Download 7 27 06 Cleveland press release with Cleveland, Miller and Smith

Media Contact: Debra Kain
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Embargoed by Journal of Clinical Investigation until July 27
Promising Therapy for ALS Delivers Antisense Drug Directly to Nervous System
Delivering agents across the blood-brain barrier likely to be effective treatment for
other neurodegenerative diseases
Researchers from the University of California, San Diego (UCSD) School of Medicine,
the Center for Neurologic Study and Isis Pharmaceutical corporation have designed and
tested a molecular therapy in animals that they hope will be a major development in the
fight to treat amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
The study undertaken in the laboratory of Don Cleveland, Ph.D., UCSD Professor of
Medicine, Neurosciences and Cellular and Molecular Medicine, and member of the
Ludwig Institute for Cancer Research, shows that therapeutic molecules known as
antisense oligonucleotides can be delivered to the brain and spinal cord through the
cerebrospinal fluid (CSF) at doses shown to slow the progression of ALS in rats. The
study will be published July 27 in advance of publication in the August issue of Journal
of Clinical Investigation.
With colleagues Timothy Miller, M.D., Ph.D., UCSD Department of Neurosciences, and
Richard A. Smith, M.D., of the Center for Neurologic Study, Cleveland found that when
effective doses of the antisense therapy were delivered, far less of a protein that causes a
hereditable form of amyotrophic lateral sclerosis was produced.
Neurotoxicity from an accumulation of mutant proteins is believed to be at the root of
many neurodegenerative diseases. ALS can be caused by a mutation in a protein called
SOD1, and the antisense drug effectively silences the gene that codes for this mutant
protein – found in the cells of patients with inherited forms of ALS.
In this disease, selective killing of spinal cord “motor neurons” occurs. Motor neurons
are long and complex nerve cells that control voluntary movement. Degeneration of
motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely
death.
Healthy “neighbor” or supporting non-neuronal cells also have a protective effect on
damaged mutant motor neurons, slowing the progression of ALS even when the nerve
cells carry the mutant gene. The researchers speculate that the non-neuronal cells play a
vital role in nourishing the motor neurons and in scavenging toxins from the cellular
environment.
The onset and progression of disease in inherited ALS is determined by the motor
neurons and microglia, small immune cells in the spinal cord, which migrate through
nerve tissue and remove damaged cells and debris. Damage to motor neurons determines
timing of disease onset. Microglia – the neighborhood, or “helper” cells – are then
activated to help nourish the motor neurons and clean out debris like a vacuum cleaner.
But because these neighboring cells are also damaged, they hurt instead of help, thus
speeding disease progression.
When the UCSD researchers isolated and shut off mutant SOD1genes in the motor
neuron cells only, the disease onset slowed, but the course of the disease eventually
caught up to the control rodents. When mutant genes in only the microglia were silenced,
the scientists found almost no effect on disease onset, however the disease progression
was significantly slowed.
This discovery, authored by UCSD investigators Severine Boillee, Koji Yamanaka,
Cleveland and others and published in June in the journal Science, confirms the
importance of the new therapeutic approach which delivers an antisense drug directly to
whole nervous system, including non-neuronal cells.
“Limiting mutant damage to microglia robustly slowed the disease’s course, even when
all motor neurons were expressing high levels of a SOD1 mutant,” said Cleveland. “Our
research suggests that what starts ALS and what keeps it going are two separate phases; it
also suggests that with the right therapy, ALS could become a manageable, chronic
disease.”
In order to deliver the antisense drug directly to the nervous system, surgeons will insert a
small pump into a patient using a fairly routine surgery that has already been approved
for management of pain. A small catheter is then implanted into the area surrounding the
spinal cord, in order to pump antisense oligonucleotide drugs directly into the nervous
system. Within a year, Cleveland hopes the strategy will be tried in humans.
The investigators noted that if the antisense approach works for ALS – by delivering
therapeutic agents for neurodegenerative diseases across the highly impermeable bloodbrain barrier – it would likely also work in other neurodegenerative conditions, including
Alzheimer’s, Parkinson’s and Huntington’s diseases.
“We know we’re on target with the pathogenic mechanism,” said Cleveland. The
remaining question is whether the gene therapy will be tolerated. “If tolerated, this sets
the stage for broader treatment of neurodegenerative disease, especially Huntington’s
disease, where there is currently no treatment, but key genes involved in promoting
disease are known.”
ALS is a progressive disease that attacks motor neurons that reach from the brain to the
spinal cord and from the spinal cord to the muscles throughout the body. Estimated to
affect some 30,000 Americans, most people are diagnosed with ALS between the ages of
40 and 70. Typically, ALS patients live only three to five years after initial diagnosis.
Cleveland was just elected to the National Academy of Science and Smith is a Skaggs
Scholar at the Scripps Research Institute. Both are consultants to Isis Pharmaceutical
Corporation, a Carlsbad, California-based company that manufactures the antisense drug.
The work was supported by funding from the ALS Association.