As a neurodegenerative disease characterized by childhood dementia, Sanfilippo syndrome causes enormous suffering in many ways, including pain, loss of speech, extreme agitation and anxiety, gastrointestinal symptoms, and profound sleep disturbance. Without an approved treatment, clinicians have had few options to help alleviate this pain until now. A groundbreaking clinical trial collaboration between study leader and principal investigator Lynda Polgreen, MD, MS, researcher at The Lundquist Institute for Biomedical Innovation at Harbor-UCLA (TLI) and Associate Professor of Pediatrics at the David Geffen School of Medicine at UCLA and Cure Sanfilippo Foundation Scientific Director and co-investigator, Cara O’Neill, MD, FAAP, used an innovative approach to treat this disease by targeting neuroinflammation, which is thought to be a key contributor to the disease’s symptoms.
The team of Dr. Polgreen used anakinra, a recombinant interleukin-1 receptor antagonist, in children and young adults with moderate to advanced stages of the disease, meaning everyone was experiencing debilitating, life-limiting symptoms at the time of study enrollment. While ongoing clinical trials are looking for a cure for Sanfilippo syndrome, such trials are limited to specific disease subtypes and include only the youngest children who show very few symptoms because the disease is considered irreversible. This has left over 99% of Sanfilippo’s population without any opportunity to receive targeted treatment. However, the research team’s groundbreaking clinical study was designed to improve representation of this long-excluded segment of the Sanfilippo community by treating people already significantly affected by their disease.
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is considered an orphan disease, which ranks it for special reasons in drug development and policy. It is a rare genetic disorder in which the body is unable to break down the complex molecule heparan sulfate. The accumulation of heparan sulfate in cells then triggers various biological consequences, including inflammation, ultimately leading to progressive dementia and disease throughout the body. Anakinra works by inhibiting interleukin-1 (IL-1), a key mediator of the inflammatory response. By inhibiting 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 affect important disease symptoms in patients with Sanfilippo syndrome.
In the phase 1/2 trial, investigators evaluated the safety, tolerability, and effects of anakinra on neurobehavioral, functional, and quality-of-life outcomes in patients with various subtypes of Sanfilippo syndrome. Results showed that anakinra was safe and associated with significant improvements in multiple symptom domains. At week 36 of treatment, 94% of participants showed improvement in at least one area. Most side effects were mild, with injection site reactions being the most common. Importantly, no serious adverse events associated with the use of anakinra were reported, underscoring its safety profile.
Dr. Lynda Polgreen, the study’s principal investigator, expressed optimism about the results, “The changes we observed in our patients represent significant improvements in the daily lives of people with Sanfilippo syndrome and their families. This trial highlights the potential of anakinra as an adjunctive option therapy and highlights the broader importance of targeting downstream effectors, such as inflammation, in lysosomal diseases.”
“Together with Dr. Polgreen, we recognized the opportunity to translate existing preclinical proof of concept research into a drug repurposing trial that had the potential to directly benefit children. The Cure Sanfilippo Foundation is proud to have partnered with and supported this highly specialized and compassionate research team led by Dr. Polgreen (TLI), including Dr. Eisengart (University of Minnesota), for addressing the urgent needs of the patient community with Sobi, who generously provided the study drug. This close collaboration and integration of patient/caregiver perspectives facilitated the use of novel outcome tools and patient-centered study design that will inform future drug development in this extremely rare disease,” reflected Dr.
“The funding provided by the Cure Sanfilippo Foundation to support all clinical trial activities and patient travel is made possible by generous donors and families who support the Foundation’s mission, creating new opportunities to transform lives. We look forward to working with Lundquist Institute to advance additional clinical programs,” said Cure Sanfilippo Foundation president and co-founder Glenn O’Neill.
This study has taken immediate steps towards addressing the need to help all people affected by this condition, regardless of their level of disability. This trial shows promise for improving the lived experience not only of people diagnosed with Sanfilippo syndrome, but also of their families dealing with the myriad stressors associated with heart disease and pain.”
Julie Eisengart, Ph.D., Associate Professor of Pediatrics and Director of the Neurodevelopmental Program in Rare Diseases at the University of Minnesota Medical School
This study supports the potential of anakinra as a treatment option for Sanfilippo syndrome. It opens the door to its application in other MPS and similar neurodegenerative disorders characterized by neuroinflammation. With these encouraging results, further research is vital to explore anakinra’s full potential in changing the trajectory of Sanfilippo syndrome and providing hope to affected families worldwide.
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Journal Reference:
Polgreen, LE, et al. (2024). Anakinra in Sanfilippo syndrome: a phase 1/2 trial. Nature Medicine1–7. doi.org/10.1038/s41591-024-03079-3.
