|Treatment Extends Survival in Mouse Model of
Spinal Muscular Atrophy
Drug therapy can extend survival and improve movement in a mouse
model of spinal muscular atrophy (SMA), new research shows. The
study, carried out at the NIH’s National Institute of Neurological
Disorders and Stroke (NINDS), suggests that similar drugs might
one day be useful for treating human SMA.
"This study shows that treatment can be effective when started
after the disease appears," says Kenneth H. Fischbeck, M.D., of
the NINDS, who helped lead the new study. The finding is important
because most children with SMA are diagnosed after symptoms of
the disease become obvious, he adds. The report appears in the
February 22, 2007, advance online publication of The Journal
of Clinical Investigation.
SMA is the most common severe hereditary neurological disease
of childhood, affecting one in every 8,000-10,000 children. Babies
with the most common form of the disease, called SMA type I, develop
symptoms before birth or in the first few months of life and have
severe muscle weakness that makes it difficult for them to breathe,
eat, and move. They usually die by age two. Other forms of SMA
are not as severe, but still cause significant disability. While
some symptoms of SMA can be alleviated, there is currently no treatment
that can change the course of the disease.
SMA is caused by mutations in a gene called SMN1. Investigators
studying the genetics of SMA have found that there is another gene,
called SMN2, on the same chromosome. While the normal
form of SMN1 produces a full-length functional protein,
most of the protein produced by SMN2 is truncated and
unable to function. The relatively small amount of normal SMN protein
produced by the SMN2 gene can reduce the severity of the
disease. Therefore, investigators are searching for drugs that
can increase the amount of normal protein produced by this gene.
The new study, directed by Dr. Fischbeck's colleague Charlotte
J. Sumner, M.D., at NINDS, tested a drug called trichostatin A
(TSA) that is in a class of drugs called histone deacetylase (HDAC)
inhibitors. These drugs increase the activity of certain genes
in the body.
Previous studies have shown that HDAC inhibitors can increase
the amount of SMN2 expression in cultured cells and that
treating pregnant mice with an HDAC inhibitor can increase the
survival of their babies with SMA. Preliminary clinical trials
are now underway to test several HDAC inhibitors in children who
have SMA. However, the drugs in those clinical trials are weak
HDAC inhibitors with other biological effects that may limit their
usefulness for treating this disease. More importantly, none of
the previous studies has demonstrated that HDAC inhibitors can
extend survival when delivered after symptoms appeared.
In the new study, the investigators tested TSA, which is a potent
HDAC inhibitor, in cells from SMA patients and in a mouse model
of SMA. They found that the drug increased the amount of SMN2 gene
activity in both the cultured cells and the mouse model.
Next, the researchers gave daily injections of TSA to the SMA
mice, starting when the mice were 5 days old. By that time, the
mice showed clear symptoms of disease: they were significantly
underweight and they had a markedly impaired righting reflex, or
ability to get on their feet after being placed on their backs.
The treated mice lived 19 percent longer, on average, than mice
that did not receive TSA. About three-fourths of the treated mice
had improved survival compared to control mice. The other fourth
showed no improvement.
The treated mice had less weight loss and better righting reflexes,
walking ability, and forelimb grip strength than mice that did
not receive TSA. Examination showed that the TSA-treated mice also
had larger neurons in the spinal cord, thicker muscle fibers, and
more muscle mass than untreated mice.
"This is a proof-of-concept experiment," says Dr. Sumner. "It
clearly demonstrates that this treatment can ameliorate the disease
in mice." While the results are exciting, there are still no studies
that have proven the effectiveness of HDAC inhibitors in humans,
The investigators are now testing whether treatment with TSA earlier
in the disease process will work better than the delayed treatment
in this study. They also plan to test other HDAC inhibitors in
mice and to study exactly how the drugs influence the disease process.
While TSA is expensive to produce and it is not approved for clinical
use, similar drugs being developed to treat cancer and other diseases
may be useful for treating SMA, Dr. Sumner says.
Reporters: for more information, call 301-496-5924 or go to www.ninds.nih.gov/PressRequest/.
Information about SMA is available at http://www.ninds.nih.gov/disorders/sma/sma.htm.
A photo of mice used in this study is available at http://www.ninds.nih.gov/img/mice.htm.
|Two mice with a genetic defect
similar to that of humans with the motor neuron disease
called spinal muscular atrophy. Both mice are 11 days old.
The mouse on the left has received treatment with a drug
called Trichostatin A that increases the activity of certain
genes. The mouse on the right did not receive the drug.
The treated mouse is able to stand upright and support
its weight on its feet. The other mouse is much smaller
due to effects of the disease, and it is unable to move
normally or to fully support its weight. Click on image for a larger view
The National Institute of Neurological Disorders and Stroke is
the nation's primary funder of research on the brain and nervous
system. More information about SMA and other neurological disorders
can be found on the NINDS web site, www.ninds.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.