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Current Projects in ALS & Motor Neuron Disorder Research

Developing a cell replacement therapy for ALS

Researchers at UC San Diego, along with co-principal investigator Sam Pfaff, Ph.D., a professor in the Salk Institute's Gene Expression Laboratory, hope to develop an ALS therapy that uses human embryonic stem cells to create astrocyte precursors that would be transplanted into patients where they would mature into new and healthy astrocytes that could halt — and perhaps reverse — the progressive ravages of ALS.

Astrocytes are glial cells, a family of cells that support the proper functioning and insulation of neurons. The particular job of astrocytes is to help with neurotransmissions and neuronal metabolism. In ALS, the decay of astrocytes and other cells eventually causes neurons to malfunction and die, leading to a host of debilitating and ultimately fatal consequences.

Previous research indicates that transplanting healthy glial cells into patients could be a possible treatment for ALS, and animal studies have shown that astrocytes possess particular promise.

This project is being funded by an $11.5 million California Institute for Regenerative Medicine (CIRM) "disease team" grant for stem cell research.

The researchers will study two methods of administering progenitors in animal models and test the safety and efficacy of these approaches, with the goal of providing proof-of-principle and laying the groundwork for clinical trials by 2014.

Identifying an FDA approved drug for slowing progression of ALS

Don Cleveland's team, in partnership with Professor Berislav Zlokovic at University of Rochester, demonstrated that administration of a serum protease known as C(APC) slowed disease progression in mice that mimic an inherited form of the fatal paralytic disease ALS.

APC is the chemical cousin of a drug currently used to treat sepsis. It is previously approved by the FDA, proven safe and is currently being given to patients for another condition.

To improve efficacy of the treatment and decrease unwanted side effects such as bleeding, researchers further investigated the drug dosing and administration.

Clinical trials are now underway for peripheral administration of APC for ALS.

A paradigm shift helps identifying how errors in RNA binding proteins cause ALS

Over the last two years, a paradigm shift in understanding what goes wrong in Amyotrophic Lateral Sclerosis has been initiated by the discoveries that mutations in a pair of RNA binding proteins (TDP-43 and FUS/TLS) are primary causes of the disease.

Through analysis of mice that are genetic mimics of inherited ALS, the Cleveland team is identifying how these mutations cause premature death of the motor neurons. New, very high throughput DNA/RNA sequencing methods are being used to identify those genes whose expression is altered by the mutations. This identification helps recognize new targets and possibilities for a successful ALS therapy.

Developing a gene silencing therapy for inherited ALS

Researchers led by Don Cleveland, Ph.D., have established the rationale for a new treatment aimed at a mutant protein linked to some inherited forms of ALS.

The treatment uses a gene silencing strategy whereby scientists find ways to gain control of the expression of genes and turn them on or off at the DNA level.

Using antisense oligonucleotide researchers were able to reach neurons and their surrounding cells throughout the nervous system. The antisense treatment, when delivered in effective amounts directly to the spaces inside the brain, extended lifespan in rates recreating many aspects of ALS.

These findings have paved the way to a therapeutic approach for ALS, in which an antisense drug is targeted to the specific cells that are reacting to the toxicity of defective protein, production of which is silenced by the treatment. Clinical trials in patients with inherited ALS, using the antisense drug made by Isis Pharmaceuticals, Inc., initiated in February 2010.

Developing viral gene delivery as a therapy in ALS

Crossing the blood brain barrier is a common major obstacle in treating ALS. Gene therapy offers a unique opportunity to develop a one-time treatment to specifically targeted populations of cells that are implicated in disease.

With the discovery that a small particle (named AAV9) can transverse the blood brain barrier and home to a class of cells that support motor neuron survival, the Cleveland team is testing whether this approach can be an effective therapy for inherited ALS. Approaches include delivery of molecules that can either silence the disease causing mutant gene or delivery of genes that can produce "growth factors" that promote the survival and health of motor neurons.