Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn

Ornithine transcarbamylase deficiency (OTCD) is an inherited metabolic liver disease which means that the body cannot maintain normal levels of ammonia. Ammonia levels can rise (called hyperammonaemic decompensations) which can be life-threatening and may result in impaired neurological development in children. OTCD is a rare genetic disorder characterised by complete or partial lack of the enzyme ornithine transcarbamylase (OTC).

OTC is a key element of the urea cycle, which is how the liver breaks down and removes extra nitrogen from the body. For people with OTCD the extra nitrogen builds up in the form of excess ammonia (hyperammonemia) in the blood.

Ammonia is toxic and people with OTCD suffer 'hyperammonaemic decompensations' when ammonia levels in the blood rise too high. The symptoms of these hyperammonaemic decompensations include vomiting, impaired movement, and progressive lethargy. If left untreated these hyperammonaemic decompensations may result in life-threatening complications or coma. OTCD is managed with drugs that reduce the amount of ammonia in the blood (ammonia-scavenging drugs) and a low protein diet. However, sometimes hyperammonaemic decompensations still occur.

Liver transplants for people with OTCD can be life-saving but there may be a long wait for a suitable liver and neurological damage may occur before a liver transplant is possible.

The HORACE study is testing a new gene therapy (AAVLK03hOTC) which specifically targets the liver so that it can start making OTC. The investigators hope that a single injection of gene therapy for children with OTCD could help the liver work normally and reduce hyperammonaemic decompensations and their associated risks.

This gene-therapy treatment could serve as a 'bridge-to-transplant' where children could grow up in a metabolically stable condition until a liver transplant is possible. This could minimise longer-term neurological damage caused by hyperammonaemic decompensations.

Eligibility Criteria:
Inclusion Criteria:

1. Patient (male or female) aged ≤16 years at time of written informed consent. For the dose escalation phase patients must be aged 6-16, for the dose expansion phase patients must be aged 0-16 (at the time of written informed consent).
2. OTC deficiency confirmed via enzymatic or molecular analysis. This may include identification of pathogenic mutations or liver OTC activity that is \<20% of normal activity.
3. Patient has severe disease defined by reduced protein allowance and prescribed at least one ammonia scavenger drug.
4. Patient (if capable of signing) and parents or legal representative have signed a written informed consent form.
5. Females of childbearing potential must have a negative pregnancy test in serum or urine at the screening and Day 0 infusion visits, and use an adequate contraception method from the screening visit until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whatever comes first.
6. Sexually active boys must use an adequate contraception method (abstinence or use of condom with spermicide) from at least 14 days prior to the infusion and until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whatever comes first.
7. Patient's ammonia level at baseline visit (pre-gene therapy infusion) is \<100µmol/L and is within the range of historical ammonia levels obtained when the patient was clinically stable.
8. Patient has been on a stable dose of ammonia scavenger and stable protein allowance for the last 4 weeks at the baseline visit.
9. Patient is willing to commit to an additional 4 years of long-term safety follow-up.

Exclusion criteria:

1. Titres of the neutralising antibodies against AAV-LK03 \>1:5 serum dilution.
2. Significant hepatic inflammation as evidenced by the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase or bilirubin \>2 x upper limit of normal (ULN), alkaline phosphatase \>3 x ULN.
3. Evidence of severe unexplained liver disease including but not limited to liver malignancy, liver cirrhosis, or acute liver failure.
4. Evidence of active hepatitis B or C virus (HBV and HCV respectively) documented by hepatitis B surface antigen (HBsAg) or HCV RNA positivity.
5. Positive PCR for human immunodeficiency virus (HIV).
6. Liver transplant including hepatocytes/cells infusion.
7. Current participation in another clinical trial of an investigational medicinal product or medical device, or participation within previous 12 months.
8. Patient has contraindication to immunosuppression.
9. Active infection (bacterial or viral).
10. Pregnant or breastfeeding females.
11. Patients with other serious underlying medical conditions including malignancy and severe (≥ grade 3) functional organ impairment (liver, kidney, respiratory) according to CTCAE v5.0. For neurological symptoms considered as sequelae of previous hyperammonaemic decompensation and which are considered as stable (i.e. not evolving), a grade 3 will be acceptable. Grade 4 and 5 will preclude inclusion.
12. Patients with any other significant condition or disability that, in the investigator opinion, may interfere with the patient's optimal participation in the study.