• Robin Ali PhD FMedSci (Chair)
• Professor Mimoun Azzouz
• Kev Dhaliwal
• Stuart Forbes
• Volker Germaschewski
• Professor Manju Kurian
• Dr David Matthews
• Rose Sheridan

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable and fatal adult-onset neurodegenerative diseases. Someone in the world is diagnosed with ALS or FTD every few minutes.

People with ALS lose nerve cells in the motor system – leading to progressive paralysis and death, usually within 2-5 years of the first symptoms.

In people with FTD, nerve cells in the frontal and temporal lobes of the brain die, affecting cognitive function and behaviour. A fault in a gene known as C9ORF72 is the most commonly known genetic cause of both conditions.

There is currently no treatment for FTD. The current treatment for ALS patients, riluzole, only marginally extends survival – typically by around three months – and does not relieve the symptoms of progressive paralysis.

In both conditions, the gene is copied into the cells by a protein, which the team identified as SRSF1.

In C9orf72-linked ALS and FTD, one the main drivers of disease is the transport of pathological, C9orf72 repeated RNA molecules from the nucleus to the cytoplasm where neurotoxic dipeptide repeat proteins (DPRs) are generated. The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door.

The team had already shown that, by using a gene therapy comprising interfering virus vehicles to reduce the levels of SRSF1 protein, there was a reduction in nuclear transport of pathological RNA molecules and generation of neurotoxic DPRs – addressing a root cause of the diseases.

In the laboratory, this gene therapy approach promotes the survival of patient-derived nerve cells and has no detrimental effects at the genome-wide level or in control cell cultures.

The team also demonstrated that SRSF1 depletion prevents paralysis in a fly model of C9ORF72-ALS/FTD, and also that this intervention is safe in healthy mice.

The purpose of this project is to conduct further studies to optimise the gene therapy treatment strategy ahead of developing a clinical trial application as follows:

• Evaluate the best delivery route for gene therapy.
• Define the dose of gene therapy needed to achieve the best reduction of SRSF1 in a mouse model of C9ORF72 disease.
• Conduct a pilot study to assess the therapeutic efficacy and any potential long-term adverse effects of the therapeutic gene therapy.
• Identify the biological processes which are modulated in the mouse brain after treatment and compare them to data available in patient-derived brain cells.
• Seek advice from regulatory bodies for a pre-clinical package to facilitate future clinical development.

The Motor Neurone Disease Association (MND Association) contributed £50,000 to the project.

This new research will be conducted in collaboration with the Cell and Gene Therapy Catapult which will provide support with designing the clinical vector and a detailed non-clinical safety strategy as well as regulatory advice to guide the team at the University of Sheffield through interactions with the Medicines and Health Regulatory Agency (MHRA).

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This study aims to move forward the development of a cutting-edge gene therapy approach for severe factor VII deficiency (SF7D), a life-threatening bleeding condition characterised by a deficiency of clotting factor VII – a protein essential for the blood to clot normally. The condition is linked to a recessive chromosome and is thought to affect around 1 in 500,000 people.

The liver is one of the prime targets for gene therapy to correct defects in a variety of clotting factor genes, but gene therapy for this condition has not been explored due to its rarity and the perceived difficulty in intervening early enough in life to prevent permanent organ damage and death.

This project is using the same virus vector platform technology that supported successful gene therapy in people with a related condition, haemophilia B, by mediating the continuous expression of a transgenic protein in these patients.

The team has developed a more potent form of the virus vector containing a codon optimised human FVII cDNA under the control of a small liver-specific promoter. The new virus vector has shown to greatly increase the transgene expression and preclinical data has enabled the potential therapy to be granted an orphan drug designation (ODD).

This study proposes/will undertake phase I/II clinical trials of the orphan drug in adults, potentially followed by trials in adolescents and children.

The team has established a wide-reaching clinical research network which, together with swift trial design and access to clusters of patients, improves the prospect of successful gene therapy for the condition.

Dravet syndrome is a rare neurological condition that is often described as a complex form of epilepsy.

Children and adults with this lifelong condition will experience severe seizures that are difficult to control. Individuals with the condition may also suffer from varying degrees of intellectual disability and a spectrum of associated health conditions (known as ‘comorbidities’) – which may include autism, ADHD, challenging behaviours and difficulties affecting their speech, mobility, eating and sleep.

80% of patients with the condition carry a mutation in the SCN1A gene which encodes a sodium ion channel, NaV1.1, which functions to maintain normal firing patterns in neurons. Mutated NaV1.1 channels in Dravet syndrome patients do not function properly, which results in abnormal neuronal activity.

There is no cure and current treatments have limited benefit, as well as side-effects.

With this funding, Dr Karda aims to develop a gene therapy for Dravet syndrome. The approach involves delivering a gene element, using a viral vector, in order to increase healthy SCN1A expression and thereby restore the number of functional sodium ion channels, which in turn should normalise neuronal excitability.

The project will test the novel gene therapy in mice which have a deletion in the Scn1a gene (mouse equivalent gene) and therefore are a model of Dravet Syndrome. The Dravet mice, like the human Dravet patients, contain one functional gene and one non-functional gene and show seizures, cognitive impairment and premature death, which makes it a clinically relevant model of disease. Treatment is expected to upregulate the Scn1a gene, producing more functional sodium ion channels, which should restore normal neuronal activity.

The aim is to generate an optimised, clinically relevant gene therapy treatment which has demonstrated robust efficacy and safety in a clinically translatable model of the Dravet syndrome disease.

The gene therapy has the potential to treat all patients with an SCN1A mutation that causes loss of function, regardless of the specific mutation. It could potentially reduce or completely stop seizures, cognitive impairment, ataxia (an inability to coordinate muscle movements) and premature death.

Idiopathic intracranial hypertension (IIH) is a rare disease that most commonly affects women of childbearing age. Patients experience extremely painful headaches and can suffer loss of vision that, for many, leads to permanent damage to their eyesight.

The condition causes fluid pressure to build up in the brain. The primary source of this fluid pressure is a structure in the brain called the choroid plexus. While drugs can control the function of the choroid plexus, research has revealed that the benefits of these drugs are highly unpredictable.

This reflects a lack of data measuring how effectively the drugs affect the function of the choroid plexus and the resulting change to brain fluid pressure.

The team’s laboratory had previously invented the first non-invasive technique, using MRI, to measure the function of the choroid plexus – the part of the brain that these drugs seek to target.

In this study, the team is using the new, non-invasive technique in combination with intra-cranial pressure monitoring techniques to see how a range of drugs already approved for IIH affect choroid plexus function and brain fluid pressure in anaesthetised mice. This will allow the team to define how drugs affect choroid plexus function and brain fluid pressure for the first time.

The resulting data will fill a gap in knowledge about the mechanisms that underlie drug treatment strategies for IIH and provide a strong foundation for improving drug treatment for patients.

The technique has potential as an enabling technology and further development through this project could enable better drug assessment in other indications linked with raised ICP and ChP dysfunction.