Sanfilippo syndrome is a genetic condition that leads to the build-up of heparan sulfate and other toxic molecules in the body. This has severe consequences throughout the whole body and especially in the brain. The damage caused in the brain leads to symptoms of developmental day, hyperactivity and other behavioural symptoms, and dementia.
There are currently no approved treatment options for Sanfilippo. Several therapeutic avenues are being explored, including gene therapy and enzyme replacement therapy, to restore the enzyme that is absent in Sanfilippo. However, other avenues aim to tackle and slow down some of the other damaging processes that occur in the disease, such as inflammation in the brain, or neuroinflammation.
What is neuroinflammation and how is it involved in Sanfilippo?
Neuroinflammation is inflammation that affects the brain or spinal cord. Researchers looking at Sanfilippo and other neurodegenerative diseases, like Alzheimer’s disease and multiple sclerosis, are finding mounting evidence that neuroinflammation contributes to neurodegeneration.
The exact mechanisms leading to neuroinflammation in Sanfilippo are still being investigated, as are the impacts of inflammation on the brain. Although various cell processes and molecules have been implicated, it is thought that the build-up of heparan sulfate and other secondary storage molecules may be directly involved in creating neuroinflammation. The build-up of these molecules may promote pro-inflammatory signals in two specific types of brain cells: the microglia and astrocytes. Microglia and astrocytes belong to a larger class of brain cells called glial cells, or glia, which provide vital support to neurons.
What are the benefits of targeting neuroinflammation?
By targeting the pro-inflammatory molecules produced by microglia and astrocytes, it may be possible to slow down neurodegeneration in Sanfilippo and improve the neurological symptoms of the disease.
There are four subtypes of Sanfilippo, and often other approaches, like gene therapy, focus only on one subtype. However, a drug that successfully reduces neuroinflammation in Sanfilippo could be used by all Sanfilippo patients. It might also be used for other neurodegenerative diseases, including other childhood dementias and adult-onset dementias.
Anti-inflammatory drugs are usually small molecules, meaning they can be synthesised more cheaply than other complex therapies like gene therapy and enzyme replacement therapy. Also, small-molecule drugs can be modified to improve their ability to reach the brain or to be taken orally.
There are examples of anti-inflammatory drugs that are being developed, trialled and approved for other diseases. General anti-inflammatory drugs may have benefits in the brain and spinal cord, and some multiple sclerosis drugs may also influence glial cells. Therapies targeting neuroinflammation are also being investigated in other dementias like Alzheimer’s, and the anti-inflammatory drug Anakinra (see below) has been shown to improve neurological symptoms in patients with an inflammatory disease called Cryopyrin-Associated Periodic Syndromes (CAPS).
What are the challenges of targeting neuroinflammation?
The main drawback of anti-inflammatory drugs is that they do not target the cause of Sanfilippo; that is, the changes in the gene, or the non-functional enzyme, which leads to the build-up of heparan sulfate. Because of this, it may be best used in addition to other approaches that do target the root cause of the disease, such as gene therapy. Combining another therapy with anti-inflammatory drugs may produce even better treatment outcomes than using either treatment alone.
Potential anti-inflammatory drugs for Sanfilippo would need to be taken long-term and are not a single-dose treatment. Because of this, any anti-inflammatory drug candidates must be carefully tested to make sure they don’t cause toxicity and adverse side effects in the patient. Other potential therapies, like enzyme replacement, pharmacological chaperone or substrate reduction therapies, would also require regular administration.
If researchers identified a potential anti-neuroinflammatory drug for Sanfilippo, preclinical studies in animals would be required before a clinical trial can take place. How long these studies might take would depend on many factors, such as whether the drug is completely new, or whether it is an existing drug that has already been tested in animals or humans.
What is the state of play for research into anti-inflammatory therapies for Sanfilippo?
A trial of an anti-inflammatory drug called Anakinra is currently underway in children with Sanfilippo. The Anakinra clinical trial has been active since December 2019 but is not currently recruiting new participants. It is sponsored by Cure Sanfilippo Foundation, The Lundquist Institute (formerly LABiomed), and Sobi (Swedish Orphan Biovitrium AB). Anakinra, also known as Kineret, is an FDA (USA) and TGA (Australia) approved drug that has been used to treat several diseases, including a CNS autoinflammatory disease that occurs in children. The drug blocks inflammation caused by the molecule interleukin-1, or IL-1, which has been shown in mice with Sanfilippo to fuel inflammation, behavioural symptoms, and cognitive decline.
Other approaches to targetting inflammation and neuroinflammation in other MPS conditions similar to Sanfilippo have also been tried or are being investigated. Further research is needed to understand neuroinflammation in Sanfilippo and identify other anti-neuroinflammatory drug candidates. Some examples of research funded by Sanfilippo Children’s Foundation in this area include:
In 2019, Professor Kim Hemsley (Flinders University) and Dr Marten Snel (South Australian Health and Medical Research Institute) received a Translational grant from the Sanfilippo Children’s Foundation to test the effectiveness of drugs that target the immune system in mice with Sanfilippo type A.
Professor Kim Hemsley, with collaborators Dr Louise O’Keefe (The University of Adelaide) and Professor Vito Ferro (The University of Queensland), received an Incubator grant awarded in 2020 to investigate the potential link between purine molecules and neuroinflammation in Sanfilippo. They are using a drug that can modify purinergic signalling to see if it improves disease symptoms.
In May 2019, clinical researcher Dr Nick Smith received funding from the Sanfilippo Children’s Foundation to investigate another key inflammatory pathway. The team will suppress an inflammatory molecule in Sanfilippo type A mice to see the effect on genes, neuroinflammation, and the structure of brain cells.
- Treatments targeting neuroinflammation are a potential therapeutic avenue for Sanfilippo.
- For Sanfilippo, anti-neuroinflammatory drugs aim to suppress inflammation that contributes to neurodegeneration, to hopefully reduce disease symptoms.
- Anti-neuroinflammatory drugs do not address the underlying cause of Sanfilippo, but could potentially slow disease progression.
- There are anti-neuroinflammatory therapies currently under investigation for Sanfilippo in Australia and around the world, including the Anakinra clinical trial.
More information on different therapy avenues currently in, or close to, a clinical trial can be found on our website: https://www.sanfilippo.org.au/research/therapy-avenues