Stem cell transplantation in a mouse model of Sanfilippo type C

21 Jun 2024

Researchers in Canada and the USA have investigated the effects of stem cell transplantation in a Sanfilippo type C mouse model. The stem cell transplant reduced inflammation in the brain and potentially extended the lifespan of the mice, highlighting the clinical potential of this therapy for Sanfilippo type C, particularly if used with other treatments.

Sanfilippo type C (MPS IIIC) is caused by a deficiency of the HGNSAT enzyme, which helps to break down the complex sugar, heparan sulfate (HS). 

While standard stem cell transplantation (without gene therapy) is used as a treatment for some other forms of MPS disorders, it has not been able to prevent the hallmark neurodegeneration seen in Sanfilippo syndrome. However, in this study, the team, led by Professor Alexey Pshezhetsky at the Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, sought to investigate whether stem cell transplants could address other important aspects of the disease such as inflammation in the brain (neuroinflammation).

To test this, the team gave 2-month-old mice with Sanfilippo type C a course of chemotherapy to remove their own bone marrow stem cells and then gave them a transplant of stem cells from healthy mice that can produce HGSNAT. 

Six weeks post-transplantation, they could see the transplanted cells had successfully repopulated the bone marrow of the Sanfilippo type C mice and led to a full restoration of HGSNAT activity in the bone marrow and spleen of the treated mice. Heparan sulfate (HS) levels in the blood were reduced to 50% of that seen in untreated mice, but there was no change in HS levels in the urine, spleen, lungs, liver, kidney, or brain.

While most cells in the bloodstream cannot access the brain due to the blood-brain barrier, some cells in the immune system (that come from the bone marrow) can cross. The team examined the mice with behavioural tests to see whether the HGSNAT-producing transplanted cells may have entered the brain to reduce neuroinflammation and improve the symptoms of Sanfilippo.

At around 6 months of age (4 months post-transplant) the Sanfilippo type C mice showed increased sociability and reduced hyperactivity. There were some signs that learning ability was also slightly improved. However, no effect was seen on anxiety levels or short-term memory. 

Mice with Sanfilippo type C that received the transplant still displayed enlarged liver, kidneys and spleen, however, the treatment improved urinary retention, a severe life-limiting symptom common in Sanfilippo mouse models but rare in patients. 

When the team looked in the brains of the treated mice, they could see that approximately half of the microglia cell population (cells that respond to damage in the brain and can cause neuroinflammation) was derived from the transplanted stem cells and inflammation was reduced by approximately 50%. They also saw a slight reduction in accumulation of abnormal proteins, or amyloid, in the brain. 

The study shows that while stem cell transplantation may not have profound effects in stopping or reducing neurodegeneration in Sanfilippo type C, it may have potential to reduce neuroinflammation and improve some symptoms. 

Although some treatments are being developed for Sanfilippo type C there are currently no active clinical trials. The team suggests that stem cell transplants could potentially be used in the future to enhance the effectiveness of other types of therapies, such as substrate reduction therapy or chaperone therapy.

Professor Pshezhetsky and his team are currently investigating this possibility in a project co-funded by Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation (USA) to investigate combined stem cell transplantation and cathepsin B inhibitors as a treatment for Sanfilippo.