Study of Cannabidiol in Sanfilippo Syndrome

Sanfilippo syndrome, or Mucopolysaccharidosis type III (MPS III), is a rare genetic lysosomal storage disease characterized by the accumulation of heparan sulfate due to insufficient production of lysosomal enzymes. Consequently, a buildup of heparan sulfate causes progressive neurodegeneration, leading to significant neurobehavioral problems. These neurobehavioral symptoms are highly disruptive and distressing to families, have a significant impact on the quality of life of the patients and their families, and likely interfere with adjunctive therapeutic attempts at supporting the child. To date, there are no approved therapies for the treatment of the neurobehavioral symptoms of Sanfilippo syndrome. Cannabidiol (CBD), a compound derived from the cannabis plant but without the psychoactive effects, has been shown to be safe and effective in the treatment of children with severe epilepsy disorders. Studies have shown that CBD improves behavior in children with autism. This study will use Epidiolex, a pharmaceutical-grade purified oral solution of cannabidiol that was approved by the FDA for the treatment of severe pediatric epilepsy disorders. Study subjects will include approximately 35 participants with Sanfilippo syndrome. Participants will undergo baseline clinical evaluations, and neurobehavioral, and functional outcomes will be collected from parent-reported questionnaires. Participants will then receive either Epidiolex or placebo for 16 weeks. Following this period and an 8-week washout, participants will cross over and receive the opposite treatment for 16 weeks. Safety labs and questionnaires will be collected throughout these periods to assess safety and efficacy. Participants and study personnel will be blinded to the treatment status of each participant. When this blinded portion of the trial is completed, all participants will receive Epidiolex open-label for 52 weeks to measure long-term safety. The type and severity of adverse events will be collected to measure safety, and different behavioral and functional outcomes will be collected to measure efficacy.

Inclusion criteria

• MPS III diagnosis confirmed by genetic testing
• ≥ 4 years of age
• Patient or parent/legal guardian is able and willing to provide informed consent. For patients 7 to 16 years of age, assent must also be provided when cognitively possible.
• If taking any of the following, no dose changes for the last 8 weeks:

• Anakinra
• Fluoxetine
• Probiotic supplement
• One of the following criteria are met:

• Previous participation in a gene/cell therapy or enzyme restorative clinical trial.
• Previously ineligible to participate in a gene/cell therapy or enzyme restorative clinical trial due to advanced disease state.
• Functional age, as measured by the Vineland, is ≤ 0.5 chronological age

Exclusion criteria

Equitable selection will be used when choosing participants. An individual who meets any of the following criteria will be excluded from participation in this study:

• Mutation known to cause slowly progressive disease
• Taken any form of cannabis, including cannabidiol, in the last 8 weeks
• Currently enrolled in another ongoing clinical trial
• Concomitant use of any of the following therapies:

• Rifampin
• Diazepam (except for intermittent use as needed for treatment of a prolonged seizure episode)
• Clobazam
• Stiripentol
• Everolimus, sirolimus, tacrolimus
• Digoxin
• Valproate
• Recreational or medical Tetrahydrocannabinol (THC) or synthetic cannabinoid medications (including Sativex) within the last three months
• Felbamate (if taking for less than one year)
• Non-pharmacological therapies (e.g. ketogenic diet) must be stable for up to four weeks prior to enrollment
• Clinical evidence of liver disease or liver injury as indicated by the presence of abnormal tests (AST or ALT > 2 x ULN; Bilirubin > 2 x ULN)
• Known hypersensitivity to any components of Epidiolex (cannabidiol)
• Pregnant or lactating women
• Any other social or medical condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated or be detrimental to the study