What Therapies Are Available For Children with Sanfilippo Syndrome?

Is there finally a cure?

Sanfilippo is a type of Mucopolysaccharidosis (or MPS), a group of neurodegenerative disorders (which includes types 1 through 4), which all have their own corresponding syndromes. Sanfilippo is MPS type 3, and is commonly referred to as “childhood dementia” because oof similarities in neurobiological processes and behavioral presentation. SF itself has 5 subtypes A through E, with A being most quick yo progress and E being least progressive. The degeneration of cells actually begins in utero but is not generally noticeable until around 2 for SF types A and B, and later for C-E. The understanding is that the enzymes in Type A and B lead to more rapid and severe neuroinflammation, thus increasing rate of cognitive and physical decline. As a result, the lifespan generally ranges from teen years (A) through 60s (E), with an average lifespan in the 20’s. SF is autosomal-recessively inherited occurs in between 1 and 4 out of 100,000 children. The symptoms can include: seizures, insomnia, gait abnormalities, vision/hearing impairments, hyperactivity, aggression/agitation, enlarged liver and spleen, joint stiffness, difficulty swallowing, excessive hair growth, and loss of language. In later stages of the disease, sleep disturbances and feeding challenges are most prominent health-wise. Because of the variable presentation and neurodegenerative nature of sanfilippo, it is often misdiagnosed in the first few years if life as ADHD, autism, or intellectual delay. During childhood, many children require behavior therapy, durable medical equipment, AAC devices, speech/language therapy, cognitive rehabilitation, physical therapy, occupational therapy, feeding therapy, and much more, not to mention mental health and respite care for parents/caregivers. This tragic disease not only affect the children and their quality of life, but not surprisingly, it greatly impacts the quality of life of the child’s parents and extended family.

All 5 types of sanfilippo result in the accumulation of heparin sulfate (HS) in the cells, which is a polysaccharide (sugar/carb), but each subtype lacks a different specific enzyme (depends on which chromosome is altered) to required to break down heparin sulfate, resulting in accumulation in all essentially all organs of the body. So how exactly does this happen?There is dysfunction within the lysosomes, which are organelles within cells that maintain cellular homeostasis and break down proteins/lipids/carbs via its acidic PH level. When a cell is “healthy”, heparin sulfate is continuously broken down and recycled by the lysosomes and then removed from the cell. In the cells in someone with sanfilippo, this recycling does not occur, and thus the HS builds up more and more over time, leading to more significant atrophy and brain dysfunction. As a result, the lysosome PH becomes higher than normal (that is, more alkaline instead of acidic) resulting in “dysfunctional mitochondria” and cell death, in addition to releasing and accumulating “bad” proteins, which form amyloid plaques and tau tangles (similar to many dementia processes). Ultimately, within the brain, there is myelin loss, which results in a slower rate of communication between neurons, and persistent neuroinflammation via toxicity of the immune cells, resulting in a neurodegenerative process disrupting homeostasis in the brain. One of the important things to note here, is that the mechanisms that result in sanfilippo (neuroinflammation, presence of toxic proteins) are not unique to sanfilippo or even other MPS disorders, thus the research coming from sanfilppo may have substantial positive effects of developing treatments and cures for other disorders, further elucidating its value and urgency.

So let’s talk treatment. Historically, there have been 4 main approaches to treating sanfillipo: gene therapy, enzyme replacement therapy, substrate reduction therapy, and stem cell treatment. Past clinical trials have included stem cell transplantation (from bone marrow and umbilical cord blood of healthy donors, which unfortunately was not successful), substrate reduction therapy (intended to reduce the synthesis of GAGs since they cannot be degraded, not successful), enzyme replacement (hijacking proteins that can then cross the BBB, provide correct form of mutated protein, minimally effective), and gene therapy (provide cells with correct form of mutated gene, very successful). So, for today’s episode I will be focusing most on gene therapy for sanfilippo types A and B, as this is where the most promising research has been observed. Positive evidence have been observed across animal models (including mice, dogs, and monkeys) and human clinical trials by transferring unaffected genes via an adeno-associated virus. Gene therapy can provide constant production of the deficient enzyme and cells can “cross-correct”, it is the most promising because only 5-15% of enzyme activity is required to maintain a healthy condition in affected patients.

I should mention that, although not a cure, in 2024, there was a clinical trial with the drug Anakinra, used to address the neuroinflammation in the brains of children with sanfilippo, as it was able to cross the BBB, with moderate success and a good safety profile, though not as effective as gene therapy. This may be helpful for those who do not have access to gene therapy or who have advanced disease. Of note, while promising, this treatment required two injections per day, which can be quite challenging for children with sanfilippo especially. There is now a new potential off-label medication, similar to Anakinra, called Rilonacept, which functions similarly by reducing systemic inflammation, but only requires one injection per week.

Clinical trials for sanfilippo have historically been challenging, secondary to extensive inclusion and exclusion criteria, small samples, and lack of control groups. There have been 4 recent clinical trials that have produced promising results, three for sanfilippo A, and one for sanfilippo B. But, in 2016, a clinical trial for SFA, demonstrated that a biologic drug, now, called UX111, that uses a virus to cross the BBB through intravenous administration, was able to deliver a functional copy of the SGSH gene (missing in those with sanfilippo) to the brain. The gene therapy demonstrated reduction in disease biomarkers (reduced GAGs, HS, liver volume, and increased brain volume) secondary to treatment. It also revealed a dose-dependent reduction of HS with normal development. The rare disease-specific small pharma company Ultragenyx took over in 2023 and current trials have revealed that administration of UX111 for SFA resulted in children continuing to develop typically for up to 2 years after treatment. Because of the time sensitivity and dire need, these trials have been accelerated via regenerative medicine advanced therapy, fast track, rare pediatric disease, and orphan drug designations in the US and PRIME and orphan drug designations in the EU. Additionally, significant improvements were observed in cognitive, adaptive, and language skills, as assessed by performance on Bayley-3 and Vineland-2, in addition to sleep and quality of life questionnaires. Not surprisingly, the younger the child was at the time of administration, the more dramatic and rapid the effect on cognitive and physical function, with progress demonstrated on psychological assessment and medical testing. UX111 has produced a clear increase in enzyme activity combined with a reduction in GAG storage and reduction in neuroinflammation, resulting in improve cognitive function and increased lifespan.

Despite these incredibly promising results, in July of 2025, Ultragenyx received a complete response letter from the FDA for UX111 which cited specific chemistry, manufacturing, and controls (CMC) related observations that were “not directly related to the quality of the product and “resolvable”, which has delayed potential approval to 2026, and at the same time FDA clinical reviews acknowledged that “robust and biomarker data are supportive.” In response, the CEO of ultragenyx stated they are attempting to resolve CMC observations immediately. As such, in January of 2026, Ultragenyx resubmitted its biologics license application for UX111, expecting a 6-month review period per FDA guidelines. In the meantime, in February of 2026, new longer-term clinical data demonstrated positive brain biochemical and clinical effect for as long as 8.5 years, which provided support to the FDA for accelerated approval. The CEO of ultragenyx expressed sadness and frustration as families had to watch helplessly and their children lose further abilities and demanded immediate access to treatment. The reason underlying the desperation from these families is time- in an effort to preserve any and all remaining skills and independence to extend quality of life for as long as possible. Even for those who are in middle or advanced stages of the disease, preserving ability to walk or swallow changes level of care and quality of life for parents and children drastically. UX111 has been able to significantly reduce HS levels in as little as one month. A single dose of UX111 can stablize HS in the cells for over 8 years.

Also in February of 2026, perhaps in response to advocates lobbying at the capitol in recent months due to lack of transparency and frustration with delays and red tape, the FDA announced draft guidance for sponsors seeking approval for targeted individualized therapies (including gene editing) by generating substantial evidence of effectiveness and safety when randomized control trials and not feasible in an attempt to “cut unnecessary red tape… and clear a path for breakthrough treatments to reach the patients who need them most”, per RFK Jr. Additionally, FDA commissioner Dr. Marty Makary stated “it is our priority to remove barriers and exercise regulatory flexibility to encourage scientific advances and deliver more cures and meaningful treatments for patient’s suffering from rare diseases.” Dr. Vinay Prasad, the Chief Medical and Science Officer for the Center for Biologics Evaluation stated: “after 25 years the FDA has…outlined a framework to facilitate these approvals. The plausible mechanism framework (reference to what is required to green light experimental therapies) is a revolutionary advance in regulatory science.” This has been a welcomed change, especially for those rare diseases that do not fit nicely into big Pharma’s business model or standard drug approval processes. In fact, the FDA is dropping the two-study requirement and now offering bonus payments to the who complete speedy drug review. Traditionally, drug companies often have little incentive to invest millions for clinical trials and wait for FDA approval so this would offer a fast track to commercializing life-saving drugs. In April of 2026, the FDA announced the acceptance of BLA resubmission (application) for UX111, stated they will review and make a decision by 9/19/26.

So aside from highlighting the need to propel the review and approval of gene therapy for sanfilippo, there are many other avenues of support for children with rare diseases that can be addressed. It can be difficult for families because there is limited expertise on sanfilippo amongst clinicians, even amongst neurologists and geneticists. There is only one MPS research center in the US (Dr Jospeh Muenzer MPS Research and Treatment Center at UNC), that has private funding to offer diagnosis and services for lower-income patients but this is the only place of its kind. Now that we have potentially life-saving treatments, there is a strong need and push for early identification and proper diagnosis, as timing is everything with sanfilippo, can save family tons of money aside from heartbreak. As of present, standard newborn screenings do not test for sanfilippo, though moving towards it in USA and Taiwan. Newborn screening is also variable from state to state depending on what additional rare disorders they choose to include, right now is it not included in any states generally, largely because of history of ineffective treatments, but there is a pilot program in NYS that will hopefully result in additional states including sanfilippo. It is also not regularly screened for via prenatal genetic counseling, which can also be life changing for those who have a child with sanfilippo and are hesitant to have more children. Newborn screening also has the potential to identify biomarkers (via blood and urine) that will potentially inform progression and other factors about the unique presentation within a child, also helps to gain approval for clinical trials and meds/treatment. Researchers are also actively attempting to identify biomarkers, in order to diagnose and treat earlier. For example,Neurofilament light chain (NfL) is a promising blood and cerebrospinal fluid biomarker for Sanfilippo syndrome. Studies, show that NfL levels are elevated in patients due to neurodegeneration and can decrease following effective therapeutic intervention, serving as a marker for drug efficacy, generally via blood test to improve cost and accessibility.

Despite these advances, it is not always easy for patients to access genetic testing, challenging to access treatments and therapies (financially, geographically, etc.). In terms of the gene therapy itself, although it is clear that gene therapies may offer significant health gains, they often come at a substantial cost. Because of this, many may continue to receive ERT or anti-inflammatory treatments, even though gene therapy is available, because of cost. However the argument is that as expensive as gene therapy might be, it actually may cost less than years of therapies, treatment, medical equipment etc. Thus, it is important to inform employers about the importance of newborn screening for proactive care. Insurance companies may also use prior authorization to flag need for care management for complex cases, which can help with approval processes, obtaining coverage, and identifying community resources, as well as streamlining acceptance of medicaid across state lines and/or access to Telehealth services, when appropriate. We need to ensure coverage and approval for medical equipment and wraparound services. For smaller employers and medicaid programs, the upfront cost (millions) is harder to be absorbed but some employer groups can use stop-loss insurance or reinsurance in order to absorb costs and assist with risk management. Another option may be  value-based agreements (reimbursement agreements between health care payers and manufacturers linked to clinical outcomes) for specialized therapies, esp those that may not have FDA approval yet. We need to allow benefit customization to meet the unique needs of rare disease patients. Those invested in a cure for these families may lobby for legislation to accelerate approval for trials and access to newly available treatments.