Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD

Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)

This is a study involving a dietary supplement. Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. The investigators will assess the effects of the supplement in domains of general cognition, memory, executive functioning, and fine motor functioning in individuals 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.

Argininosuccinate Lyase Deficiency, Urea Cycle Disorder, Urea Cycle Disorders, Inborn, Argininosuccinic Aciduria

Active Comparator: Nitric oxide supplement Active Comparator will l not contain nitric oxide supplement. Placebo Comparator: Placebo Placebo will not contain nitric oxide supplement.

Randomization for treatment assignment is by the providing Institution's Investigational Pharmacy Services.

During this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily.

During this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily.

Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA

Wechsler Intelligence Scale for Children OR Wechsler Adult Intelligence Scale - 4th Edition (in subjects > 16 years of age)

Inclusion Criteria: Age > 6 and <50 years Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing Has a history of compliance with diet and treatment 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) 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: 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.) Known hypersensitivity to Neo-ASA or nitrite Individuals currently being administered other investigational agents

According to the policy of the National Institutes of Health (one of the study sponsors) research data may be put in a secure, limited-access database known as dbGaP. The data will include any genetic test results as well as other information about medical problems. There will be NO identifiers included (no name, data of birth, address, social security number, etc.). Access to this information is restricted by the National Institutes of Health. Only doctors and scientists who get approval from the National Institutes of Health can access this de-identified data.

Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.

Nagamani SCS, Erez A, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [updated 2019 Mar 28]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/

Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. 2011 Nov 13;17(12):1619-26. doi: 10.1038/nm.2544.