Will a Haunting Rare Disease Finally Meet Its Match?
Regina Kelder

Will a Haunting Rare Disease Finally Meet Its Match?

In Sanfilippo syndrome, a missing gene, and the critical enzyme it codes, cause a cataclysmic chain reaction in the CNS. What are researchers doing to try and reverse it?

Given the complexity and size of the human genome, it’s hard to imagine that a glitch in a single gene can lead to so much devastation. Yet that’s the reality of Sanfilippo syndrome, or “MPS type III” an inherited disease that strikes about 5 in a million – sadly, most affected children do not survive beyond their teens.

Sanfilippo primarily affects the brain and spinal cord. The missing gene, and the critical enzyme it codes, causes a cataclysmic chain reaction in which sugar molecules build up in the central nervous system (CNS), destroying nerve cells and eventually causing cognitive decline, seizures, and a loss of mobility.

It’s difficult to get a therapy into the brain cells that need it most for MPS type III – in this disease subtype, the enzyme has to be produced on site in the brain where the disease impact is the hardest. There are other types of MPS (MPSI and II; Hunter or Hurler syndromes) that impact other organs more than the brain and early in a patient’s life. Their conditions can be held at bay with enzyme replacement therapy or bone marrow transplantation. Both of these temporary fixes get the normal amount of the enzyme into the blood and throughout the body. Eventually these patients also need brain access for enzymes, as told on line by Mark Dant, father of a child with MPSI and head of the EveryLife Foundation for Rare Diseases.   

Sanfilippo’s many subtypes

There are four different subtypes of Sanfilippo—A, B, C and D—which are caused by different gene mutations. They are all grouped under the Sanfilippo header because they all cause similar problems in clearing away toxic sugar buildup in the brain. The mutations impact four enzymes: heparan N-sulfatase (“SGSH”), α-N-acetylglucosaminidase (“NAGLU”), acetyl-CoA:α-glucosaminide acetyltransferase (“HGSNAT”), or N-acetylglucosamine-6-sulfatase (“GNS”).  

So, if a doctor meets a family affected by this disease, they have to approach treatment options differently for the three subtypes of MPS and four types of Sanfilippo.  This makes each disease subtype so rare, that it’s very hard to find patients and design meaningful clinical trials.

Glimmers of hope

The advent of affordable genetic testing, and the resurging fields of cell and gene therapy are now making therapies possible. Gene therapy has rapidly advanced, thanks to the availability of a number of adeno-associated vectors (AAV) which act as taxis for repair genes to enter brain cells. These have been studied in many clinical trials with good clinical tolerability, and have made differences in genetic expression of brain enzymes for other conditions like hemophilia. The low turnover of brain cells actually offers an advantage here; if the one dose has sufficient impact, the cells should, as long as they live, newly express the repair enzyme, and will start to clear toxic buildup. This should prevent CNS deleterioration and possibly help patients who are experiencing CNS dysfunctions. For Sanfilippo, gene therapy products employing AAVs have already started development for subtypes A and B; genetically modified cell therapy is an option being considered as well.

Delivering the enzyme’s DNA to restore health

Gene therapy, as the name suggests, employs genes as the actual drug to treat or prevent disease. Helping cure Sanfilippo would require introduction of a healthy copy of the enzyme’s gene (termed “gene therapy”), or repairing the existing gene (termed “gene editing”). There are currently two investigational gene therapies using AAV vectors that chauffeur healthy copies of the SGSH gene, the root cause of Sanfilippo subtype A. The French biotech firm, Lysogene has made remarkable progress, and recently received approval from the US FDA to begin a Phase II/III efficacy trial of its customized AAV product “LYS-SAF302” and is seeking the same approval from European regulators.

Dallas-based Abeona Therapeutic has also progressed two gene therapies for Sanfilippo syndrome—ABO102 replaces SGSH gene for Sanfilippo subtype A and ABO101 replaces NAGLU for Sanfilippo subtype B. Phase I/II trials are ongoing for both products. Since the launch of the ABO102 study in 2016, about a dozen patients enrolled at Nationwide Children’s Hospital in Columbus, Ohio, as well as clinical centers in Spain and Australia, have received gene therapy. The trial is still recruiting patients, but an 18-month post-treatment review by independent reviewers showed a strong biomarker response (decreases in heparan sulfate, which Sanfilippo patients cannot degrade properly), in both their urine and cerebral spinal fluid. The gene therapy also reduced large liver buildups, another hallmark of the disease.

Meanwhile, the biotech LA BioMed in California is using the gene editing tool CRISPR/Cas9 to create a cell based treatment for Sanfilippo syndrome. The innovative research is using CRISPR to transform a patient’s own neural stem cells (NSCs) to make the critical enzyme. Implanting these edited cells back into the brain should help restore function. “Using a patient’s own cells and modifying them as needed, drastically reduces concerns about the body having a reaction to the cells, therefore allowing the regenerative cells to remain in the brain and provide benefit indefinitely. This would be an incredible achievement and benefit to the children suffering from MPSIII,” said Cara Parsons O’Neill, Chief Scientific Officer at the Cure Sanfilippo Foundation, which is funding the project.

Looking ahead

For parents like Virginia couple Matt and Shannon O’Neill, who lost their daughter, Waverly to Sanfilippo three years ago and their son Oliver in December, effective treatments did not come soon enough. “How incredible will it be when parents are told their child has Sanfilippo, BUT there is a very successful treatment option available.That makes it all worthwhile,” wrote Shannon on her blog eight years ago