Sanfilippo Children’s Foundation was proud to be a sponsor of the 3rd International Conference on Sanfilippo Syndrome & Related Diseases organised by our colleagues at the Fondation Sanfilippo Suisse. Bringing researchers together to share their progress is crucial to spark new collaborations and accelerate research, as well as keeping the community informed of progress.
The conference was delivered online on 12th and 13th November 2020 and featured a range of excellent international speakers. The presentations covered early diagnosis of Sanfilippo Syndrome, experimental treatments for Sanfilippo Syndrome that are under investigation in the laboratory, and updates on clinical trials that are underway or planned.
Professor Lucy Raymond from the UK and Dr Francisco del Castillo from Spain told us of the rapid genetic testing protocols being trialled to screen children at birth, or as early as possible in their diagnostic journey following suspicion of a metabolic disorder such as Sanfilippo. The new techniques use whole genome screening or large panels of suspected genes, rather than relying on doctors to gradually narrow down the diagnosis and then request tests for specific gene mutations (often taking several years).
The use of these new techniques in clinical practice may still be some way off, but will become more and more crucial to provide access to clinical trials and enable the earliest possible intervention once effective treatments become available.
New experimental therapies in the laboratory
We heard from Dr Coutinho of Portugal about a new way to deliver a drug to the brain to block the production of glycosaminoglycans, like heparan sulphate, that build up in the brain in some forms of MPS disease.
Dr Coutinho received an incubator grant from the Sanfilippo Children’s Foundation in early 2020. Her early results show the drug is working in cells grown in the laboratory and she is working with collaborators to perfect the delivery method (nano-carrier) to ensure it reaches the brain. She also described her work to obtain stem cells from the baby teeth of children with Sanfilippo which will allow her to grow neurons in the lab to better test the effect of the drug.
Dr Brian Bigger of the UK talked about a new approach to dampen down the damaging inflammation in the brain in Sanfilippo Syndrome. He has shown that heparan sulphate accumulation not only directly damages neurons, but also activates microglia and astrocytes. In a healthy brain these cells provide support to neurons, but when they are activated they can damage the cells around them instead.
He has shown that blocking an inflammatory molecule called IL-1 can reduce this damage in mice with Sanfilippo. Dr Bigger’s findings spurred Cure Sanfilippo Foundation (USA) to develop a clinical trial in collaboration with The Lundquist Institute. The trial is testing an IL-1 blocking drug usually used to treat rheumatoid arthritis, called Anakinra, in children with Sanfilippo. The trial has completed recruitment and will continue to follow the patients for two years.
Dr Anastasia Henry from Denali Therapeutics, described the progress they have made to develop a system to deliver enzymes to the brain. A key problem for enzyme replacement therapies is the blood brain barrier which blocks the movement of most large molecules into the brain. Denali’s system takes advantage of a natural carrier system which can be adapted to transport different enzymes across the blood brain barrier. They have made excellent progress using this system in mice with MPS II (Hunter syndrome) and are now adapting it to transport the SGSH enzyme that is missing in Sanfilippo Type A with encouraging preliminary results in mice.
We heard about the progress of several clinical trials of gene, cell therapy and enzyme replacement clinical trials underway or in the planning phase. Some have shown early signals for safety and efficacy, with the youngest patients treated in some of the trials showing signs of slowing of disease progression. Importantly, several of the clinical trials are also testing and validating new ways of monitoring outcomes in children with Sanfilippo, which will benefit all future clinical trials, making it faster and easier to detect whether a treatment is working and with less invasive tests. This includes video recordings to track development as an alternative to cognitive testing and other tests for hearing loss and sleep.
Lysogene trial of AAV gene therapy for Sanfilippo Type A - In this trial the gene therapy is injected directly into the brain. So far 19 children aged between 10 months and 5 years have been treated in the trial and the children are being followed for cognitive development, behaviour and quality of life. The speaker noted that the trial is currently not recruiting further participants while they investigate an unexpected observation seen in MRI scans of children that was not associated with any clinical symptoms. She also acknowledged the death of one of the patients in the trial, however in keeping with regulatory requirements for all clinical trials, the death is being investigated for any link to the treatment before any further information can be released.
Abeona trial of AAV gene therapy for Sanfilippo types A and B - These two early phase trials, known as Transpher A and B, are investigating the correct dosage of gene therapy which is delivered via an injection into a vein. So far, 17 type A patients have been treated with most receiving the highest dose, and 9 type B patients have been treated. Preliminary data shows sustained reduction in heparan sulphate levels in the cerebrospinal fluid and an early indication that the youngest patients in the trials are following a more normal developmental trajectory. Importantly, there have been very few, and only mild adverse events in relation to the treatment so far.
Gene-modified cell therapy for Sanfilippo Type A - Dr Robert Wynn from Manchester described the work they have been doing to treat patients with some forms of mucopolysaccharidoses using a transplant of blood stem cells. The stem cells are removed from the patient, the gene for the missing enzyme is inserted into the cells using gene therapy and then the cells are transplanted back to the patient. The blood cells are able to travel to the brain and deliver larger amounts of enzyme than unmodified cells can. They have so far performed the transplant in 3 patients with Sanfilippo type A. Early tests indicate that heparan sulphate is reduced in the cerebrospinal fluid. The patients will be followed for 3 years with tests checking for sustained reductions in heparan sulphate in the brain and cognitive development. A trial for Sanfilippo type B is planned to start in 2021.
Tralesinidase-alpha for Sanfilippo Type B - This trial was originally started by BioMarin, with Allievex taking over in 2019. In this treatment the enzyme NAGLU is fused to another molecule to increase its chance of entering neurons. The drug is delivered by injection into the cerebral ventricles. Dr Steve Maricich described the 2 years follow up data that they now have on 13 patients, with the two youngest patients showing relatively normal cognitive development and two patients who were a little older when treated showing stable cognitive function. The data also shows improvements in both hearing and sleep and normalisation of liver size. Dr Maricich noted that a reasonably high number of mild adverse events and some serious adverse events had been identified, with these being generally consistent with the route of delivery and similar to those seen in other trials of enzyme replacement therapies.
Trehalose for all types of Sanfilippo - Dr Raj Mehra, CEO and Founder of Seelos Therapeutics described their experimental work on Trehalose, a small molecule that stimulates a process called autophagy (which literally means ‘self-eating’) that helps to clean up the debris in cells. Trehalose can cross the blood brain barrier and has been shown to be safe in human studies of some types of muscular dystrophy, motor neuron disease and spinal cerebellar ataxia. In these diseases it showed some improvements in strength and swallowing. In mouse studies and in cells from patients with Sanfilippo Syndrome the drug shows encouraging signs of working to clear heparan sulphate accumulation. Seelos Therapeutics are collaborating with Team Sanfilippo Foundation to commence a clinical trial, with the first step being to gather the natural history data that is needed to show whether the trial is working to improve development. They are particularly in need of data from children with Sanfilippo types C and D.
It is important to note that all the information presented here on clinical trials is preliminary and all the follow-up of patients and collection and analysis of data needs to be complete before we will have a full picture of the safety and efficacy of these treatments. More information on all the trials, which trials are recruiting and the eligibility and exclusion criteria can be found on our website here https://www.sanfilippo.org.au/research/therapy-avenues