Gene Therapy Platform

First-in-class AT

The Sanfilippo programme is a Public Private Partnership (PPP) between ESTEVE and the UAB (Universitat Autònoma de Barcelona) for development of gene therapies for the treatment of mucopolysaccharidoses.

Mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunction of enzymes needed to metabolize glycosaminoglycans, a group of long-chain sugars found in the extracellular matrix and in cell membranes.

Esteve's gene therapy program relies on state-of-the art science developed at the CBATEG (Center of Animal Biotechnology and Gene Therapy) of the UAB by the research group led by Prof. Fàtima Bosch.

The most advanced project in this program consists on the development of a novel gene therapy treatment for Sanfilippo A syndrome, or mucopolysaccharidosis type IIIA (MPSIIIA), which is caused by the lack of functional heparan N-sulfatase, also known as sulfamidase. Other projects in the platform are a gene therapy for Sanfilippo B syndrome or mucopolysaccharidosis type IIIB (MPSIIIB), which is caused by the lack of functional alpha-N-acetylglucosaminidase, and a gene therapy treatment for Hunter syndrome, or mucopolysaccharidosis type II (MPSII), which is caused by the lack of functional iduronate 2-sulfatase.

Sanfilippo A, Sanfilippo B and Hunter Syndromes are classified as rare diseases by their very low prevalence. These diseases may present in phenotypes ranging from attenuated to severe, depending on the degree of cognitive impairment. For the severe phenotype, symptoms and signs of the disease are associated with delayed psychomotor development and behavioral disturbances, which normally begin to appear between the ages of 1-4 years old. The clinical profile evolves generating serious behavioral problems, sleep disorders, severe mental retardation, mobility problems, seizures, breathing and swallowing problems, among others, with the patient eventually entering a vegetative state. In the severe phenotypes, mortality occurs early with patients rarely surviving beyond the second decade of life.

The gene therapy platform consists of the development of a viral vector containing the correct copy of the malfunctioning gene for each of the diseases, that is, sulfamidase for MPSIIIA, alpha-N-acetylglucosaminidase for MPSIIIB and iduronate 2-sulfatase for MPSII. These viral vectors, upon administration, will enter certain patient cells, allowing the correct gene to express and produce the enzyme which is constitutively defective or absent.

All programs have been designated as an Orphan Drug by both the European Medicines Agency (EMA) and the Federal Drug Administration (FDA).


Molecule: New advanced (gene) therapy medicinal products. Adeno-associated viral vector of serotype 9 (AAV9) containing:

MPSIIIA: the human sulfamidase gene (AAV9-sulfamidase)

MPSIIIB: the human alpha-N-acetylglucosaminidase gene (AAV9- alpha-N-acetylglucosaminidase)

MPSII: the human iduronate 2-sulfatase gene (AAV9- iduronate 2-sulfatase)

Mechanism of Action: Induction of long-term constitutive expression of the corrective enzyme. Therapeutic approach aimed as treatment to correct the specific cause of the disease and both neurological and somatic pathological alterations.

Delivery Route: Intracerebroventricular (ICV) injection into the cerebrospinal fluid (CSF).

Stage of Development:

MPSIIIA: Entering clinical trials 1Q 2018.

MPSIIIB: Preclinical

MPSII: Preclinical

Regulatory Status (MPSIIIA, most advanced program):

Orphan Drug designation by both the EMA and FDA.

Scientific Advice with the Spanish Medicines Agency (AEMPS) performed.

Protocol Assistance with EMA performed.

Paediatric Investigation Plan being discussed with EMA's Paediatric Committee.

Intellectual Property:

MPSIIIA: Product patent application published on 15 December 2011 (WO 2011/154520 A1). Other patent applications in progress.

MPSIIIB: Product patent application published on 13 May 2015 (WO 2015/173308 A1). Other patent applications in progress.

MPSII: Product patent application filed.



-Haurigot V. et al. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. The Journal of Clinical Investigation, 2013, Jul 1

-Haurigot V. and Bosch F, Toward a gene therapy for neurological and somatic MPSIIIA. Rare Diseases, 2013, Dec 12, 1:e27209


-Ribera A. et al. Biochemical, histological and functional correction of mucopolysaccharidosis Type IIIB by intra-cerebrospinal fluid gene therapy. Human Molecular Genetics, 2015, 1–18


The collaboration between ESTEVE and Dr. Fatima Bosch's internationally recognized research group at the Center for Animal Biotechnology and Gene Therapy of the Autonomous University of Barcelona (CBATEG-UAB), was initiated after the preliminary results obtained by the group of Dr. Bosch demonstrated the potential of treating these patients by gene therapy. This project was initiated in the CBATEG at the request of MPS-Fabry Association Spain.

In the collaboration Dr. Bosch's laboratory at CBATEG-UAB is responsible for animal models studies and ESTEVE is responsible for regulatory affairs, intellectual property, coordinating drug production under GMP (good practice manufacturing) and studies of preclinical safety and clinical development.

ESTEVE has exclusive worldwide commercial and license rights.

PRECLINICAL PROFILE (MPSIIIA, most advanced program)

Pharmacology, pharmacokinetics (biodistribution) and tolerability studies have been performed in a mouse model of MPSIIIA (mice that are spontaneously deficient in the gene expressing sulfamidase) and in Beagle dogs, as large animal model, to study the biodistribution using different routes of administration.

The MPSIIIA mice closely reproduce the devastating human disease including the neurodegeneration, neuroinflammation, hepato-splenomegalia, and shortened lifespan.

Preclinical results support the safety and efficacy of the therapeutic approach.


Natural history study of Sanfilippo A syndrome in progress.

Development of a manufacturing process with pharmaceutical quality (GMP) for Sanfilippo A gene therapy. Being a very complex process and a major challenge to be faced, we are taking the necessary steps for setting up an adequate manufacturing process which will allow the availability of sample supplies for the clinical trial.

Currently, the first Phase I / II clinical study is being carried out in patients with Sanfilippo A Syndrome according to the protocol authorized by the Spanish Agency for Medicines and Sanitary Products (AEMPS). Information is available in the European Clinical Trials Register (

Due to the early stage of development of this therapy, we are not in a position to supply the drug for compassionate use.


The Sanfilippo project has mostly been funded with Esteve's own resources, as well as help coming from the budget of the Ministry of Economy and Competitiveness and the Ministry of Health, Social Policy and Equality, through competitive calls tenders from the Spanish Government for research projects, in which this project received recognition for its scientific excellence.

Funding has never been requested or received from patient associations.

Related Publications

Other Projects

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