5115: Manipulating the Gut Microbiome in Urea Cycle Disorders

Status: closed

 

For Diseases

We will be studying two groups for this study:

  1. Healthy Adults aged 18-60
  2. People who have been diagnosed with one of the following 4 urea cycle disorders:
    • Carbamyl Phosphate Synthetase Deficiency

    • Ornithine Transcarbamylase Deficiency (OTC)

    • Argininosuccinate Synthetase Deficiency (Citrullinemia, ASSD)

    • Argininosuccinic Lyase Deficiency (Argininosuccinic Aciduria, AL)

 

Background

Urea cycle disorders (UCDs) are a group of disorders resulting from a complete or partial deficiency of one of the 6 enzymes or 2 transporters that comprise the urea cycle, the essential biochemical pathway which converts toxic ammonia into urea. These disorders have as a common feature, a reduced or complete inability to convert ammonia into urea, thereby resulting in high ammonia levels, or hyperammonemia. If untreated, hyperammonemia may result acutely in lethargy and coma, and chronically in intellectual disability.

 

About this Study

The specific aim of this study is to investigate whether this drug can help lower ammonia levels and increase urea levels in patients with UCDs. Individuals with UCDs cannot remove ammonia, a waste product, from the blood.

This study will look at how a single oral dose of AHA can inhibit intestinal bacterial urease in healthy subjects as well as in patients with partial UCDs, and determine if it is safe. We propose a study with two components: the first without AHA, and the second after a single dose of AHA.

There are two study days. The study days must be at least 3 days apart and will take about 4-6 hours on each day. You will not know which day you are receiving the drug.

For each visit day, you will be asked to:

  • Fast 4 hours prior to your visit
  • Give multiple blood samples (1 to 2 teaspoons each time) through an IV
  • Give twourine samples
  • Allow us to insert an IV that will provide you with a tracer called 13C-urea

On the one visit day:

  • We will review your medical history and medical records
  • We will give you a tracer called 13C-urea into your arm through an IV (this is a second IV that is in the opposite arm from the IV that we get your blood samples from)
  • You will give us 7 blood samples through an IV
  • You will give us two urine samples

On the other visit day:

  • We will give you the study drug (Lithostat)
  • We will give you a tracer called 13C-urea into your arm through an IV (this is a second IV that is in the opposite arm from the IV that we get your blood samples from)
  • You will give us 8 blood samples through an IV
  • You will give us two urine samples
 

Target Enrollment

To be eligible to participate, you must:

For healthy adults:

  • Ages 18-60 years
  • Compliant with receiving medications orally and intravenously
  • Compliant with providing blood and urine samples

For adult UCD patients:

  • Ages 18-60 years
  • Compliant with receiving medications orally and intravenously
  • Compliant with providing blood and urine samples
  • Established diagnosis of CPSD, OTCD, ASSD or ASLD as follows:
    • Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver or an identified pathogenic mutation
    • Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, linkage analysis in an affected family, less than 20% of control of OTC activity in the liver, or elevated urinary orotate (greater than 20 uM/mM) in a random sample or following allopurinol loading with absence of argininosuccinic acid
    • Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AS gene
    • Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AL gene

You are not eligible to participate if:

For both healthy adults and adults UCD patients:

  • Current or prior Helicobacter pylori infection
  • Chronic gastrointestinal illness (e.g., inflammatory bowel disease)
  • Chronic renal failure
  • Taking probiotic medications within a week of study start date
  • Currently pregnant or lactating. Documentation of a negative pregnancy test within a week prior to testing is required, unless pre-menarchal or menopausal, experiencing menses that week, or other circumstances which preclude pregnancy (e.g. hysterectomy).
  • Presence of acute infection at the time of inclusion
  • Participation in any other clinical interventional trial or received experimental medication within the last 30 days
  • Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study
 

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

  • Children’s National Medical Center
    Primary Contact: Leslie M. Atley
    Children's National Medical Center
    111 Michigan Avenue, NW
    Washington, DC 20010
    202-476-6137
    latley@childrensnational.org  

    Secondary Contact: Dr. Nicholas Ah Mew
    Children's National Medical Center
    111 Michigan Avenue, NW
    Washington, DC 20010
    202-476-5863
    nahmew@childrensnational.org
 
 

Total Enrolled

 4