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A Novel Gene Therapy to Prevent Seizures in Children with Mito

The Problem

Some of the most severe presentations of mitochondrial disease (mito) occur in children. In these children, many of the cells in their body carry dysfunctional mitochondria due to a genetic defect . With impaired mitochondrial function, there is a significantly reduced supply of energy to the body. The organs that demand the highest energy supply are severely affected, including the brain, which can lead to symptoms like seizures. Approximately 40% of mito patients have seizures.

Pontocerebellar hypoplasia type 6 (PCH6) is a devastating disorder causing early seizures in infancy with developmental delay. Sadly, a quarter of these patients die in infancy. Mitochondrial epilepsy is different to regular epilepsy, meaning standard epilepsy treatments do not work. In fact, they often result in further mitochondrial damage. In children, mitochondrial seizures can cause irreversible brain damage and abnormal brain development.

As with most mitochondrial disorders, there is no treatment available for these children. Gene therapy offers an attractive solution, but it comes with its challenges. Testing a gene therapy needs to target the symptom-causing cells, in this case brain cells (neurons).

"In children, mitochondrial seizures can cause irreversible brain damage and abnormal brain development."

OUR SOLUTION

Dr Riley and her team are developing and validating the efficacy and safety of a viral-based gene therapy for PCH6 using ‘brains in a dish’. To do this they will reprogram patient stem cells into brain organoids, and ensure these mini-brains present with the same seizure type as the patient. Encouragingly, seizures have been recapitulated in an organoid model of a different disease, Rett syndrome, showing promise for this method. Dr Riley will use these mini-brains to validate the best treatment before testing it in mice to check for toxicity.

It is expected that this study will establish stem cell lines for RARS2 (the gene responsible for PCH6) which can be biobanked for future studies and drug screening trials, increase understanding of RARS2-related mito, and create a RARS2 vector for gene therapy trials.

“Development of a gene-therapy pipeline offers real hope for a cure for the mitochondrial disease community.”

The Next Step

This project has assembled an integrated team of global leaders in the relevant technologies, with privileged access to all the required technologies, expertise and reagents. This includes Dr Lisa Riley, A/Prof. Leszek Lisowski, Dr Anai Gonzalez-Cordero, Dr Wendy Gold, Dr Bindu Parayil Sankaran, Dr Kaustuv Bhattacharya. The team will utilise world-leading infrastructure available at the Children’s Medical Research Institute and the Children’s Hospital at Westmead.

To test the therapeutic potential of this gene therapy, mice will be used for the pre-clinical study. It will then be transitioned to the clinic if successful. The Sydney Children’s Hospitals Network is the largest network of hospitals and services for children in Australia and are national leaders in novel therapies for rare disorders. The Westmead Research Precinct has the expertise and infrastructure to support translation of this pre-clinical study to the clinic with a large clinical vector manufacturing facility.

To proceed, we seek funding to the value of $200,000 (or $100,00 per year over two years) to facilitate:

Personnel fees - $70,000 or $35,000/year

$35,000/year for 2 years for a PhD student

Supplies - $130,000 to cover:

$2000 for animal costs
$124,080 for consumables
$3920 for use of equipment

(detailed budget available on request)

The Outcome

The success of this project would provide an established pipeline for the development of gene therapies not only for PCH6 but for other mitochondrial diseases, especially epileptic encephalopathies.

Development of a gene-therapy pipeline offers real hope for a cure for the mitochondrial disease community.