ESTEVE and the UAB advance in the development of a treatment for Sanfilippo Syndrome Type A

11/03/2014

Thanks to the agreement signed with REGENX, ESTEVE will be able to use the NAV rAAV9 vector in the development and commercialisation of its gene therapy for the treatment of mucopolysaccharidosis III type A. The NAV rAAV9 viral vector forms part of the gene therapy being researched and would allow the human sulfamidase gene, absent or defective in patients with Sanfilippo IIIA, to arrive, enter and express itself in neurons and hepatic cells. This would lead to a stable production of sulfamidase and would compensate for the absence of this enzyme in patients.

The objective of the agreement signed with Généthon is to produce a gene therapy product currently being researched for its administration in clinical trials. This would facilitate developing preclinical safety models, clinical development and finally the commercial distribution of the treatment.

Public-Private Partnership ESTEVE-UAB

The Sanfilippo project, begun by the research group led by Dr Fàtima Bosch (CBATEG), came to form part in 2009 of a public-private partnership between ESTEVE and the Universitat Autònoma de Barcelona (UAB). The objective of the partnership is to develop gene therapies which can treat this syndrome and other related diseases of the mucopolysaccharidoses group.

In this joint collaboration, ESTEVE is responsible for the activities related to management and protection of industrial property, regulative actions and procedures, the coordination and supervision of GMP production, the development of preclinical safety and clinical development. The CBATEG research group at the UAB provides scientific knowledge in relation to the aforementioned activities and is responsible for developing the gene therapy, including the design of a viral vector and the preclinical studies of the disease.

The gene therapy currently under research consists in the NAV rAAV9 viral vector, under REGENX licence, which contains an optimised version of the human sulfamidase gene which enhances its expression. Preclinical trials in disease models conducted by CBATEG support the potential efficacy of this therapeutic option. The treatment consists in administering the gene therapy into the cerebrospinal fluid, the fluid found in the brain and spine. The advantage of the NAV rAAV9 viral vector is its high affinity with the brain (main organ affected by the disease) and, as all adeno-associated viruses, it is innocuous; there are no known human diseases caused by the virus. The human sulfamidase gene introduced by the vector into the neuron's nucleus is what initiates the production of sulfamidase. And thus the enzyme is produced and secreted into the cerebrospinal fluid, where it is distributed throughout the brain and spinal cord, and it reaches the neurons in which no viral vector has been incorporated. In addition, a small of the gene therapy passes from the cerebrospinal fluid to the blood stream, reaching other organs, such as the liver, and there it enters the hepatic cells, producing and secreting sulfamidase which is then distributed throughout the body through the blood stream.

The results of the preclinical trials in disease models indicate that once the levels of enzyme activity are re-established, both in the brain and in the rest of the body, the accumulation of glycosaminoglycans (the substances in charge of metabolising sulfamidase) in the cells disappears, making the neuroinflammation and dysfunction also disappear from the brain and other affected organs. The animal's behaviour normalises and its life expectancy extends to the normal average.

The research group led by Dr Fàtima Bosch demonstrated in preclinical models that the administration in the cerebrospinal fluid can be made with a single intracranial injection, as is done when treating hydraencephaly in children. This represents an important innovation, since the intervention is commonly carried out by paediatric neurosurgeons and assure that the product is evenly distributed throughout the brain.

The project, designated as an orphan drug by both European (EMA) and American (FDA) authorities, is currently in the preclinical phase, with the manufacturing of the first sample drugs needed to test for drug safety and which would allow to continue on to the Phase I/II clinical trails in 2015.

The Sanfilippo project has received funding from the Spanish Ministry for Health, Social Policies and Equality, by the Spanish Ministry for Economics and Competitiveness and by FEDER.

About Sanfilippo Syndrome Type A

The Sanfilippo Syndrome Type A is a devastating disease causing progressive mental deterioration in patients, who rarely survive past adolescence. The diagnosis of many rare diseases is extended in time and is normally made when all clinical symptoms are evident. The Sanfilippo Syndrome, a lysosomal disease caused by the lack of activity of the sulfamidase enzyme, affects approximately one in every 100,000 births and continues to be under diagnosed.