Gene Therapy for Tay-Sachs and Sandhoff diseases

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.

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.

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 .