Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD

Argininosuccinate lyase deficiency (ASLD; also known as argininosuccinic aciduria) is the
second most common urea cycle disorder (UCD) and accounts for 15-20% of all disorders of
ureagenesis. Individuals with ASLD can have unique clinical and physiologic characteristics
as compared to other UCDs. Previous work from the members of the UCDC have shown that in
spite of having fewer episodes of hyperammonemia as compared to those with proximal blockade
of the urea cycle, individuals with ASLD can develop intellectual and learning disabilities.
Neurocognitive deficits have been observed even in individuals without any documented
hyperammonemia. Furthermore, hepatic abnormalities including hepatomegaly, hepatic injury,
fibrosis and even frank cirrhosis, and vascular issues like hypertension are well known in
the disorder. Previous work from the members of the UCDC has demonstrated a tissue- and
molecular-specific role for ASL in the generation of NO. ASL is not only required for the
synthesis of L-arginine, the substrate for the synthesis of NO, but is also an integral
member of a complex that is critical for synthesis of NO from arginine. Loss of ASL can thus
lead to systemic and tissue-specific NO deficiencies, which could potentially contribute to
the complex phenotype including the neurocognitive deficits. A rational therapeutic option
would hence be to use a NOS-independent NO supplement.

The purpose of this study is to determine whether a dietary NO supplement, Neo-ASA, would
improve general cognition, memory, executive functioning, fine motor functioning, and
attention in individuals with ASLD. In this single-center trial, double-blind, randomized,
placebo-controlled, crossover study, individuals with ASLD will be assigned to receive a
medication containing NO dietary supplement for 24 weeks and a placebo for 24 weeks. General
cognition, memory, executive functioning, and fine motor functioning will be assessed and
compared at the end of treatment with placebo and Neo-ASA.

Inclusion Criteria:

1. Age > 6 and <50 years

2. Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing

3. Has a history of compliance with diet and treatment

4. Negative pregnancy test and ability to use birth control method for the entire
duration of the study (if the subject is of child-bearing potential)

5. Males who enroll in the study (and their partners) should argee to use an acceptable
form of birth control for the entire duration of the study

Exclusion Criteria:

1. Clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE (or
for conditions not covered by the CTCAE, a severe or life-threatening toxicity) at
enrollment which, in the view of the investigator compromises safety. (Elevated plasma
levels of aspartate and alanine aminotransferases, or low serum potassium will not be
considered as exclusion criteria as these are phenotypic manifestations of ASLD.)

2. Known hypersensitivity to Neo-ASA or nitrite

3. Individuals currently being administered other investigational agents