ASA/ASL Deficiency
Urea Cycle Disorders Consortium Study 5114: Nitric Oxide Supplementation on Neurocognitive Functions in Patients With Argininosuccinate Lyase Deficiency (argininosuccinic aciduria, ASL deficiency)
Status: Recruiting
Principal Investigators: Sandesh Nagamani, MD, Brendan Lee, MD PhD, Baylor College of Medicine, Houston TX
For questions or to join the study, contact the study coordinator:
Saima Ali, RN, FNP-C
Phone: 832-822-4183
Email: sma1@bcm.edu
Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo (both in the form of a lozenge) for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. The investigators will assess the effects of the supplement on general cognition, memory, executive functioning, and fine motor functioning in individuals with ASLD.
Eligibility requirements:
- Ages over 6 years and less than 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 agree to use an acceptable form of birth control for the entire duration of the study.
Detailed Description:
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 Urea Cycle Disorders Consortium (UCDC) has shown that individuals with ASLD can develop intellectual and learning disabilities despite having fewer episodes of hyperammonemia as compared to the proximal urea cycle disorders OTC deficiency and CPS1. Neurocognitive deficits have been observed even in ASL individuals even without any documented hyperammonemia. Furthermore, liver abnormalities including hepatomegaly, hepatic injury, fibrosis and cirrhosis, and vascular issues like hypertension are well described in ASLD. Previous studies have demonstrated a tissue and molecular-specific role for ASL in the generation of nitric oxide (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 ASL phenotype, including neurocognitive deficits. A rational therapeutic option could be use a NOS-independent NO supplement.
Purpose of the Study: 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 an NO dietary supplement, Neo-ASA, 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.
Study Procedures: This study will requires 4 visits to the clinical research center and 2 laboratory draws at a facility close to the place of residence of the participant over the duration of the entire study.
Week 1 visit procedures, treatment period 1
- Obtain informed consent
- Measure vital signs - heart rate, blood pressure, respiratory rate, and body temperature
- Measure height and weight
- Record medical history
- Perform physical examination
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC), comprehensive metabolic panel (CMP), ammonia; Research laboratory tests: nitrite, nitrate, and biochemical tests)
- Collect urine sample for laboratory test (Safety: urine pregnancy test for women of child- bearing age)
- Complete checklist for inclusion and exclusion criteria for enrollment
- Perform neuropsychological testing
- Blood may be collected establish lymphoblast culture
- Skin biopsy may be performed to establish a fibroblast culture
- Randomization for treatment assignment by Investigational Pharmacy Services of Texas Children’s Hospital
- Administer medication and monitor for 2 hours
Week 6 laboratory procedures, treatment period 1
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC) and comprehensive metabolic panel (CMP))
- Document adverse events
- Document concomitant medications
Week 12, follow up over telephone, treatment period 1
- Document adverse events
- Document concomitant medications
Week 24 visit study procedures, treatment period 1
- Measure vital signs - heart rate, blood pressure, respiratory rate, and body temperature
- Measure height and weight
- Record medical history
- Perform physical examination
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC), comprehensive metabolic panel (CMP), ammonia; Research laboratory tests: nitrite, nitrate, and biochemical tests)
- Perform neuropsychological testing
Following a washout period (no treatment administered) of 8 weeks, study procedures for treatment arm 2 will be initiated:
Week 1 visit procedures, treatment period 2
- Measure vital signs - heart rate, blood pressure, respiratory rate, and body temperature
- Measure height and weight
- Record medical history
- Perform physical examination
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC), comprehensive metabolic panel (CMP), ammonia; Research laboratory tests: nitrite, nitrate, and biochemical tests)
- Collect urine sample for laboratory test (Safety: urine pregnancy test for women of child- bearing age)
- Perform neuropsychological testing
- Administer medication for treatment period 2 and monitor for 2 hours
Week 6 laboratory procedures, treatment period 2
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC) and comprehensive metabolic panel (CMP)
- Document adverse events
- Document concomitant medications
Week 12, follow up over telephone, treatment period 2
- Document adverse events
- Document concomitant medications
Week 24 visit study procedures, treatment period 2
- Measure vital signs - heart rate, blood pressure, respiratory rate, and body temperature
- Measure height and weight
- Record medical history
- Perform physical examination
- Collect blood sample for laboratory tests (Safety: complete blood count (CBC), comprehensive metabolic panel (CMP), ammonia; Research laboratory tests: nitrite, nitrate, and biochemical tests)
- Perform neuropsychological testing
ClinicalTrials.gov info: Nitric Oxide Supplementation in ASL deficiency
Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinic Aciduria (ASA/ASL)
Status: Closed/Completed
Drs. Sandesh Nagamani and Brendan Lee will study whether a dietary supplement of nitric oxide (NO) will lessen or correct the effects of NO deficiency on the arteries of individuals with argininosuccinic aciduria (ASA/ASL). The goal of the study is to better understand the role of nitric oxide deficiency in ASA and determine whether NO supplementation is an effective treatment for patients with ASA.
Eligibility requirements:
- At least 8 years old with known diagnosis of ASA/ASL.
- Travel to Baylor College of Medicine in Houston, Texas.
- Maintain the diet and treatment plan prescribed while you are in the study.
All procedures (lab testing) and the NO supplement are provided at no cost to the participant. Travel and lodging are covered.
Background
This project focuses on studying the efficacy of nitric oxide (NO) supplementation as a treatment for the long-term complications in argininosuccinic lyase deficiency (ASLD), the second most common urea cycle disorder and a human model of NO deficiency. We hope to translate our discovery of a structural requirement for argininosuccinate lyase (ASL) for metabolite channeling of arginine to an NO synthetic complex, into a novel therapy for this disorder which is effectively diagnosed by comprehensive newborn screening. The study of ASL’s function beyond ureagenesis was prompted by the complex natural history of some ASLD patients and observations by a number of Urea Cycle Disorders Consortium (UCDC) investigators. This included neurocognitive delay, hepatic disease, and systemic hypertension that were independent of recurrent hyperammonemia. ASL is the only mammalian enzyme that can synthesize L-arginine, the sole substrate for NO synthesis by nitric oxide synthase (NOS). By studying a novel hypomorphic and conditional mouse model of ASLD and human ASLD patients, we showed that a deficiency of ASL not only leads to decreased synthesis of intracellular L-arginine but also decreased utilization of extracellular L-arginine for NO synthesis. ASL serves distinct catalytic vs. structural functions that provide a structural model for understanding why ASLD patients defy the arginine paradox, i.e., they are unable to generate NO efficiently in spite of supplemental arginine therapy. NO is a ubiquitous signaling molecule with diverse roles in vascular biology, neurogenesis, and neuronal functioning and its dysregulation is implicated in pathogenesis of hypertension and memory deficits. ASLD mice treated with liver-directed gene therapy to correct the hepatic ureagenesis defect and mice with endothelium-specific loss of ASL demonstrate endothelial dysfunction and systemic hypertension that can only be corrected by NO supplementation.
In a proof-of-principle case study, we successfully treated an ASLD patient with long-standing hypertension refractory to multiple antihypertensive medications with NO supplementation. Interestingly, NO supplementation in this patient was also associated with improvement in neuropsychological parameters. These data imply that NO deficiency at the tissue level contributes to the complications of ASLD, and preventing hyperammonemia alone may not prevent long-term morbidity in ASLD. If successful, these studies have the potential to provide the first non-nitrogen-scavenging medication to reduce the morbidity inpatients with ASLD and potentially, other urea cycle disorders (UCD).
The Effect of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)
Status: UCD Consortium Study 5102, Closed, Study completed
RESULTS OF STUDY:
In addition to its role in the urea cycle, argininosuccinate ASL is also essential for endogenous (produced within the body) synthesis of arginine. Patients affected by ASA deficiency can have liver involvement ranging from liver enlargement (hepatomegaly) with elevations of liver enzymes to severe liver fibrosis. The cause for the increased incidence of liver dysfunction in ASA is not known, but has been thought to be due to increased argininosuccinate upstream of the enzymatic block in the urea cycle, or decreased arginine downstream of that block. The standard of care for patients with ASA has historically included arginine supplementation that compensates for the decreased endogenous synthesis in addition to promoting the excretion of nitrogen as argininosuccinic acid.
The investigators hypothesized that if increased levels of argininosuccinic acid were the predominant cause for liver dysfunction, a high dose of therapeutic arginine (500mg/kg/day) would be associated with worsening of liver functions as compared to a low dose of arginine (100mg/kg/day) combined with sodium phenylbutyrate, which would result in lower levels of argininosuccinic acid levels. To evaluate the effects of these two treatments on liver function in patients with ASA, a randomized double-blind placebo controlled cross-over trial was carried out by Dr. Brendan Lee and his team at Baylor as part of the Urea Cycle Disease Consortium research. Eleven patients completed both arms of the trial and were included in the analysis.
As expected, patients had significantly increased levels of phenylacetylglutamine and phenylacetic acid while on low-dose arginine with sodium phenylbutyrate, and higher plasma arginine and citrulline levels while on high-dose arginine. Ammonia control was comparable between the two arms of the trial. Patients had statistically significant increases in plasma ASA levels while on high-dose arginine. AST levels were increased in the high-dose arginine arm. Patients with abnormal liver transaminases seemed to have the most increase in liver enzymes while on high-dose arginine. The function of the liver as assessed by PT, INR, Factors VII, IX and fibrinogen were comparable between the two arms of the study.
These results reveal that high dose arginine may lead to higher liver inflammation in patients with ASA, especially in patients with existing liver dysfunction. The results have therapeutic implications, as they suggest it may be optimal to treat ASA patients who have liver dysfunction with lower doses of arginine combined with nitrogen scavenging therapy with sodium phenylbutyrate.
From left: Brendan Lee, MD, PhD, Oleg Shchelochkov, MD, Sandesh Sreenath Nagamani, MD
Background
Brendan Lee, M.D., Ph.D., at Baylor College of Medicine in Houston, Texas, conducted a research study to determine the effectiveness of Sodium Phenylbutyrate (Buphenyl™) and low–dose arginine vs. high-dose arginine in patients diagnosed with argininosuccinic aciduria (ASA).
Reference
A Randomized Controlled Trial to Evaluate the Effects of High-Dose Versus Low-Dose of Arginine Therapy on Hepatic Function Tests in Argininosuccinic Aciduria
Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC; Members of the Urea Cycle Disorders Consortium, Lee B. Mol Genet Metab. 2012 Nov;107(3):315-21. Epub 2012 Sep 17. PMID: 23040521
