Gene therapy using a special type of virus vector to deliver the functional DDC gene is well-tolerated and might improve motor development in children with aromatic l-amino acid decarboxylase (AADC) deficiency in the future, a Phase 1/2 clinical trial shows.
The findings of the study, “Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial,” were published in The Lancet Child & Adolescent Health.
AADC deficiency is a rare genetic disorder caused by mutations in the DDC gene, which provides instructions to make the AADC enzyme. This enzyme is necessary for the production of neurotransmitters — chemical substances that allow communication between nerve cells — in the brain, particularly dopamine and serotonin.
Because AADC deficiency is caused by defects in a single gene, it has become one of the primary targets for gene therapy, which encompasses a group of techniques whose main goal is to correct the faulty gene causing the disease.
Adeno-associated viruses have emerged as attractive vectors for delivering gene therapies for single-gene diseases, having shown promise after injections in the putamen for treating Parkinson’s disease, a condition also characterized by dopamine deficiency.
These viruses infect both dividing and non-dividing cells, allow for long-term gene expression, and their infection causes no harm to patients, investigators explained.
In a previous study, the same team of researchers described the clinical outcomes associated with the compassionate use of this gene therapy in four children with AADC deficiency. Encouraged by those findings, the group launched a new trial to assess the safety and effectiveness of this treatment in a larger group of patients.
The open-label, Phase 1/2 trial (NCT01395641), based at the National Taiwan University Hospital in China, enrolled 10 children with a confirmed diagnosis of AADC deficiency from October 2014 to December 2015; their average age was 2.71 years.
All children underwent stereotactic brain surgery — a minimally-invasive surgery in which patients undergo brain surgery while their brain is being imaged to guide the surgeon — to receive the viral vectors containing the functional DDC gene.
Primary effectiveness outcomes included higher levels of neurotransmitters’ metabolites — homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) — in the patients’ cerebrospinal fluid (CSF, the liquid that circulates in the brain and spinal cord) and attaining a score greater than 10 points in the second edition of the Peabody Developmental Motor Scale (PDMS-2), corresponding to a significant improvement in motor function, one year after surgery.
Secondary safety outcomes included assessments of CSF leakage, brain bleeding, and other adverse side effects associated with gene therapy one year after brain surgery. All patients were evaluated at baseline (before undergoing brain surgery), then three, six, nine and 12 months after gene therapy, and every six months after that for a period of one year. In addition, all children were examined three to seven days after surgery to assess the presence of surgical complications (CSF leakage and brain bleeding).
Brain surgery and viral vector administrations were well-tolerated by all children participating in the study.
All patients met the study’s primary effectiveness goal. On average, PDMS-2 scores increased by 62 points and HVA concentrations also increased by 25 nmol/L compared to baseline. However, no significant differences were found on 5-HIAA concentrations one year after gene therapy, compared to baseline.
A total of 101 side effects were reported over the course of the study, with the most common being fever (16%) and involuntary movements of the mouth and face (10%). Serious side effects were registered in six children, including one death unrelated to brain surgery or gene therapy, one episode of life-threatening fever, and 10 medical complications that required patient hospitalization.
All children experienced involuntary muscle movements after undergoing gene therapy, which were resolved after treatment with risperidone, a mild anti-psychotic medicine.
Importantly, while none of the participants had head control before receiving the gene therapy, four gained some head control and five had good head control and could sit briefly with support. One additional patient could even stand with support.
“In conclusion, our findings show the efficacy and safety of AAV2-hAADC [adenoviral gene therapy] for children with AADC deficiency. A Phase 2b trial (NCT02926066) is ongoing to further assess the safety and efficacy of AAV2-hAADC in a larger patient population with dose escalation,” the scientists wrote.
“We are also developing a systemic treatment to replenish neurotransmitter production in the whole brain and the autonomic nervous system [the part of the nervous system that controls bodily functions, such as breathing and blood pressure, without a conscious effort] in the body,” they added.
“Although AADC deficiency is a rare disease, the gene therapy technology developed in this disease could be applicable to other conditions,” they explained.