Sanfilippo disease type C is a rare inherited neurodegenerative lysosomal storage disease caused by mutations in HGSNAT. University of Manchester scientists have developed a new gene therapy they hope will treat children with a rare but devastating brain disease, and plan to take it to a clinical trial in the near future. US-based biotech Phoenix Nest Inc. has signed a licensing deal with The University of Manchester, through its IP commercialisation company UMI3, to take the treatment to the next stage, which will involve a clinical trial on patients with Sanfilippo disease type C.

Sanfilippo C disease is a rare autosomal recessive lysosomal storage disease. It is caused by a deficiency in one of the enzymes needed to break down the glycosaminoglycan (GAG) heparan sulfate which is found in the extracellular matrix and on cell surface glycoproteins. It affects children as early as 3 years of age, resulting in severe and rapidly progressive brain neurological disease (lat. Neurological morbis). There is currently no effective treatment option for Sanfilippo disease type C as the protein is transmembrane and cannot move between cells. This means that maximal vector distribution within the brain is critical for treatment success.

The technology is developed by Professor Brian Bigger in collaboration with Dr. Els Henckaerts’ laboratory at King’s College London, and recently published in the journal Brain. It involves the use of a specially modified virus called adeno-associated viral vector (AAV), which has been specifically altered to efficiently deliver the missing HGSNAT gene to the brain to treat the disease. Working with an international group of scientists, the team was able to demonstrate complete behavioural and brain correction of Sanfilippo disease type C in mice. The study was funded by MRC, King’s College Commercialisation Institute, Jonah’s Just Begun, Sanfilippo Sud, Sanfilippo Barcelona, Sanfilipo Portugal, Sanfilippo Brasil, Le Combat de Haitem-Contre Sanfilippo, JLK- Sanfilippo Research Foundation, Sanfilippo Children’s Foundation, and VML charities and it has been great working with them towards a cure for this horrible disease.

The technology, developed in Professor Brian Bigger’s laboratory involves the use of an adeno-associated viral vector (AAV) to drive the expression of a codon-optimized Heparan-Alpha-Glucosaminide N-Acetyltransferase (HGSNAT) gene. Working with scientists from King’s College London the team created a novel viral capsid dubbed “AAV true type”, with better distribution within the brain than other AAV vectors. The team was able to demonstrate complete behavioural and brain correction of the mouse model of MPSIIIC against the gold standard AAV9 vector. The King’s College London technology is based on the discovery of a novel AAV vector with an altered protein coat, which makes the virus work better within the brain. This new vector is called AAV-TT (AAV-true type). The technology works better than the AAV9 vector, currently the gold standard for gene delivery to the brain. AAV gene therapy for MPSIIIC was awarded Orphan Drug Designation by the European Medicines Agency (EMA) and is the subject of patent GB1612104.

According to Prof Brian Bigger, Professor of Cell and Gene Therapy at The University of Manchester this gene therapy technology will be used by biotech company Phoenix Nest Inc to treat Sanfilippo syndrome Type C. Sanfilippo is an incredible challenge as you have to be able to treat so many cells in the brain for complete success. In this work, the combination of the true type vector with improved brain distribution and the method of delivery were both critical for success. The scientists were really impressed to finally completely correct working memory and hyperactivity in the mouse model – traits shared by children with the disease. 

About MPSIIIC (Mucopolysaccharidosis type IIIC or Sanfilippo syndrome type C)

MPSIIIC is a rare neurodegenerative lysosomal storage disease caused by mutations in the Heparan-Alpha-Glucosaminide N-Acetyltransferase (HGSNAT) gene. Children are affected early in life, with a progressive cognitive and behavioural decline and a subsequent decline in motor function to early death, usually in the late twenties. MPSIIIC has no effective treatments as the protein is transmembrane and cannot move between cells. Enzyme replacement therapies are therefore ineffectual. The technology was recently commercialised that takes the treatment to the next stage, which will involve a clinical trial on patients with Sanfilippo disease type C. Working together with Phoenix Nest Inc scientists hope to successfully apply this therapy in treating children with MPSIIIC in the next few years.