Sanfilippo syndrome is a fatal, childhood, neurodegenerative, disorder—with no approved treatment—that involves neuroinflammation among multiple pathologies. Characterized by childhood onset dementia, Sanfilippo syndrome causes immense suffering in many ways, including pain, loss of speech, extreme agitation and distress, gastrointestinal symptoms, and profound sleep disturbance. Now, a clinical trial collaboration used an innovative approach to treat this disease by targeting neuroinflammation, thought to be a key contributor to disease symptoms.

The team used anakinra, a recombinant interleukin-1 receptor antagonist, in children and young adults with moderate to advanced stages of the condition. Anakinra works by inhibiting interleukin-1 (IL-1), a key mediator of the inflammatory response. By blocking the activity of IL-1, anakinra reduces harmful inflammation in the body and brain. For the first time, this study provides evidence that anakinra can positively impact meaningful disease symptoms in patients with Sanfilippo syndrome.

“The changes we observed in our patients represent significant improvements in the day-to-day lives of individuals with Sanfilippo syndrome and their families,” noted Lynda Polgreen, MD, investigator at the Lundquist Institute and associate professor of pediatrics at the David Geffen School of Medicine at UCLA. “This trial highlights the potential of anakinra as an adjunctive treatment option and underscores the broader importance of targeting downstream effects, such as inflammation, in lysosomal diseases.”

This work is published in Nature Medicine in the paper, “Anakinra for Sanfilippo syndrome: a Phase I/II trial.

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare genetic disorder in which the body cannot break down the complex molecule heparan sulfate. It is one of seven mucopolysaccharidosis disorders that share a deficiency in lysosomal enzymes needed to degrade glycosaminoglycans (GAGs). Accumulation of heparan sulfate in cells triggers several biological consequences, including inflammation, ultimately leading to progressive dementia and body-wide disease.

In the Phase I/II trial, researchers evaluated anakinra’s safety, tolerability, and effects on neurobehavioral, functional, and quality-of-life outcomes in patients with several subtypes of Sanfilippo syndrome. Results showed anakinra was safe and associated with significant improvements in multiple symptom domains. By week 36 of treatment, 94% of participants showed improvement in at least one domain.

More specifically, “Twenty-three participants (6–26 years of age) were enrolled. Twenty continued treatment to week 8, and 15 (75%) required an increased dose at week 8 or week 16. There was an improvement in at least one domain in the multi-domain responder index (MDRI) in 18 of 21 (86%) at week 8 and in 15 of 16 (94%) at week 36. Seven participants withdrew (intolerability of daily injections and lost to follow-up) before week 36.”

Most adverse events were mild, with injection site reactions being the most common and no serious adverse events related to the use of anakinra were reported.

While ongoing clinical trials are searching for a cure for Sanfilippo syndrome, such trials are restricted to specific disease subtypes and include only the youngest of children exhibiting very few symptoms because the disease is considered irreversible. This has left more than 99% of the Sanfilippo population without any opportunity to receive focused treatment. However, the research team’s clinical study was designed to improve the representation of this long-excluded segment of the Sanfilippo community by treating individuals who have already been significantly impacted by their disease.

“This study has made immediate strides toward addressing the need to help all people touched by this condition, regardless of their level of disability,” noted Julie Eisengart, PhD, associate professor of pediatrics and director of the neurodevelopmental program in rare disease at the University of Minnesota Medical School. “This trial shows promise for improving the lived experience of not only the people diagnosed with Sanfilippo syndrome, but also their families who face countless disease-related stressors and heartache.”

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