ALS Gene Discovery

Several years ago a consortium of researchers led by Neurologists, Robert Brown (Harvard) and Teepu Siddique (Northwestern), found that a gene that causes familial ALS resides on chromosome 21. Although this was a big step forward, it wasn't certain how long it might take to identify the gene. As it turned out the work went faster than expected and in early 1993 it was found that a known gene (superoxide dismutase) was the culprit. A lot is known about this enzyme which is generally referred to as SOD. Several forms of SOD exists in cells where they function to detoxify free radicals. Free radicals are highly unstable molecules which can damage the genetic blueprint of the cell and disrupt normal cellular functions. It is not certain why motor neurons seem to be particularly susceptible.

With the announcement of the gene discovery researchers have begun to consider their treatment options. As a first step in trying to provide replacement enzyme therapy for patients with familial ALS, CNS undertook the treatment of a patient with superoxide dismutase. Unfortunately, treatment is complicated by the fact that large proteins do not reach the brain due to the existence of a "blood-brain barrier". One way to get around this is to inject SOD directly into the spinal fluid. Before undertaking this in a human, arrangements were made with researchers at the National Institute of Health to conduct studies in monkeys. Intraventricular and intraspinal injections of SOD into monkeys appeared to be well tolerated and it was possibly to tighten in the brain. Based on this, approval was given to CNS to proceed with human studies. These were the first ever undertaken in ALS patients. Pharmacokinetic data indicated that it is possible to achieve high levels of SOD in the spinal fluid (see figure). 

Unfortunately, treatment failed to arrest the course of the disease in a single patient in our study or in a separate study at Harvard (3 patients reported by Merit Cudkowicz & Robert Brown in the journal Neurology).

More recent information suggests that mutant-SOD aggregates in nerve cells.  This has been convincingly demonstrated in cells and animals, suggesting that neurodegeneration is a result of a breakdown in the cytoskeleton of the nerve.  Assuming this is the case in  patients with familial ALS antioxidant therapy is unlikely to be helpful.

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