A gene therapy approach to childhood parkinsonism

Infantile parkinsonism is a severe progressive disease that is incurable and children affected die in adolescence. It begins in infancy with features similar to adult Parkinsons disease with severe difficulties with movement and unsteadiness. The faulty gene that causes this condition has been identified and its function understood. This makes it a potential condition that could be treated by gene therapy as no other treatments have worked or helped so far.

The faulty gene is responsible for producing proteins involved in transporting a chemical in the brain that controls movements. In this condition the protein does not work effectively leading the severe movement difficulties and death in adolescence.

I will research ways to deliver a normal form of the gene to a mouse model with the disease. An animal study is required as it is not safe to study these techniques directly in humans. There is a mouse model that simulates the human from of infantile parkinsonism condition well. This mouse does not produce any of form of the protein and shows all the signs with movement difficulties and reduced longevity seen in the human form of the condition.

We would aim to give the mouse the normal gene through an injection into the blood stream. We would assess for improvements in movements, weight gain and lifespan to assess whether the gene treatment has helped. We would assess carefully for side effects and ability for the gene treatment to reach the brain in the mouse, the area where we want the treatment to work.

We would study the mice to see if the normal function of the gene is restored and would see this with improvements in movements and longevity of the mice. We would assess the mice to ensure the gene treatment is safe and effective and assess the best age to give the treatment and ideal dosage. Further studies of the effects of the gene treatment will be performed by assessing tissue samples from the mice. Successful gene therapy study in mice will help us to proceed to establish future studies in humans. In the future these techniques may also be applicable to other incurable childhood brain disorders.

Dopamine transporter deficiency syndrome (DTDS) is a newly recognised autosomal recessive neurotransmitter disorder clinically characterised by progressive infantile parkinsonism dystonia. It is caused by loss-of-function mutations in the SLC6A3 gene that encodes for the dopamine transporter (DAT).This progressive condition does not respond to medical or surgical treatments leading to early death.

Gene therapy is increasingly being considered as a realistic treatment option for human disorders including a number of successful clinical gene therapy trials. Indeed there has been a recent clinical gene therapy trial showing positive results in children with AADC deficiency. This is another devastating genetic neurotransmitter disorder lacking in medical treatment. This study demonstrated improvement in oculogyric crisis and motor abilities in all children treated and provides impetus to study potential gene therapy in DTDS.

A proof of concept study would be required to describe expression of transgene delivery and restoration of DAT expression in the first instance. We aim to develop a gene therapy strategy in the knockout mouse model of DTDS. We hypothesise that by inserting human DAT through gene transfer to the DAT-KO mouse model will restore gene function and DAT expression and function.

The key aims of the study are to:

1. Establish a DAT-KO mouse colony at UCL
2. Develop a safe and efficient vector for transgene delivery to the central nervous system in DAT- KO mouse model
3. Demonstrate efficacy through restoration or augmentation of DAT expression through locomotor phenotyping and tissue histological study.
4. Establish optimal time of administration of gene transfer
5. Establish optimal dosage and correlate dosage effects

In the longer term this study would underpin future translation to clinical trials of gene therapy in DTDS. The expertise gained may also be applicable to other untreatable childhood neurological diseases.

Through this study we would aim that gene vector design, safety and efficacy, optimal method, dosing and timing of gene transfer therapy will have been established in the DAT KO mouse. We would hope that successful gene therapy in a murine model may lead to further translational study.

With Dr Kurian's complimentary work in cell line model and Professor Thrasher's expertise in translating animal study to clinical trial we would hope to use the data from this project to underpin future clinical study. The long term goal of this research may lead to the development of suitable vector delivery systems to be used in DTDS patients trial in patients within a 10 years time-line.

The findings of this study and future application are especially beneficial and relevant to children with DTDS. It will be of relevance to other children with neurotransmitter disorders, movement disorders. In addition, techniques developed from this study may be applicable more widely for research in to gene transfer therapeutic options for other related movement disorders and other untreatable childhood neurological disorders.

Dr Kurian is an established expert clinician in childhood movement disorders and has access to recruit future children with DTDS for study. As Great Ormond Street houses the National Neurotransmitter laboratory in the UK, all children found to have a characteristic neurotransmitter profile associated with DTDS will be easily identified for consideration for clinical study and recruitment for further study through Dr Kurian's established collaboration with Professor Simon Heales, Clinical Chemistry unit, Institute Child Health and Great Ormond Street Hospital.

The findings of this research will be disseminated through relevant scientific meetings and publication in high impact factor journals that would lead to further national and international awareness of this condition and awareness of our collaborative's long term aims of translational research towards future clinical trials. This will lead to further collaboration with other groups which is often required in rare diseases and gene therapy trials.

In addition the members of this collaborative group are already sit on the scientific boards of relevant international family and patientsgroups for children with Neurotransmitter disorders (AADC Trust and Pediatric Neurotransmitter Disorder) who would also be informed of the findings of this work. This again will enhance all future collaboration at an international level to bringing this work towards clinical trial and ensuring ths research of the highest standard is undertaken.