Promising therapy for ALS delivers antisense drug directly to nervous system

The study conducted 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.

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.

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 the June 2 issue of the journal Science – confirms the importance of the new therapeutic approach, which delivers an antisense drug directly to the 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.”

Within a year, Cleveland hopes the first clinical trial will be initiated in humans. 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.

The investigators noted that if the antisense approach works for ALS – by delivering therapeutic agents for neurodegenerative diseases across the highly impermeable blood-brain 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 genetic-based 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.”