Safety Study of High Doses of Zinc in ALS Patients

Physicians at Phoenix Neurological Associates (PNA) are looking for individuals diagnosed
with ALS to participate in an open label phase II safety trial with zinc in conjunction with
copper, used in combination with Riluzole for treating ALS. This investigator initiated trial
conducted by Drs. Todd Levine and David Saperstein will help determine if zinc given at high
doses is safe and tolerated and could possibly slow the progression of ALS.

Over fifty years ago an epidemic of ALS was discovered on the Island of Guam where a disease
complex of ALS was found to be one hundred times more prevalent than in the rest of the
world. Research on ALS in Guam linked ALS, along with Parkinson's Disease and Dementia, with
a neurotoxin, β-methylamino-L-alanine (BMAA). BMAA is a non-essential amino acid and is
produced by a cyanobacterium found in large concentrations in the food consumed by the people
on Guam. Subsequently several groups have identified high concentrations of BMAA in brain
tissues of patients from North America and Europe with several neurodegenerative diseases
including ALS, Parkinson's Disease and Alzheimer's Diseases.

A small proportion of ALS, (about 2%), is associated with a mutation in the superoxide
dismutase (SOD1) gene. Mice who express this mutant gene exhibit a progressive, ALS-like
neurodegenerative disease.Since it is known that SOD1 binds zinc, and many of the mutant
forms of this enzyme associated with ALS show altered zinc binding, zinc may play a key role
in all pathological processes associated with ALS. Previous studies have shown that in ALS
mutant G93A SOD transgenic mice, actual zinc supplementation delayed death. Zinc has also
been thought to serve as an endogenous antioxidant in the central nervous system and help
protect the BBB against oxidative stress and prevent BMAA from crossing into the brain.

It has been demonstrated that BMAA binds exceptionally strongly to transition metal ions such
as zinc, copper, and nitrogen. If BMAA crossed over the permeable BBB, and enters a
compartment in which glutamate was bound to zinc, then the glutamate/zinc complex would
dissociate in favor of zinc having a stronger affinity to BMAA. This could lead to higher
levels of unbound glutamate which is believed to be highly neurotoxic in ALS patients. We
hypothesize by exposing patients to high levels of zinc, both BMAA and glutamate would be
kept in a bound complex with zinc, i.e. eliminating competitive binding for zinc, which lead
to less excitotoxic free glutamate and glutamate toxicity would be reduced.

Inclusion Criteria:

1. Age 18-85

2. Male or Female

3. Clinically definite or probable ALS by El Escorial criteria

4. ALS-FRS > 25

5. If on Riluzole they must be on a stable dose for at least 30 days prior to screening

6. Capable of providing informed consent and complying with trial procedures

Exclusion Criteria:

1. Patients with FVC below 50%

2. History of liver disease

3. Severe renal failure

4. Creatinine greater than or equal to 1.5 mg/dL

5. History of intolerance to zinc or copper

6. Evidence of motor neuron disease for greater than 5 years

7. Any other co-morbid condition which would make completion of the trial unlikely

8. If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to
use birth control.

9. Any other trial medications. Non-trial medications are not cause for exclusion

10. Patient with history of significant anemia

11. Elevated levels of zinc at baseline

12. Patients with copper levels below normal at baseline