Gene Therapy for Tay-Sachs and Sandhoff diseases

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Gene Therapy for Tay-Sachs and Sandhoff diseases

Our aim is to treat the genetic problem that causes relentless and lethal neurodegenerative diseases (Tay-Sachs and Sandhoff diseases - termed GM2 gangliosidosis) in young people. A radical approach is needed because lysosomal diseases, of which GM2 gangliosidosis is a classical prototype, account for nearly half the burden of progressive intellectual and neurological deterioration diagnosed in UK children. No effective treatment is known and the caseload burden of progressive intellectual and neurological deterioration identified in 1164 children in the United Kingdom has immense human and societal costs. About 70 lysosomal diseases are known - two-thirds of which damage the brain. The importance of lysosomal disorders has recently been shown by the discovery that defective lysosomal function predisposes to Parkinsonism, thus investing this small cellular particle with central importance in the brain and neurodegenerative diseases which are prevalent in many communities.

Over 15 years of intensive scientific research we have perfected gene transfer to the living mammalian brain: we use agents (inactivated passenger viruses that do not cause disease), shown by others to be safe in humans, in efforts to advance treatment for such conditions. Deficient lysosomal components have the special advantage that gene transfer can be used to treat a small focus of tissue but the corrective factor is secreted from this target to be taken up by cells far away. In this way, inoculation of the vector for gene therapy into the brain on a single occasion can rescue the function of a large field of brain tissue and so greatly improve survival in young animals that would otherwise be moribund within a few months. We justify our plans in these studies to translate our previous research findings into patients because we have found that function of an essential enzyme in brain lysosomes can be maintained throughout the entire central nervous system (brain and spinal cord). Moreover, definitive correction of the defect resolves the disease hallmarks and prevents critical loss of brain cells, which cannot otherwise be replaced. Outcomes are optimal when gene therapy is given early.

We will develop Investigational Medicinal Products for first-into-human gene transfer studies as part of a clinical trial; there will be a single procedure by a neurosurgeon skilled in the safe administration of treatments to brain structures. This will involve generating effective treatments that can be tested for the first time in living human patients known to afflicted by GM2 gangliosidosis. Our trial will be based on our proof-of-concept studies with correction over years of the disease in Tay-Sachs and Sandhoff diseases authentically modelled in living animals; it will explore safety and early signs of effectiveness (phase I/II clinical trial).

A successful outcome would advance treatment for stricken children and young persons with this disease as well as patients affected by other, more familiar and prevalent neurodegenerative diseases.

Technical Summary

The overarching research objective is completion of a clinical trial of gene therapy for Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) - relentless neurodegenerative conditions due to inborn defects in lysosomal beta-hexosaminidases that degrade GM2 ganglioside. Definitive correction by gene transfer is warranted since there is no effective treatment: lysosomal diseases, of which Tay-Sachs is emblematic, account for 45% of progressive neurodegeneration diagnosed in UK children.
Investigational Medicinal Products for first-into-human gene transfer will be developed by extending preclinical research to generate safe and effective GMP-grade clinical vectors for use in an open-label phase I/II single-centre clinical trial in infants and young patients with GM2 gangliosidosis. Therapeutic vectors expressing human hexosaminidase subunits will be surgically delivered to intracranial structures on a single occasion using convection-enhanced delivery.
The research stratagem is based on proof-of-concept studies showing long-term restoration of lysosomal function by recombinant adeno-associated viral (rAAV) vectors expressing wild type enzyme subunits in GM2 gangliosidosis modelled authentically in mice and cats. Once-only intracranial inoculation of monocistronic vectors preserves neurological function and induces >2 year survival in animals that would otherwise be moribund by 4 months.Outcomes are optimal when gene therapy is given early.
We justify translation to patients because enzymatic augmentation is sustained throughout brain and spinal cord with rescue of disease hallmarks and neuronal loss. We will study rAAV vector serotypes (eg 2/1 and 2/rh.10) for optimally safe and effective expression; preclinical research will be dovetailed with patient evaluation for study enrollment. Individual patient outcomes will be assessed longitudinally using neurological, neuropsychiatric and MR studies with life-quality scoring and compared with the natural disease course.

Planned Impact

Outcomes and Impact
Beneficiaries: Successful conduct of the clinical trial of gene therapy with the desired safety and efficacy outcomes would directly benefit the participants, (patients with Tay-Sachs and Sandhoff disease and their immediate families and carers). Therapeutic efficacy in terms of arrest or reversal of neurodegeneration would be a powerful incentive for participation by other stricken patients in the UK and abroad.

Indirect beneficiaries: Patients, neuroscientists and other investigators and companies seeking to access therapeutic expertise in other brain diseases, particularly those caused by lysosomal defects, using gene transfer technology.

Proposed next steps: Indications of therapeutic success in these devastating disorders will resonate widely and stimulate interest from the European Commission through the European Brain Council and numerous emerging Biotech companies with dormant patents and interests in clinical gene therapy - in some cases including the brain as a target. The support of the Medical Research Council in the UK, University Development Offices through this application will provide a platform to secure interest from leading gene therapy companies for phase III studies and the continuing market development, to which they are committed.

Role of commercial organization: As their patents in common disorders expire, several large-Pharma companies with near-empty discovery portfolios are now taking on 'niche-busting' initiatives in rare diseases, including lysosomal diseases - research into metabolic medicine and lysosomal disorders has recently attracted substantial investment from global companies such as Pfizer, Sanofi and Glaxosmithkline pharmaceuticals. By this means also there is material investment in metabolic expertise and rare neurodegenerative disorders - with the profitability of orphan biologics and improved stratagems for human gene therapy, the field is becoming more attractive for pharmaceutical partners.The commercial private sector may thus benefit from the investment opportunity as set out. Policy-makers seeking fresh perspectives on emerging technologies would also benefit from the outcomes of this research, which would also enhance perceptions of inventiveness and scientific originality in the UK - and is also likely to attract international notice.

Long-term European development
The European Brain Council (EBC) is formed by European organisations in neurology and other clinical neurosciences as well as patient organisations and industry; the Brains for Brains Foundation is affiliated. Recently the applicant presented a case for the exceptional importance of neurodegenerative lysosomal diseases at a well-attended convention of MEPs. The need for early diagnosis and improved commitment to research was fully accepted. With the conduct of the phase I/II trial in 2014, the proposed research coincides with the European Year of the Brain. The EBC, which involves all membership organisations in its projects and activities, may also be approached to support the project for long-term investment and comprehensive development during its three-year campaign. The Year of the Brain project has gathered momentum rapidly, with enthusiastic support from the European Parliament and member states. The proposed gene therapy research and its envisaged clinical development is well-positioned to take advantage of the investment opportunities and awareness promoted through the European Year of the Brain campaign. The campaign is motivating further support and research into vital neuroscience initiatives and we contend that the successful conduct of the research programme in Tay-Sachs and Sandhoff diseases is likely to be seen for its iconic significance in the field. Furthermore, it will emphasise the need for realistic development of clinical gene therapy - particularly its more general application within the portfolio of UK medical research .

Publications

10 25 50

publication icon
Bradbury AM (2013) Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy. in Molecular therapy : the journal of the American Society of Gene Therapy

publication icon
Cachón-González MB (2014) Reversibility of neuropathology in Tay-Sachs-related diseases. in Human molecular genetics

publication icon
Cox TM (2015) Innovative treatments for lysosomal diseases. in Best practice & research. Clinical endocrinology & metabolism

publication icon
Cox TM (2015) Gaucher disease and comorbidities: B-cell malignancy and parkinsonism. in American journal of hematology

publication icon
Duran R (2013) The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease. in Movement disorders : official journal of the Movement Disorder Society

 
Description I was honoured by the National Tay-Sachs and Allied Diseases Association (NTSAD) at their 60th Anniversary celebration. This is the largest and oldest charity of its kind dedicated to Tay-Sachs and Sandhoff diseases
Geographic Reach North America 
Policy Influence Type Participation in a national consultation
Impact My attendance at this event held by the charity seems to have led to donations much in excess of the target ($100,000) and was $127000. During the event I met donors and Trustees and advised a panel of gene therapy vector experts, neurosurgeons, veterinarian researchers, patients and clinicians to assist in the design, selection and monitoring of a gene therapy clinical trial
URL https://www.ntsad.org/index.php/2017-imagine-believe
 
Description Biomedical Research Centre
Amount £114,300,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description MRC DPFS
Amount £213,410 (GBP)
Funding ID MR/K025570/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description Weizmann Institute of Science - UK Joint Research Program 2014 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution Molecular and genetic analysis of lysosomal disease models; industrial collaborations for MTA and studies of molecular pathogenesis jointly
Collaborator Contribution Identification of molecular targets of possible therapeutic significance which can be studied by outbreeding in different genetic contexts
Impact Paper in Nature Medicine 2014
Start Year 2013
 
Title Orphan Drug Designation for Gene Therapy CAM-GM201 and CAM-GM202 from FDA; EMA with designation as an advanced medicinal therapy and with the granting of eligibility for a Pediatric Priority Review Voucher from the FDA 
Description Part of our Intellectual Property development strategy - and with protection as well as potentially considerable financial value 
IP Reference  
Protection Protection not required
Year Protection Granted 2017
Licensed No
Impact Investor interest
 
Title CAM-GM2 gene therapy vectors for GM2 gangliosidosis 
Description recombinant Adeno-Associated Gene therapy vectors for intracranial administration in human GM2 gangliosidosis 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2017
Development Status Actively seeking support
Impact Outcome of COMP - positive opinion EMA/OD/182/17 
URL http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/...listing/
 
Company Name Cambridge Gene Therapy Limited 
Description This is the inception of a spin-out company (incorporated 13/12/2017) to raise the funds needed for the conduct of the planned phase 1/2 clinical trial of gene therapy in Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis). At this time we are seeking investments from Cambridge Seed Funds and Cambridge Innovation Capital and will be seeking one other major partner. 
Year Established 2017 
Impact Considerable interest from investors local and international. We are currently actively conducting due dilligence searches and developing the IP strategy.
 
Description European Tay-Sachs Family Conference, Monsee, Austria 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Cox's talk sparked interest and heightened awareness of lysosomal disorders, especially regarding Tay-Sachs and Sandhoff diseases

Parents of young children sufferers were kept abreast of Professor Cox's current ongoing research into Tay-Sachs and Sandhoff diseases and were made aware of his current and future plans for gene therapy
Year(s) Of Engagement Activity 2013
 
Description Gordon Research Conference Inaugural Keynote Lecture 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The lecture sparked great interest and enthusiasm

Professor Cox was approached by many attending professionals requesting further information
Year(s) Of Engagement Activity 2011
 
Description Gordon research conference - lysosomal diseases 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact GRS - The purpose was educational engagement for basic and clinical scientists in lysosomal diseases: Decoding Lysosomal Signals to Understand Disease Mechanisms and Define New Therapeutic Strategies for Lysosomal Storage Disorders. This Gordon Research Seminar attracted 50 participants - all slots filled. I delivered the opening keynote lecture.
At the subsequent 2017 GRC (Gordon Research Conference) ); a paper on upcoming new data was presented from our institution describing a unique new disease due to human mutations in the endosomal-lysosomal related protein of the HOPS complex, VPS 33A. A research poster by my senior colleague describing strong modifier effects related to genetic background in a severe neurological disease in mice (twitcher 2J and twitcher 5J) that accurately model human Krabbe disease. I delivered an opening translational lecture on therapeutics in sphingolipidoses and chaired a half-day session on lysosomal therapeutics. al our contributions appeared to be well received.

Finally I was a discussion leader in a half-day session dedicated to therapeutic advances in this field.
Later I was proposed and after a majority democratic vote, elected Vice-Chair to be followed by Chair of the GRCs in 2019 and 2021.

I also delivered a keynote lecture at the 2016 Zing conference in Cambridge on Lysosomal diseases to a mixed professional and biochemical audience.
Year(s) Of Engagement Activity 2011,2013,2015,2017
URL https://www.grc.org/home.aspx
 
Description Hunterian Oration 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The lecture sparked huge interest

Professor Cox's lecture entitled: 'Rising in the East' sparked huge interest and it was indeed an honour to be invited to give the Hunterian Oration
Year(s) Of Engagement Activity 2012
 
Description IBMC Seminar, Porto, Portugal 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Much discussion was forthcoming

The talk was greatly appreciated and evoked much discussion
Year(s) Of Engagement Activity 2014
 
Description Loire Valley meeting, Chateau des Grotteaux, France 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion was lively and thought-provoking

Huge interest and discussions evoked
Year(s) Of Engagement Activity 2014
 
Description MPS Congress, Madrid, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Cox's talk sparked interest, as well as questions and discussion afterwards

Interest and awareness were heightened
Year(s) Of Engagement Activity 2013
 
Description Sheep Veterinary Society, Redworth Hall Hotel, Darlington 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The talk attracted interest and allowed all to share their views

Professor Cox has been invited to write a Paper by the Sheep Veterinary Society
Year(s) Of Engagement Activity 2014
 
Description Tay-Sachs Family Conference, Disneyland, Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The meeting inspired and gave hope to parents whose children are suffering from Tay-Sachs, Sandhoff and other rare lysosomal disorders

Inspiration and hope was instilled in parents and other family members of children suffering from these rare lysosomal conditions
Year(s) Of Engagement Activity 2014
 
Description Un Conte de deux Cites (Cle du Lysosome Award) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Cox's talk sparked huge interest and admiration for his research work into lysosomal disorders

Much awareness was raised into lysosomal disorders
Year(s) Of Engagement Activity 2013
 
Description University of Cambridge Department of Medicine Research Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The talk sparked questions and raised awareness

New insights into Gaucher disease were shared
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description Vaincre les Maladies Lysosomales (VML Society), College de France, Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Cox's talk heightened awareness and sparked interest and questions

Professor Cox was warmly received and congratulated on his presentation
Year(s) Of Engagement Activity 2013