people with myeloid leukemia, neurofibromatosis and other conditions,
FTIs' side effects were minimal.

The 2003 discovery of the HGPS gene, named lamin A (LMNA), laid the groundwork 
for the clinical trial. Indeed, in 2003, Dr. Collins was quoted as saying, "This
genetic discovery represents the first piece in solving the tragic puzzle of 
Progeria. Without such information, we in the medical community were at loss 
about where to focus our efforts to help these children and their families. Now,
we finally know where to begin."

They began by zeroing in on the LMNA gene and the HGPS genetic mutation, a 
single-letter "misspelling" in the LMNA gene located on chromosome 1. This gene 
carries the DNA recipe for lamin A, the protein glue that holds together the 
cell's nucleus. The mutated LMNA gene generates an abnormal Lamin A protein 
(also called progerin) that disrupts the cell's nuclear membrane. Because 
progerin wreaks havoc, cells become unstable and abnormal. The resulting gross 
disfigurement of the cell's nucleus is described as "blebbed," or lobular in 
shape.

(Recent research indicates that all people, not just children with HGPS, produce
small amounts of progerin, and that this mutant protein may play roles in aging
or longevity.)

Studying cells from HGPS patients, the NHGRI scientists found that the minute 
change in the LMNA gene's DNA sequence dramatically changed the way in which the
sequence was spliced by the cell's protein-making machinery. The end result was
the production of an abnormal lamin A protein that is missing a stretch of 50 
amino acids near one of its ends.

Even before Dr. Francis Collins, M.D., Ph.D., the former National Human Genome 
Research Institute, and his research team tracked down the genetic mutation 
responsible for HGPS, Dr. Goldman had earned a stellar reputation for his 
cutting-edge basic research on the Lamin proteins in the cell nucleus.

Lamins were first described in the 1950s, and their protein structure was 
unraveled in the 1970s. The biochemistry of lamin A/C processing was 
characterized in the 1980s.

Until the late 1990s, however, funding for nuclear lamina research was sparse. 
Still, the link to HGPS in 2003 electrified the field, since Dr. Goldman and 
other lamin researchers had a good hunch about what might be going wrong in this
children's disease of accelerated aging.

Years of basic research studies showed that the Lamin A protein production 
depends on the farnesyl group molecules' attaching themselves to the pre-lamin A
protein. This attachment - and progerin production - can be blocked by a FTI 
drug, NHGRI scientists soon discovered in their studies of laboratory cultures 
of cells from HGPS patients.

And, the laboratory research continues. In October, the Proceedings of the 
National Academy of Sciences published findings that the experimental FTI cancer
drug, tipifarnib, can prevent -- and even reverse -- potentially fatal 
cardiovascular damage in a transgenetic mouse model of HGPS. Dr. Collins and 
Elizabeth Nabel, M.D., director of the National Heart, Lung and Blood Institute 
(NHLBI), headed these studies. Dr. Collins has continued to conduct research as 
a special volunteer in the Genome Technology Branch of NHGRI's Division of 
Intramural Research.
Symposium speakers

Robert D. Goldman, Ph.D., a pioneer in basic research relevant to understanding 
how the HGPS gene mutation disrupts human body cells. The head of cell biology 
at Northwestern University Medical School in Chicago (and ASCB's current 
president), Dr. Goldman has long studied the normal structure and function of a 
major component of the scaffold-like network of proteins just inside the 
membrane that surrounds and protects the cell's nucleus. His research team 
identified the component, called nuclear lamins, as the culprit in HGPS;

Gene-hunter Francis Collins, M.D., Ph.D., the former National Human Genome 
Research Institute (NHGRI) director who headed the research team that pinpointed
HGPS' genetic mutation in 2003. Just two years later, NHGRI scientists 
identified the class of experimental cancer drugs, called farnesyl transferase 
inhibitors (FTIs), that can prevent the cell damage caused by the gene mutation 
and thus might provide an effective therapy against the disease;

Harvard Assistant Professor Mark Kieran, M.D., Ph.D., the principal investigator
of the Boston Children's Hospital phase 2 clinical trial that is evaluating a 
FTI drug in children with HGPS. He is director of Dana-Farber Cancer Institute's
Pediatric Medical Neuro-Oncology;

Leslie Gordon, M.D., Ph.D., parent of a child with the disease and medical 
director of the Progeria Research Foundation, which is funding the clinical 
trial and which has been the "mover and shaker" in accelerating research on the 
disease.

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