The development of gene therapy for Niemann-Pick type C disease

Lead Research Organisation: University College London
Department Name: School of Pharmacy

Abstract

Niemann-Pick type C disease (NPC) is a devastating and ultimately fatal genetic disorder that profoundly affects the brain and other organs of the body. A diagnosis is usually made in infancy/childhood where approximately half of the patients have liver abnormalities. Ten per cent of these patients will die from liver failure before six months of age. The symptoms of NPC patients that survive infancy are dominated by progressive degeneration of the brain with debilitating consequences and subsequent death, usually in the second decade of life. The genetic defect causing NPC in the vast majority of cases is caused by mutations in a gene called NPC1. This causes an accumulation of a number of complex substances such as cholesterol in cells of the body resulting in the symptoms seen the brain and visceral organs. Currently, there are no major specific disease modifying treatments for NPC patients and the need to develop effective life-saving therapies is overwhelming. Gene therapy involves the delivery of a functional copy of a gene into a cell in order to compensate for a defective version. In most cases, the genes are delivered into cells using viral vectors. These vectors are based on viruses that have been stripped of their harmful components, rendered safe and used as a vehicle to efficiently deliver therapeutic genes to cells of the body. Using this approach, gene therapy has demonstrated life-saving and life-changing results in clinical trials. The objective of this project is to develop gene therapy for treating NPC. We have made a viral vector that can efficiently deliver a therapeutic version of the NPC1 gene into cells. We propose using this vector in a pre-clinical proof-of-concept gene therapy study to rescue a mouse model of NPC that recapitulates the symptoms seen in human patients. The aims of this research project are: (1) To deliver the viral vector carrying the therapeutic NPC1 gene directly into the brain of new-born NPC mice to assess, using a range of analyses, whether this ameliorates of prevents the symptoms in the brain. Our preliminary data shows that this has significant therapeutic affect but requires further investigation; (2) To deliver the viral vector intravenously into the bloodstream of new-born NPC mice and assess the therapeutic affect. This viral vector is known to deliver genes to visceral organs and also cross into the brain following intravenous injection. This approach offers potential treatment for both the brain and visceral organs symptoms such as in the liver; (3) To simultaneously deliver the viral vector both directly to the brain and also intravenously to effectively increase the systemic dose and assess the therapeutic efficacy; (4) To deliver the viral vector using the most therapeutically efficacious route of administration (identified in aims 1, 2 and 3) to progressively older mice and assess the therapeutic effect. The purpose of this is to gauge how the gene therapy may perform in more symptomatic mice. This would mimic the potential clinical situation where diagnosis of NPC may be delayed and patients have developed symptoms. It is our hope that this study will provide proof-of-concept data supporting the clinical application of gene therapy as an effective treatment for NPC patients.

Technical Summary

NPC is a prematurely fatal autosomal recessive metabolic disorder. A diagnosis is usually made in infancy with approximately half the patients having increased liver bile acid levels. 10% of these patients will die of liver failure within six months of life and those that survive infancy will face progressive neurodegeneration leading to cerebellar ataxia, dysphagia, dementia and death usually in the second decade of life. Most NPC cases are caused by mutations in the NPC1 gene that encodes a late-endosome/lysosome transmembrane protein. The exact role of NPC1 is unknown although it probably has a role in trafficking of cholesterol and sphingolipids as these lipids accumulate in lysosomes of NPC patients and mice. There is currently no major specific disease modifying therapy for patients with NPC and there is an overwhelming need to develop more effective treatments. This project aims to conduct a proof-of-concept pre-clinical study to evaluate the efficacy of AAV9-mediated gene therapy to rescue a mouse model of NPC from neurological and visceral symptoms. We have constructed an AAV9 vector that carries the full-length therapeutic version of the NPC1 gene (AAV9-NPC1). Our preliminary data shows that intracerebroventricular injection of AAV9-NPC1 to newborn NPC1 mice provides significant therapeutic benefit and improves the weight and behaviour compared to uninjected NPC mice. However, more studies are required and our main objectives are to conduct survival, behavioural, biochemical, histological, neuropathology and imaging assessments to ascertain whether: (i) intracerebroventricular; (ii) intravenous or; (iii) a combination of intracerebroventricular and intravenous routes of administration prevent neurological and visceral symptoms and rescue the NPC mice from premature death. Finally, (iv) we will use the most therapeutically efficacious route of administration to treat progressively older and symptomatic NPC mice to evaluate the effect of age on outcome.

Planned Impact

Who will benefit from this research?
Our proposal will have broad-ranging impact on several groups. These include: academics (Academic Impact) and healthcare professionals associated with NPC research and treatment, respectively. Ultimately, this research is aimed at impact to the individual NPC patients but also the family members upon whom there is a significant emotional and financial burden (Economic/Societal Impact). The data produced from this proposal would be used to create interaction with clinicians and the growing number of pharmaceutical companies (e.g. GSK, Pfizer, Genzyme and others) concerned with the development of gene therapy for metabolic disorders.

How will they benefit from this research?
Academics/clinicians will gain an insight into whether AAV-mediated gene therapy can ameliorate or prevent the symptoms of the NPC mouse and extend the lifespan. This may also serve as a model to other neurodegenerative diseases similar to NPC involving defective membrane-bound proteins. This pre-clinical study will provide data for engagement with regulatory bodies, relevant pharmaceutical companies and downstream translation to the clinic for direct patient benefit. In addition, we will transfer technical and managerial skills to a new generation of research scientists, either directly (to postdoctoral RAs) or indirectly (to undergraduate or Ph.D. students involved in our research). This will also help to develop an international skill base through the subsequent mobility of these new scientists. Former Ph.D. students and postdoctoral scientists have had positive career trajectories by training in our labs and are now in posts at many other Universities (e.g. Cardiff University, University College Dublin, Dalhousie University and UCL) or industry/healthcare (e.g. Plasticell, National Health Service). Studies from FMP's laboratory led to the development of miglustat that is EMEA (2002) and FDA (2003) approved for treating Gaucher disease and EMA approved (2009) for use in NPC patients. Pre-clinical testing of an AAV vector by SNW's lab contributed to a recent successful clinical trial for haemophilia B. Furthermore, an application to the EMA sponsored by the UK Gauchers Association for orphan designation has been granted for work conducted by AAR and SNW on AAV-mediated gene therapy for neuronopathic Gaucher disease funded by a previous MRC grant (G1000709).

What will be done to ensure that they have the opportunity to benefit from this research?
In the short term (1-3 years), our research will benefit research scientists and clinicians via the presentation of new research findings at lectures in the UK and internationally to scientific and lay audiences, by publishing in internationally-recognised scientific journals, and by engaging with national/international press, television and radio. The past impact of our work on gene therapy, neurodegenerative disorders and NPC is evidenced by the large number of invited lectures that the AAR, FMP and SNW have given and publication of findings in high impact factor journals freely accessible through open access agreements. All applicants are actively involved in public engagement and activities involving patient/family associations. To ensure our findings reach a clinical audience, we are collaborating with Professor Gissen who is directly involved in the care of paediatric NPC patients and the implementation of clinical trials at Great Ormond Street Hospital and the associated UCL Institute for Child Health. AAR's location at UCL allows development of findings and realisation of impact via: i) UCL Advances - a Centre for Entrepreneurship and Business Interactions; ii) UCL Business PLC - a dedicated technology transfer company; iii) UCL Consultants Ltd that facilitates consultancy contracts; iv) UCL Partners - one of five accredited academic health science systems in the UK translating cutting-edge research and innovation into measurable health gains for patients.

Publications

10 25 50
 
Description Participation in The Future of Medical Innovation in the UK: Opportunities and Challenges - House of Commons
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Invited seminar at the Open University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact An invited seminar on gene therapy to academic department - faculty and students.
Year(s) Of Engagement Activity 2019
 
Description Keynote presentation at Centre for Doctoral Training UCL-Nottingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Keynote presentation on gene therapy to postgraduate students at UCL and University of Nottingham
Year(s) Of Engagement Activity 2018
 
Description Niemann-Pick UK Interactive Workshop and Family Meeting 
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 The activity was based around attending the Niemann-Pick UK annual meeting and interacting with patients, families and carers. Furthermore, clinical experts and representatives from industry were present. This gave us the opportunity over 2 days to describe our project and how it may be a powerful therapy in the future. It also allowed us to update the medical experts on our latest research findings and discuss the pathway required for clinical translation of the projects and what needs to be done to achieve this.
Year(s) Of Engagement Activity 2017
URL http://www.npuk.org/npuk-annual-family-conference-interactive-workshop-2017/
 
Description Patient and family group presentation - ANPF, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact This was a presentation to the ANPF, a Niemann-Pick type C patient and family group based in Spain. The audience consisted of approximately 90 people and 10 healthcare professionals. The intended purpose was to present our research to them and explain how it works and the potential it may have for translation to the clinic one day. This resulted in a robust debate and Q&A session after the presentation.
Year(s) Of Engagement Activity 2017
URL https://anpf.es/ii-conferencia-cientifico-familiar-asociacion-niemann-pick/
 
Description Patient and family group presentation - Ara Parseghian Medical Research Foundation conference on Niemann Pick Type C Disease, USA 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Ara Parseghian Medical Research Foundation conference on Niemann Pick Type C Disease is intended to bring together researchers from around the world to discuss their work and to engage with patients and family/carers. The project and data that we presented has potentially led to avenues of collaboration in the USA and also informed the patients/families of new therapies currently being developed. The presentation sparked a significant Q&A session and debate among the families and professional scientists and practitioners.
Year(s) Of Engagement Activity 2017
URL http://parseghianfund.nd.edu
 
Description Patient group workshop - Fundacion Niemann-Pick de Espana 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact A presentation and debate at a workshop organised by a Spanish patient and family organisation. The presentation allowed us to describe what gene therapy is and the potential it has in treating diseases such as Niemann-Pick type C in the future. Many of the attendees did not have a firm understanding of knowledge of gene therapy and so they reported that the talk was well-received and very useful.
Year(s) Of Engagement Activity 2017
URL http://www.fnp.es
 
Description Presentation at NCL2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A keynote presentation on the future of gene therapy. Q and A afterwards.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the Association Niemann-Pick de Fuenlabrada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation of data to families of patients with NPC. Discussion afterwards around clinical translation of the programme.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the British Society of Gene and Cell Therapy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A presentation was given to an audience consisting of gene therapy experts, medical practitioners, postgraduates students and undergraduate students. This was an update on the project and how it was progressing.
Year(s) Of Engagement Activity 2017
URL https://www.bsgct.org/wp-content/uploads/2016/01/BSGCT2017-A4-Programme.pdf
 
Description Presentation at the European Brains for Brain Meeting - Germany 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A presentation to the Brains for Brain foundation in Frankfurt Germany. Attendees were primarily scientists, clinicians and representatives from industry. We delivered a presentation that highlighted the potential that gene therapy had for treating neurological diseases such as Niemann-Pick type C Disease. This sparked debate and discussion afterwards especially amongst the clinicians regarding the potential for clinical translation.
Year(s) Of Engagement Activity 2017
URL http://www.brains4brain.eu
 
Description Presentation at the Niemann-Pick Family Association 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A presentation to an audience of clinicians, scientists, industry reps and family members.
Year(s) Of Engagement Activity 2018
 
Description Presentation to the Metabolic Clinicians at Great Ormond Street Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact A presentation to the metabolic clinical team at Great Ormond Street Hospital on the work and progress so far. This generated a robust discussion amongst the clinical staff on how to move the study towards translation.
Year(s) Of Engagement Activity 2017
 
Description YouTube video on Gene Therapy for Niemann-Pick type C - commissioned by Niemann-Pick UK 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact An interview on the development of gene therapy for Niemann-Pick type C disease commissioned by the NPUK patient and carer group that was posted as a YouTube video. The aim was to reach as wider audience as possible to explain what gene therapy is and how it could benefit patients suffering with Niemann-Pick Disease. This video, to date, has had close to 400 views.
Year(s) Of Engagement Activity 2017
URL https://www.youtube.com/watch?v=P941wHlgcak