Discussion list Sanfilippo EURORDIS



Therapeutic Approaches

Pharmacological Approaches
Gene Therapy
Cell Therapy
Substrate(s) Deprivation


Sanfilippo Syndrome is a lysosomal storage disease belonging to the group of mucopolysaccharidoses. Deficiency in one of four enzymes, required for heparan sulfate (HS) degradation is responsible for MPS III subtypes. A very mild quantity of enzyme is necessary to ensure a normal life. Below such quantity, especially when close to zero, the deficit is critical. The disease appears when the substrate accumulation into the lysosomes is faster than the breaking off realized by one of the four enzymes, conducting to a progressive storage of the substrate (see What is Sanfilippo Syndrome?).

At this time, the only treatments available aim at alleviating symptoms such as hyperactivity, aggressivity, ear infections… and will be provided in multidisciplinary visits (neurology, ear, nose and throat, orthopaedics), as in French Reference Centres. However, the efficiencies of these treatments are usually limited for children with Sanfilippo Syndrome, as goes to the behavioural problems.

The improvement achieved in the field of molecular biology and physiopathology in the last few years is a great opportunity for the research to focus on the deepest causes and mechanisms of the disease and not only on the symptoms. It appears that the understanding of the different steps of the biochemical process of HS accumulation into the cells is critical to determine the different therapeutic approaches to cure the disease.

It is important to bear in mind that therapeutic strategies in the future may vary according to the patient her- or himself, the evolution of the disease or the genotype. This might potentially be the case due to the existence of four subtypes of MPS III and/or due to the existence of various types of mutations.
Consequently, it is important to build up all the potential therapies that could cure the disease including gene therapy, cell therapy, pharmacology, and substrate deprivation.

Pharmacological Approaches

- Enzyme replacement therapy (ERT): Substitutive recombinant enzymes can be developed to compensate for their deficiency, as in Fabry disease and Gaucher disease. ERT clinical trials are in process in Europe on MPS I, II and VI and might also be applicable to Niemann-Pick B. Recombinant enzymes for MPS III A and B exist. The problem that remains is that of the crossing of the blood brain barrier. Investigations about intracerebral injections of such enzymes are in progress.

- Read-through of a stop codon allows a premature stop codon in protein production to be released. With the aid of specific small molecules, this post transcriptional mechanism might be applied to an enzyme and thus enhance its enzymatic activity.

- Pharmacological chaperones are molecules that interact with misfolded proteins to restore their stability, trafficking, and function. It is a promising path for certain diseases such as Fabry, for missense mutations. Lysosomal storage diseases such as Sanfilippo are also diseases in which a protein folding defect is the primary cause of the disease. There is no dedicated chaperones project on Sanfilippo but this option should be seriously considered in the future for MPS III patients with missense mutations.

Gene Therapy

With genetic diseases, gene therapy involves replacing the function of a defective or missing gene with that of a therapeutic gene. Researchers have developed several types of vectors and techniques for gene transfer: viral vectors (a virus whose pathogenic elements have been replaced by the gene-drug), synthetic vectors (chemical compounds that bind to the therapeutic gene) and « physical » techniques (electroporation, biolistics...). Following various trials on MPS III B mice, gene therapy studies are in progress on MPS III B dogs in France and in the USA.

Cell Therapy

Replace deficient or missing cells by healthy ones is the challenge of cell therapy. It consists in transplanting normal cells from a healthy donor into the patient. Considerable work remains to be done, but this approach offers extraordinary possibilities. Sanfilippo Syndrome may be eligible for this therapeutic approach.

Substrate(s) Deprivation

Inhibitors may have an effect to reduce the biosynthesis of the substrate and/or of secondary accumulated components. Such secondary accumulations have been evidenced in MPS III and various inhibitors having an effect on gangliosides have been tested on MPS III mice. Their efficiency in terms of neurology has not been evidenced yet. Zavesca ®, an orphan drug authorized on both the US and European markets for Gaucher I disease, inhibits the biosynthesis of glycosphingolipides. Clinical trials are currently in progress in diseases with neurological impacts namely Gaucher type III, Niemann-Pick C and Tay-Sachs. Results should be communicated soon.

An isoflavone called Genistein has been identified as a substrate inhibitor in vitro. Pre clinical studies on animal have been launched in October 2005.


Alliance Sanfilippo - BP 88 - 92203 - Neuilly sur Seine Cedex - France - Tel. + 33 6 14 03 84 87