A rare disease a day: Sanfilippo Syndrome

It is with great sadness that today’s post is dedicated to the memory of Benjamin Alexander Siedman. His foundation Ben’s Dream – The Sanfilippo Research Foundation has done so much to fund research and raise awareness of the disease which will be the focus of this installment of A rare disease a day (following on from Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome and Fabry disease).

At the outset I should mention that I have been closely involved with Sanfilippo disease for a couple of years working with Jonah’s Just Begun, Phoenix Nest and several scientific collaborators focused on the disease. I was going to address this disease later in the month, but I feel it is timely to do so now in the light of Ben’s passing.

Mucopolysaccharidosis Type III also known as Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood and the most frequent lysosomal disease currently lacking a specific therapy. All subtypes of MPS III have similar clinical phenotypes with onset in infancy or early childhood: progressive and severe neurological deterioration, hearing loss, and visceral manifestations. There are also patients who are “mildly” affected, who instead develop dementia and other neurological problems in their teens or twenties and worsen.  Most patients die before adulthood but some survive to the fourth decade with progressive dementia and retinitis pigmentosa. All subtypes of MPS III are inherited in an autosomal recessive pattern, so that parents may have more than one child affected by this deadly disease. There is currently no cure or effective treatment available for MPS III. The cause of MPS III is an inherited mutation in one of four enzymes required to catabolize heparan sulfate (HS). The four subtypes of the disease are defined by the enzyme deficiency: MPS III type A (heparan N-sulfatase); MPS III type B (α-N-acetylglucosaminidase); MPS III type C (heparan sulfate acetyl CoA: a-glucosaminide N-acetyltransferase, HGSNAT); and MPS III type D (N-acetylglucosamine 6-sulfatase). The incidence of Sanfilippo syndrome ranges from 1:100,000 for type A to 1:1,500,000 for type D. But these figures vary by country.

Enzyme Replacement Therapy (ERT) is complicated by needing to cross the blood brain barrier. Recombinant enzyme for Type A, Type B, have been published in studies with fibroblast or animal cells while Type C and Type D appear not have been studied or published. The most advanced ERT is idursulfase, sulfamidase (SHP610 (HGT1410) Shire, MPS IIIA) Phase 1/ 2 completed and preparation is underway for a Phase 2b trial according to their website. 

Gene therapy has been attempted for MPS IIIA, most notably, Lysogene obtained orphan drug designation for their treatment which is still in clinical trials. Gene therapy for MPS IIIB has been used in mice and several groups are involved. To date nothing has been published for MPS IIIC and MPS IIID.

Significant work exists on substrate reduction therapies. For example the flavonoid Genistein has reached clinical studies although there appear to be differing opinions on efficacy and high doses may be necessary.   A new clinical trial is recruiting currently at the University of Manchester.

MPS III is a good candidate for chaperone therapy, because it is estimated that a threshold activity of approximately 10% of control is sufficient to prevent storage. A subgroup of MPSIIIA patients with the frequent Ser298Pro mutation have already been identified as well-suited for chaperone therapy. For MPS IIIB structural work using a bacterial homolog identified 3 potential chaperones (2AcDNJ, 6AcCAS and PUGNAc) that bind the active site. These compounds are however non-specific as they bind other enzymes. For MPS IIIC the residual HGSNAT activity of approximately 10% was estimated to be sufficient to prevent storage suggesting that even a minor increase in enzyme activity obtained by PCT is likely to have an impact on disease pathology and be beneficial for patients. Glucosamine has already been identified as a chaperone for MPS IIIC, but there have been no published studies in mouse models etc. Glucosamine has a KI of 0.28 mM as an inhibitor, while treatment of patient fribroblasts (homozygous for the N273K mutation) with 14 mM glucosamine resulted in  increased N-acetyltransferase activity, reaching 3 fold induction after 5 days of treatment.Glucosamine has been suggested to cross the BBB of rats

 There are still many opportunities for sanfilippo syndrome research, such as the development of new animal models, high throughput screening for chaperones and ERT for enzymes not addressed to date. Of course a great deal of the funding for such research has come from parent / patient lead groups such as : Ben’s Dream , Jonah’s Just Begun, Sanfilippo barcelona, Sanfilippo sud,  JLK-Sanfilippo Research Foundation as well as Team Sanfilippo and the MPS Society. A natural history study and patient registry for MPS IIIC was recently announced in 2013 and a poster will be presented at the World Symposium 2014 this week in San Diego. An example of using the ODDT mobile app within the Sanfilippo community will also be presented as a poster at the same conference. I will try to update this post with any new Sanfillipo research from this meeting too.




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