Stem cell gene therapy for fatal childhood disease ready for human trial

Scientists in Manchester have developed a stem cell gene therapy to reverse a fatal childhood illness and will work with Orchard Therapeutics to test it in a human trial.

University of Manchester and Central Manchester University Hospital NHS Foundation Trust (CMFT) researchers have developed the pioneering approach for Sanfilippo disease (also known as mucopolysaccharidosis type III or MPS III) – a genetic condition for which there is currently no effective treatment.

The most common of the four types of Sanfilippo (type A) affects around 100 children in the UK, or one in 89,000 births, and it is this type that is targeted by the new treatment.

Sanfilippo is caused by a lack of the SGSH enzyme, which helps to break down and recycle long chain sugars. This results in a build-up of sugars in the body and particularly the brain.

Following a licence agreement with Orchard Therapeutics, a new UK-based clinical-stage biotechnology company, the gene therapy developed in Manchester will be trialled in humans. The University of Manchester’s technology transfer company, UMI3, negotiated the terms of the deal with Orchard Therapeutics, which have not been disclosed.

This licence agreement with Orchard will allow us to take the technique we have developed to trials in humans

Dr Brian Bigger, who leads the Stem Cell and Neurotherapies Laboratory at The University of Manchester and developed the technique in partnership with the Trust scientists said: 'This licence agreement with Orchard will allow us to take the technique we have developed to the next and crucial stage of trials in humans. We are hopeful that this treatment may help to treat the early onset dementia in these patients and saving children’s lives.

'If we can show that it is possible to treat single gene brain diseases, such as Sanfilippo, with stem cell gene therapy, this will pave the way for treating other lysosomal storage and neuro-metabolic disorders.'

The treatment works by genetically correcting the patients’ own stem cells and implanting them into bone marrow to release the missing enzyme in a way that reaches the brain, thereby correcting the condition.

The new study will take place at CMFT, supported by the NIHR/Wellcome Trust Manchester Clinical Research Facility.

Professor Robert Wynn, Consultant Paediatric Haematologist at Royal Manchester Children’s Hospital and chief investigator for the clinical study explained: 'This new clinical study aims to explore whether we can use stem cell gene therapy to produce blood cells that express corrected versions of the missing enzyme.

'We know that in conditions similar to Sanfilippo blood cells from a bone marrow donor can deliver such enzymes effectively. This new gene therapy builds on the decades of experience of CMFT physicians in bone marrow transplantation of children with these other metabolic diseases.'

The Manchester team has developed a way of overproducing the SGSH enzyme specifically in bone marrow white blood cells.

This was achieved by developing a lentiviral vector – a tool commonly used by molecular biologists to deliver genetic material into cells – specifically for use in humans, which will be tested in the trial. The lentiviral vector delivers the SGSH gene to bone marrow cells, which, when implanted into the body are able to traffic to both the bone marrow and the brain and deliver SGSH enzyme throughout the body, thus correcting the disease.