A gene therapy approach to childhood parkinsonism
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
Organisations
- University College London (Fellow, Lead Research Organisation)
- University College London (Collaboration)
- Italian National Research Council (Collaboration)
- UNIVERSITY OF ABERDEEN (Collaboration)
- Oregon Health and Science University (Collaboration)
- Duke University (Collaboration)
- Professor John Glover Memorial Fund (Collaboration)
- Italian Institute of Technology (Istituto Italiano di Tecnologia IIT) (Collaboration)
- Synpromics (Collaboration)
- New York University (Collaboration)
- Italian Institute of Technology (Project Partner)
People |
ORCID iD |
Joanne Ng (Principal Investigator / Fellow) |
Publications
Baruteau J
(2018)
Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.
in Nature communications
Chu W
(2024)
Gene therapy for neurotransmitter-related disorders
in Journal of Inherited Metabolic Disease
Chu WS
(2021)
Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies.
in Frontiers in immunology
Counsell JR
(2018)
Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice.
in Molecular therapy. Nucleic acids
Danti FR
(2017)
GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome.
in Neurology. Genetics
Diggle CP
(2016)
Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.
in American journal of human genetics
Karda R
(2014)
Perinatal systemic gene delivery using adeno-associated viral vectors.
in Frontiers in molecular neuroscience
Karda R
(2020)
Generation of light-producing somatic-transgenic mice using adeno-associated virus vectors.
in Scientific reports
Karda R
(2019)
Production of lentiviral vectors using novel, enzymatically produced, linear DNA.
in Gene therapy
Lemprière S
(2021)
Gene therapy effective in model of infantile parkinsonism
in Nature Reviews Neurology
Marecos C
(2014)
What is new for monoamine neurotransmitter disorders?
in Journal of inherited metabolic disease
Martinelli S
(2020)
Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism.
in Parkinsonism & related disorders
Mencacci NE
(2016)
De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.
in American journal of human genetics
Meyer E
(2017)
Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
in Nature genetics
Meyer E
(2017)
Corrigendum: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
in Nature genetics
Mohammad SS
(2020)
Magnetic resonance imaging pattern recognition in childhood bilateral basal ganglia disorders.
in Brain communications
Ng J
(2014)
Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders.
in Paediatric drugs
Ng J
(2021)
ATP1A3-related neurological disorders and cerebellar ataxia in childhood.
in Developmental medicine and child neurology
Ng J
(2021)
Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.
in Science translational medicine
Ng J
(2014)
Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.
in Brain : a journal of neurology
Ng J
(2023)
Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases.
in Movement disorders : official journal of the Movement Disorder Society
Ng J
(2020)
DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia
in Movement Disorders
Ng J
(2015)
Monoamine neurotransmitter disorders--clinical advances and future perspectives.
in Nature reviews. Neurology
Ng Joanne
(2021)
Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism
in SCIENCE TRANSLATIONAL MEDICINE
Ngoh A
(2017)
TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus.
in Tremor and other hyperkinetic movements (New York, N.Y.)
Papandreou A
(2018)
Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.
in Journal of inherited metabolic disease
Papandreou A
(2018)
Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.
in Journal of inherited metabolic disease
Papandreou A
(2016)
Delineation of the movement disorders associated with FOXG1 mutations.
in Neurology
Privolizzi R
(2021)
Viral gene therapy for paediatric neurological diseases: progress to clinical reality.
in Developmental medicine and child neurology
Rossignoli G
(2021)
Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies.
in Brain : a journal of neurology
Suff N
(2018)
Ascending Vaginal Infection Using Bioluminescent Bacteria Evokes Intrauterine Inflammation, Preterm Birth, and Neonatal Brain Injury in Pregnant Mice
in The American Journal of Pathology
Suff N
(2020)
Cervical Gene Delivery of the Antimicrobial Peptide, Human ß-Defensin (HBD)-3, in a Mouse Model of Ascending Infection-Related Preterm Birth.
in Frontiers in immunology
Thaventhiran JED
(2020)
Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
in Nature
Description | 5th International Pediatric Movement Disorders Symposium Travel grant |
Amount | € 500 (EUR) |
Organisation | International Parkinson and Movement Disorder Society (MDS) |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2017 |
End | 04/2017 |
Description | Development of novel synthetic promoters for neurological gene therapy and childhood parkinsonism |
Amount | £155,000 (GBP) |
Funding ID | 550099 |
Organisation | Synpromics |
Sector | Private |
Country | United Kingdom |
Start | 01/2019 |
End | 12/2022 |
Description | GOSHCC Starter Grant |
Amount | £87,000 (GBP) |
Funding ID | 1PAAE |
Organisation | Great Ormond Street Hospital Children's Charity (GOSHCC) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2013 |
End | 09/2016 |
Description | Gene therapy for Childhood Parkinsonism: Dopamine transporter deficiency syndrome |
Amount | £495,190 (GBP) |
Funding ID | MR/R015325/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2018 |
End | 12/2020 |
Description | Gene therapy for epileptic encephalopathy |
Amount | £1,523,125 (GBP) |
Funding ID | REF 560284 |
Organisation | UCB Pharma |
Sector | Private |
Country | United Kingdom |
Start | 09/2020 |
End | 10/2022 |
Description | MRC Developmental Pathway funding scheme |
Amount | £591,951 (GBP) |
Funding ID | MR/R015325/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Description | Ono Pharmaceuticals Rising Star |
Amount | £65,000 (GBP) |
Organisation | Ono Pharmaceutical |
Sector | Private |
Country | Japan |
Start | 06/2017 |
End | 12/2017 |
Description | Project Grant |
Amount | £32,500 (GBP) |
Funding ID | Project M576 or A1204 UC |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 06/2017 |
Description | Project grant |
Amount | £30,000 (GBP) |
Organisation | Gracious Heart Charity Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2014 |
End | 09/2017 |
Description | Project grant |
Amount | $150,000 (USD) |
Organisation | NBIA Disorders Association |
Sector | Public |
Country | United States |
Start | 08/2014 |
End | 09/2017 |
Description | Rosetrees Trust Continuation funding |
Amount | £102,742 (GBP) |
Funding ID | A1793 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2021 |
Description | Synpromics |
Amount | £122,800 (GBP) |
Organisation | Synpromics |
Sector | Private |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2018 |
Title | Adeno associated virus preparation |
Description | Establishing making of adenoassociated virus production and purification. |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | Enables AAV production within our research group and reduces reliance on other groups |
Title | Behavioural studies of DAT-KO mice |
Description | Motor behavioural analysis in transgenic mouse colony |
Type Of Material | Physiological assessment or outcome measure |
Provided To Others? | No |
Impact | Enables standardised outcome measure for future gene therapy efficacy |
Title | Cloning therapeutic vectors |
Description | Cloning of transgenes into viral vectors to develop gene therapy vectors. |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | Vital for rescue of mouse model of disease for this proof of concept gene therapy model |
Title | Electrophysiology |
Description | Electrophysiology of neurons in the striatum of mice were assessed to look at the effects of gene therapy. Mice were collected and brain slices taken for patch-clamp electrophysiology. There were clear differences in firing rates of DAT knockout and wildtype animals. In DAT knockout animals treated with gene therapy the firing rates was restored back to wildtype animal patters. |
Type Of Material | Physiological assessment or outcome measure |
Provided To Others? | No |
Impact | This is another readout to assess the effect of gene therapy |
Title | Elisa |
Description | Quantification method for protein expression delivered by gene therapy |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | Quantification of protein expression in target organs and off target transduction |
Title | Establishment of DAT-KO mouse colony |
Description | Establish colony at UCL as model of childhood dopamine transporter deficiency syndrome for proof of concept study of gene therapy. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | Establish colony at UCL as model of childhood dopamine transporter deficiency syndrome for proof of concept study of gene therapy. |
Title | Immunoblotting |
Description | CSF analysis of dopaminergic system related proteins in patient CSF. |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | These observations may demonstrate effects down and upstream of loss of function of dopamine transporter May be a future method to understand disease mechanism in patients |
Title | Immunocytochemistry |
Description | Staining of neuronal cultures |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | To demonstrate location of gene therapy expression protein |
Title | Immunohistochemistry |
Description | Immunohistochemistry used to assess marker gene studies in mouse brain transduction. Immunohistochemistry also used to delineate neurohistopathology in transgenic mouse models of neurological disease |
Type Of Material | Antibody |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Enable marker gene studies for other viral vectors and neurohistopathology in other mouse models. |
Title | MACS cell seperation for Neuronal isolation |
Description | Isolation of neurons using magnetically labelled cells and antibodies using MACS brain dissociation and seperation kits. |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | Able to isolate cell lines and perform invitro studies from in vivo tissues that have been treated with gene therapy |
Title | Neurotransmitter analysis |
Description | HPLC analysis of neurotransmitter metabolites in mouse brain homogenates |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Reliable biochemical assay for future outcome measure of gene therapy efficacy |
Title | Stereotactic injection |
Description | We have now established stereotactic delivery of AAV vectors to adult mice as a clinically applicable delivery method for translational studies to evaluate gene therapy. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We were awarded MRC DPFS grant and Rosetrees Trust project grant funding to develop this clinically applicable delivery method. This will be considered the delivery method taken towards clinical translation of an clinically applicable gene therapy vector. |
Title | Stereotactic injection of mice to model human delivery |
Description | We have modelled gene therapy delivery in mice that would be applied for DAT deficiency patients in a clinical trial. We demonstrated gene transfer and function with restricted targetting to the area of interest in patients. |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2019 |
Provided To Others? | No |
Impact | Having developed this methodology we are now moving to translating the gene therapy in clinical trial with MRC follow on DPFS application for first in human study |
Title | Database of undiagnosed childhood movement disorders |
Description | Children referred to Dr Kurian Childhood movement disorder clinic with undiagnosed movement disorders. Database established to enable grouping of phenotypes to facilitate analysis of whole exome sequencing data. |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | Database established to enable grouping of phenotypes to facilitate analysis of whole exome sequencing data. |
Description | Dr Gabriele Lignani |
Organisation | University College London |
Department | Department of Clinical and Experimental Epilepsy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Further analysis of the gene therapy in DAT knock mouse model was possible using ex vivo electrophysiology. DAT knockout mice treated with gene therapy and their litter mate controls (untreated knockouts and wildtype mice) were collected for analysis. Brain slices were prepared for patch clamp electrophysiology by Dr Lignani. |
Collaborator Contribution | Dr Llignany performed patch clamp electrophysiology and showed differences between wildtype and DAT knockout animals in neuronal firing rates. The DAT knockout animals treated with gene therapy showed the neuronal firing rate was restored to wildtype firing patters. |
Impact | These data will be compiled for publication for gene therapy approach for DAT deficiency. |
Start Year | 2016 |
Description | Gene therapy for neurological disease Dr Ahad Rahim |
Organisation | University College London |
Department | School of Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint experience in gene therapy approaches to neurological diseases |
Collaborator Contribution | Refinement of neuronal gene therapy tranduction approaches for both neurological and multisystem neurological diseases |
Impact | Joint grant applications leading towards preclinical gene therapy study of brain iron disorders |
Start Year | 2013 |
Description | Gene therapy infantile epileptic encephalopathy and intellectual disability |
Organisation | University of Aberdeen |
Department | Translational Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Project to develop gene therapy for childhood epilepsy disorder. We supported establishment of new transgenic colony and in vivo validation of neonatal gene therapy approach for Professor Schorge's research group. Previously her group has focussed on adult epilepsy models. |
Collaborator Contribution | Establish collaboration with Professor Abbott at University of Edinburgh who runs the patient registry and established other transgenic models of disease. |
Impact | MTA for transgenic animals, future publications planned. Further longer term project grant application with Ono Pharmaceutics, outcome awaited |
Start Year | 2017 |
Description | In vitro modelling of Dopamine Transporter |
Organisation | Oregon Health and Science University |
Country | United States |
Sector | Academic/University |
PI Contribution | We have identified novel missense mutations in SLC6A3 for modelling. |
Collaborator Contribution | Professor Aaron Janowsky research group and undertaking in vitro modelling of Dopamine transporter missense mutations identified in new patient cohort |
Impact | Manuscript in preparation |
Start Year | 2018 |
Description | In vivo modelling of Dopamine transporter |
Organisation | Professor John Glover Memorial Fund |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We have identified novel missense mutations in DTDS patients |
Collaborator Contribution | Professor De Schiavi's research group have modelled and characterised c. elegans models of 2 novel missense mutations in DTDS |
Impact | Manuscript in preparation |
Start Year | 2017 |
Description | In vivo modelling of SLC6A3 mutations |
Organisation | Italian National Research Council |
Department | Institute of Biosciences and Bioresources |
Country | Italy |
Sector | Public |
PI Contribution | Professor Elia Di Schiavi's research group have previously modelled disease causing SCL6A3 mutations identified by our research team. We have established a collaboration to model 4 novel missense mutations identified in a cohort of 7 new Dopamine transporter deficiency patients. |
Collaborator Contribution | Professor Di Schiavi's group have modelled 2 of the 4 novel missense mutations in c elegans model supporting predicted loss of function. |
Impact | Future publication in progress of new cohort of DTDS patients. |
Start Year | 2017 |
Description | Maarten Reith |
Organisation | New York University |
Department | School of Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | We identify novel genotypes in DAT deficiency syndrome for further function study. |
Collaborator Contribution | Maarten Reith's group provide expertise and support in functional modelling of novel genotypes in the dopamine transporter. His group provided the plasmids initially used in cloning of gene therapy constructs. |
Impact | Original publication in Brain 2014: 137; 1107-1119 Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood |
Start Year | 2013 |
Description | Marc Caron |
Organisation | Duke University |
Country | United States |
Sector | Academic/University |
PI Contribution | We have delineated the clinical phenotypes and genotypes of dopamine transporter deficiency leading to greater understanding of the animal model developed prior to the clinical disease identification. |
Collaborator Contribution | Marc Caron developed the DAT-KO mouse and delivered a personal seminar on this model to our group. He provides expertise in this model to support this project. |
Impact | The expertise from Marc Caron and his laboratory enabled the rapid and successful establishment of the DAT-KO transgenic colony at UCL |
Start Year | 2013 |
Description | Raul Gainetdinov |
Organisation | Italian Institute of Technology (Istituto Italiano di Tecnologia IIT) |
Country | Italy |
Sector | Academic/University |
PI Contribution | Professor Gainetdinov kindly provided the DAT-KO mouse to enable a colony to be established at UCL for this fellowship. |
Collaborator Contribution | Establish colony at UCL as model of childhood dopamine transporter deficiency syndrome for proof of concept study of gene therapy. |
Impact | DAT-KO colony established at UCL |
Start Year | 2013 |
Description | Simon Heales |
Organisation | University College London |
Department | Institute of Child Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Clinical input into the neurotransmitter analysis of patients referred to Professor Heales Neurotransmitter laboratory |
Collaborator Contribution | Able to link CSF neurotransmitter patients and DAT=KO mouse model of DTDS deficiency. |
Impact | Collaboration between clinicians, clinical biochemists and gene therapy groups for biomarker analysis in murine models of human disease. |
Start Year | 2013 |
Description | Synpromics Ltd |
Organisation | Synpromics |
Country | United Kingdom |
Sector | Private |
PI Contribution | Collaboration with Synpromics Ltd, leaders in gene control to develop novel promoters for dopamine transporter deficiency gene therapy |
Collaborator Contribution | We will be collaborating to develop novel synthetic promoters that are selective for dopaminergic neurons. This aim is to increase efficiency and specificity of gene expression in AAV gene therapy vectors for Parkinsonian disorders and may allow non invasive delivery for clinical translation. |
Impact | New project to develop novel promoters commenced in January 2018. Subsequent to this project we have been awarded UCL Synpromics Impact studentship |
Start Year | 2018 |
Title | Gene therapy for Dopamine transporter deficiency |
Description | The rAAV gene therapy for Dopamine transporter deficiency syndrome has be evaluated preclinically to demonstrate proof of principle in neonatal mouse model rescuing the dopamine transporter knockout phenotype. We have undertaken preclinical refinement to model clinical delivery method with stereotactic delivery of the gene therapy to adult knockout mice with dose ranging study. A patent has been filed on this gene therapy and guidance from MHRA has been given on next stages to clinical trial. The gene therapy product is now actively seeking support to fund next stage GMP vector production and clinical trial. |
Type | Therapeutic Intervention - Cellular and gene therapies |
Current Stage Of Development | Refinement. Non-clinical |
Year Development Stage Completed | 2020 |
Development Status | Actively seeking support |
Impact | Translation of this gene therapy and future clinical trial will pave the way for other CNS gene therapy approaches for children with rare genetic neurological disease in the UK. |
Description | AADC deficiency research trust |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | 50 patients and family members is childhood neurotransmitter disease attended conference with clinicians and researchers working in the neurotransmitter field. There was opportunity to engage with families to discuss their treatment experiences, suggestions for future research, participation in current research. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.aadcresearch.org/ |
Description | AADC deficiency research trust conference |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | The conference combines patients and families with AADC deficiency and experts in neurotransmitter disease and gene therapy. The conference focussed on the launch for gene therapy clinical trial for this disease and also patients describing their main clinical difficulties. After this conference further efforts for fundraising and applications for a European site for gene therapy clinical trial were further discussed |
Year(s) Of Engagement Activity | 2014 |
Description | Patient group dialogue |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Engagement with patients with 20 Parkinson's disease to discuss gene therapy, the delivery methods and reasons for and against gene therapy trials. Patients reported they would now be more interested in receiving gene therapy. |
Year(s) Of Engagement Activity | 2018 |
Description | School work experience placement |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | School work experience for sixth form students. Exposure to role of animal work in novel therapy development. |
Year(s) Of Engagement Activity | 2018 |
Description | Spring Meeting for Clinician Scientists in training |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Dr Ng was selected to be interviewed for podcast for the Academy of Medical Sciences Spring meeting for Clinician Scientists in training. In this podcast she was able to discuss the success of the gene therapy developed from this award. |
Year(s) Of Engagement Activity | 2016 |
URL | https://soundcloud.com/acmedsci/joanne-ng/s-BA6yt?in=acmedsci/sets/spring-meeting-2016/s-5kJCb |
Description | Video for MRC insight |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Ng was invited to video a mock MRC clinical training fellowship interview for training purposes. The video is a guide to give insight into MRC fellowship application process. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.insight.mrc.ac.uk/2016/09/27/interview-day-whats-it-like-to-face-a-fellowship-panel/ |
Description | Visit Gracious Heart Foundation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Supporters |
Results and Impact | The talk lead to further questions from the public and supporters of the charity. Also lead to other medical research charities contacting our group with further funding proposals to support our studies. The talk raised awareness of alternative diagnosis for cerebral palsy. Many practitioners involved in conductive education for children with cerebral palsy were present and keen to be aware of alternative diagnoses and treatments. |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.graciousheart.co.uk |