Many efforts have been made to improve care and find a cure for patients with Sanfilippo disease. While some pursuits have fallen short, others hold promise.
In the study “How close are we to therapies for Sanfilippo disease?” researchers at University of Gdańsk, Poland, reviewed the latest preclinical and clinical advances in this field. The review study was published in the journal Metabolic Brain Disease.
Sanfilippo disease, also known as mucopolysaccharidosis (MPS) type III, is caused by genetic mutations in genes that are involved in the degradation of heparan sulfate (HS). These lead to the accumulation of HS in cells, mostly affecting the central nervous system.
As the disease progresses patients lose their ability to move and no longer respond to external stimuli. This typical clinical manifestation can be difficult to overcome, and underscores the need for therapies that target the brain.
Because of the nature of the disease, therapeutic strategies being explored mostly are focused on the replacement of the defective enzymes or the reduction of HS levels.
Enzyme replacement therapy
Preclinical studies have demonstrated that use of engineered enzymes is an attractive option for enzyme replacement therapy (ERT). However, these often fail because they cannot pass the brain’s protective layer, the blood-brain-barrier. But mice studies have shown that, when fused to other proteins, ERT has an enhanced ability to reach target cells and reduce Sanfilippo symptoms.
Shire has tested the safety and tolerability of sulfamidase enzyme replacement therapy (ERT)rhHNS administered via a surgically implanted intrathecal route — spinal canal — drug-delivery device in Sanfilippo type A patients. While the Phase 1/2 clinical trial (NCT01155778) demonstrated that the treatment was generally safe, it required cautious interpretation of efficacy results because four out of 12 patients experienced cognitive decline and six achieved stable disease.
Currently, a Phase 2 extension study (NCT02350816) is enrolling patients who participated in a previous Phase 2 open-label multicenter trial (NCT02060526) to evaluate the long-term safety and effectiveness of Shire’s recombinant enzyme.
BioMarin also is developing an ERT targeting Sanfilippo type B, which effectively reduced heparan sulfate levels. The company is recruiting participants for a Phase 1/2 trial (NCT02754076) being conducted in Germany, Spain, Taiwan, Turkey, and United Kingdom.
An alternative strategy to ERT that is being actively explored is gene therapy, which can deliver a healthy version of the faulty genes directly to affected cells. Similar to ERT, gene therapy also is meant to overcome the blood-brain-barrier challenge, ensuring a targeted delivery to brain cells. To a great extent, the delivery system used accounts for the main limiting factor for the effectiveness of this strategy.
Results from a Phase 1/2 study (ISRCTN19853672) in seven patients with Sanfilippo type B showed that gene therapy was safe and well-tolerated, and could effectively target brain cells. The treatment showed patients had reduced cognitive decline, with the best results being reported in younger patients, and suggesting that this type of treatment should be administrated in early stages of the disease.
The use of flavonoid compounds also has been proposed as way to reduce the production of heparan sulfate and other similar molecules. Preclinical results showed this strategy was effective to reduce heparan sulfate levels in mice.
Results from a Phase 2 trial, published in the journal Molecular Genetics and Metabolism, showed that administration of 150 mg/kg per day of genistein, a flavonoid that is found in plants, was safe and well tolerated in Sanfilippo patients.
However, this strategy raises some safety concerns as it can alter liver function, especially when administered at high doses.
An ongoing Phase 3 trial (2013–001479-18) is further evaluating the safety and effectiveness of genistein to treat patients with every type of Sanfilippo disease.
“There is an outstanding progress in both understanding mechanisms of the disease and developing treatment methods,” researchers concluded in their review. “From experiments on cellular and animal models, as well as from results of the first clinical trials, it appears that ERT, substrate reduction therapy, and gene therapy are the most advanced therapeutic procedures that are currently tested in clinical trials.”