It's not a cure, but a novel form of gene therapy has
delayed symptoms and almost doubled life expectancy in mice
with the equivalent of Lou Gehrig's disease, a team from
the Salk Institute and Johns Hopkins reports in the Aug. 8
issue of Science.
In experiments with mice destined to develop the
condition, injection of the gene for insulin-like growth
factor-1 into muscles protected nerve cells, extended
survival and improved strength, said the scientists, who
are planning a clinical trial they hope to be able to begin
in the next year.
The most beneficial treatment ever seen in the mice,
it is also the first to extend animals' survival when given
after symptoms develop, the researchers said. In the
experimental mice and in people with the disease, known as
amyotrophic lateral sclerosis or ALS, nerves that control
muscles gradually die, leading to paralysis and death.
"ALS is a terrible disease, and patients have few
treatment options today. We're very excited about this,"
said Jeffrey Rothstein, professor of
neuroscience and director of the
Packard Center for ALS
Research at Johns Hopkins. "Even in mice, progression
of the disease is so rapid that we only test possible
treatments before the mice get sick. It is amazing that
this gene therapy can slow progression even after symptoms
Gene therapies use a virus to deliver specific genetic
instructions to cells and usually have to be delivered
directly to where the gene is needed. But instead of
injecting this "adeno-associated" virus into specific
nerves in the brain and spinal cord — a feat that is
likely impossible — researchers at the Salk Institute
discovered and took advantage of the virus's ability to
migrate from muscle into the nerves that control them. The
nerve cells then made the IGF-1 protein.
"IGF-1 protein has been used in clinical trials but
with marginal results," said Fred H. Gage, professor of
genetics at the Salk Institute. "The biggest challenge has
been to deliver the protein across the blood-brain barrier
into the central nervous system."
Studying a fluorescent version of the adeno-associated
virus, Salk research fellow Brian Kaspar discovered that it
could travel from muscles into nerves. Once in the nerves'
nuclei, the cells' machinery pumped out the glowing
The virus's ability to migrate (known as "retrograde
delivery") into nerves from muscle gets the therapeutic
IGF-1 protein where it appears to be needed most--the brain
and spinal cord. The researchers showed that when IGF-1 is
only produced in muscle, the benefit is minimal.
Key to the work is a mouse model of ALS, developed in
part at Johns Hopkins. Without any treatment, these mice,
engineered to make extra superoxide dismutase-1, develop
the first symptoms of weakness at 90 days of age and
succumb to the paralysis within the next 45 days.
Injection of the IGF-1 gene therapy into both
quadriceps (upper hindlimb) muscles and into muscles
between the ribs that help control breathing maintained
strength and lengthened survival.
Mice that received IGF-1 gene therapy at 60 days of
age developed symptoms 31 days later than untreated mice
(i.e., at 121 days) and lived, on average, 40 days longer.
The treated mouse that survived the longest lived 265 days,
while the longest-lived control mouse lived just 140 days.
Mice that received injections of IGF-1 gene therapy at 90
days of age lived an average of 22 days longer than their
In addition to planning a clinical trial, the
researchers also will continue to investigate how IGF-1
protects nerves to improve understanding of the disease and
increase the therapeutic potential of IGF-1.
About 30,000 people in the United States have ALS, and
about 5,000 new cases are diagnosed each year. Most will
die within five years of their diagnosis. While excessive
SOD-1 in mice simulates the effects of the human disease,
the cause of ALS in people is not known.
The Johns Hopkins researchers were funded by Project
ALS. The Salk researchers were funded by Project ALS,
Christopher Reeve Foundation, the National Institute on
Aging and the National Institute of Neurological Diseases
Authors on the paper are Kaspar, Gage and Nushin
Sherkat of the Salk Institute for Biological Studies, and
Rothstein and Jeronia Llado of The Johns Hopkins University
School of Medicine.