A breakdown of Sanfilippo Syndrome
What are Lysosomal Storage Diseases?
Lysosomes are cytoplasmic organelles harbouring over 100 hydrolytic enzymes involved in the degradation of essentially all types of biological macromolecules. Any failure in the biogenesis, lysosomal targeting, supramolecular organization or function of one or more lysosomal enzymes can result in the progressive metabolic diseases called lysosomal storage diseases (LSD) because of the massive accumulation of the undegraded substrates of the deficient enzymes in the lysosomes of the affected tissues. More than 50 LSD are currently known, caused by genetic blocks in the breakdown of macromolecules in the lysosomes of cells. These diseases comprise ~14% of all inherited diseases of metabolism and together they affect one of every 7700 newborn children. LSD that affect the central nervous system or those caused by defects in membrane enzymes typically do not respond to bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) based on the infusion of recombinant enzyme missing in the patients.
What is Sanfilippo Syndrome?
Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood. 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). 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 is currently no cure or effective treatment available for MPS III. There are however many therapies in early development (Table), including gene therapies, enzyme replacement, chaperone and substrate reduction. With Sanfilippo MPSIII Type A and IIIB there is currently a large focus on gene therapy evaluating different vectors (adeno-associated virus (AAV) e.g. AAV5, AAV9, AAVrh.10 etc) across many different groups. Less research appears to be focused on types C, D.
Sanfilippo syndrome type B
Mucopolysaccharidosis Type IIIB (MPS IIIB or Sanfilippo disease type B) is caused by a deficiency of alpha-N-acetylglucosaminidase (NAGLU) that normally helps all cells degrade heparan sulfate glycosaminoglycans (GAG). Much of the pathology is neurodegenerative in nature. A healthy preschool age child begins to develop behavioral problems, has difficulty learning new things, and eventually forgets how to walk, talk, eat, and sit, gradually becoming vegetative over the next several years. It is fatal in all children stricken with this disease, is incurable and currently untreatable.
Sanfilippo syndrome type C
Mucopolysaccharidosis Type IIIC (MPS IIIC or Sanfilippo disease type C) is one such LSD that is caused by deficiency of enzyme heparan sulfate acetyl CoA: -glucosaminide N-acetyltransferase, (HGSNAT) responsible for degradation of heparan sulfate, a repeating carbohydrate generally found attached to proteoglycans. The clinical phenotype includes onset in infancy or early childhood, progressive and severe neurological deterioration causing hyperactivity, sleep disorders and loss of speech accompanied by behavioral abnormalities, neuropsychiatric problems, mental retardation, hearing loss, and visceral manifestations, such as mild hepatomegaly, joint stiffness, vertebral bodies and hypertrichosis. Most patients become demented and die before adulthood but some survive to the fourth decade with progressive dementia and retinitis pigmentosa.
Sanfilippo syndrome type D
Mucopolysaccharidosis Type IIID (MPS IIID) is caused by a deficiency of N-acetylglucosamine 6-sulfatase which removes sulfate groups from 6-sulfated N-acetylglucosamine residues at nonreducing ends of heparan sulfate glycosaminoglycans. Twenty-two mutations have been described, including missense mutations, nonsense mutations, rearrangements, deletions, frameshift mutations and splice-site mutations. Some deletions are small, e.g. 3 amino acids. The degree to which these mutations affect protein folding and therefore may respond to chaperone therapy is currently unknown. There is currently no treatment for MPS IIID.
How Common is Sanfilippo syndrome?
MPS IIIC has an estimated incidence of 1/100,000 live births. MPS IIID was discovered in 1980, so there are few estimates of its prevalence. Over a 17-year period, there were 6 cases of MPS IIID in France and 2 in the United Kingdom, providing an estimated incidence of 1 in 2,500,000. Given how recently this syndrome was discovered, it is likely that the disorder is underdiagnosed. Assuming the estimate is correct, with roughly 4 million births per year in the United States, we would anticipate that 1-2 babies would be born each year with MPS IIID.
Stages of Sanfilippo Syndrome
Sanfilippo is progressive and separated into stages.
In the first stage: The child presents with delayed speech as well as mild facial abnormalities. Their appearance is described as coarse. Affected children are prone to sinus and ear infections, diarrhea, enlarged tonsils and hepatosplenomegaly. Children are hyper and agressive; frequent temper tantrums. Fearless. Minor bone deformities are common.
In the second stage: Some children will go through a period of sleeplessness. Walking and pacing, crying and screaming for no apparent or clinically diagnosed reason. They’re compelled to chew on things, throw objects, their behavior becomes very difficult. Over time, speech and cognitive skills decline; then diminish. The child’s motor skills and bodily functions will decline.
Last stage: The disease takes it’s final toll. The child will lose the ability to walk, talk and eat on his own while his body shuts down. The slightest infection can result in death. Most children don’t make it to the second decade of life. Some survive into their late 20’s with 24 hour care.
Features of Sanfilippo Syndrome
- Sanfilippochildrens facial features are clinically described as coarse.
- Prominent foreheads, large head circumferences,
- Coarse thick hair, bushy eyebrows,
- Thick skin,
- Full lips,
- Low thick ears,
- Low nasal bridge,
- Full round bellies.
Treatments and Research
Chaperone therapy uses active site specific inhibitors to restore mutant enzyme conformation and activity. MPS IIIC is a good candidate for chaperone therapy because it is estimated that a threshold activity of approximately 10% is sufficient to prevent storage. Thus, even a minor increase in enzyme activity obtained by chaperone therapy is likely to have an impact on disease pathology and be beneficial for patients. Dr. Alexey Pshezhetsky’s group demonstrated that for 5 missense mutations (N273K, R344C, R344H, S518F and S541L), the mutant enzyme could be rescued by treating patient’s cells with the competitive inhibitor of HGSNAT, glucosamine. These “responding” mutations are among the most frequent, so that the majority of known MPS IIIC patients are affected with at least one of them and could benefit from a small molecule chaperone to induce proper folding and stabilization of the mutant protein.Efforts to identify chaperones include high throughput screening and computational screening. Other successful examples of chaperone therapies include Tafamidis (Pfizer) which slows progression of familial amyloid polyneuropathy, was discovered by structure based design and is approved for use in Europe. Chaperone therapies in clinical trials include migalastat HCL (Amicus Therapeutics) for Fabry Disease and Pompe Disease. Recent reviews focused on chaperones for lysosomal storage diseases, or treatments in general indicates that MPS III has few if any lead compounds. We have licensed lead molecules that Dr. Alexey Pshezhetsky identified as chaperones.
Enzyme Replacement Therapy
Research in the canine model of MPS type I shows that intrathecal enzyme replacement therapy can distribute broadly throughout the neuraxis, penetrate into deep brain structures, and achieve therapeutic concentrations there. Similarly, other groups have found excellent distribution and penetration of therapeutic enzymes for MPS II and IIIA. The success of the intrathecal approach in animal models has led to clinical trials of intrathecal enzyme replacement therapy for MPS I, II and IIIA, and metachromatic leukodystrophy, and intracerebroventricular enzyme replacement therapy for late-infantile neuronal ceroid lipofuscinosis. These clinical trials demonstrate the proof of principle of using the CSF to deliver enzyme therapy to the brain, which will be necessary in order to treat MPS IIID. We have licensed an enzyme replacement therapy that Dr. Patti Dickson has developed. MPS III treatment must gain access to the brain. Our strategy proposes to deliver recombinant human alpha-N-acetylglucosamine-6-sulfatase (rhGNS) intrathecally (into the spinal fluid) to effectively treat the underlying causes of the neurologic symptoms that dominate MPS III pathology. Encouraging preliminary data from the Dickson lab shows robust expression of rhGNS in Chinese hamster ovary cells that could make scale-up feasible.
Our approach is highly collaborative. We use the NIH SBIR and STTR grant mechanism to fund our research with collaborators. For example with Dr. Dickson we recently obtained our first collaborative grant. Dr. Ekins has leveraged such small business grants to help build up several companies including GeneGo, Snowdon Pharmaceuticals and most recently Collaborative Drug Discovery Inc.
The following shows a list of some examples of treatments under development and the research groups involved for Sanfilippo Syndrome. This is by no means exhaustive and we are aware of other efforts but these are not public knowledge in many cases.
We are currently pursuing research on Chaperone therapy (IIIC) and NIH funded research on stem cell/ gene therapy (IIIB) and enzyme replacement therapies (IIID)
Ekins S and Wood J, Incentives for starting small companies focused on rare and neglected diseases, Pharm Res, 33(4):809-15, 2016.
Wood J, Siedman S, Siedman J, Levy P, Brown K, McBride K, Flanigan K, Marques R, Feldman A, Plecha R and Ekins S, Sanfilippo syndrome registry project and natural history studies: an example of patients, parents and researchers collaborating for a cure. Orphanet J Rare Dis 9: (Suppl 1), p7, 2014 http://www.ojrd.com/content/9/S1/P7
Wood J, Sames L, Moore A, Ekins S, The multifaceted roles of rare disease parent / patient advocates in drug discovery, Drug Disc Today, 18: 1043–1051, 2013. http://www.drugdiscoverytoday.com/download/1215
Publications by our CEO can be found here