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The purpose of this study is to evaluate the safety and efficacy of MVX-220 gene therapy in children and adults with Angelman syndrome with UBE3A gene deletion, uniparental disomy, or imprinting center defect genotypes.
MVX-220 is an investigational gene replacement therapy intended to provide a functional copy of the UBE3A gene to individuals with Angelman syndrome. This study is designed to evaluate the safety, tolerability and efficacy of MVX-220 in participants with Angelman syndrome who have deletion, uniparental disomy, or imprinting center disorder genotypes. The study has 2 primary cohorts: Cohort 1 that includes adults followed by Cohort 2 that includes children. All patients will receive a single dose of MVX-220 administered by injection into the cisterna magna. There is no control group and all individuals will receive the gene therapy. An independent data safety monitoring board will review the safety information from Cohort 1 before individuals can be enrolled in Cohort 2. An optional cohort of adults and/or children (Cohort 3) may be enrolled based on a review of data from Cohorts 1 and 2. All patients will be required to take steroids before and for a brief period during the study to help mitigate the risk of immune response to the gene therapy. Patients will be followed for safety and efficacy for an initial 2-year period post-treatment and then transition to less frequent monitoring schedule for an additional 3 years. The total duration of follow up in the study is 5 years.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1: Adults ages 18-50 | Experimental | MVX-220, single dose intra cisterna magna injection |
|
| Cohort 2: Children ages 4-8 | Experimental | MVX-220, single dose intra cisterna magna injection |
|
| Cohort 3: Optional cohort, adults and children ages 4-50 | Experimental | MVX-220, single dose intra cisterna magna injection |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MVX-220 | Genetic | AAVhu68 viral vector |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest as assessed through clinical safety, laboratory tests, ECG, vital sign measurements, and physical examinations | Up to Week 104 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in communication ability as assessed by the Observer Reported Communication Ability (ORCA) measure | The ORCA measure is a caregiver reporter assessment of communication ability that was developed specifically for Angelman syndrome. The ORCA measure produces a single score that is an estimate of an individual's overall level of communication ability, with higher T-scores reflecting greater communication ability. |
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Key Inclusion Criteria:
The participant's parent/legal guardian must provide written informed consent.
Symptoms consistent with AS and documented genetic confirmation of one of the following genotypes resulting in a diagnosis of AS:
The participant must be 18 to 50 years of age, inclusive (for adult participants), or 4 to 8 years of age, inclusive (for pediatric participants), at Screening.
The participant must have the ability to ambulate independently.
The participant must be on stable antiepileptic medications (with no changes within 1 month prior to the Screening visit, except for weight associated dose adjustments).
Key Exclusion Criteria:
Clinically significant medical finding other than AS, that, in the judgment of the Investigator would make the participant unsuitable for participation.
Laboratory abnormalities including but not limited to:
Any known history and/or family history of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) or multisystem inflammatory syndrome (MIS).
Any known history and/or family history of disordered complement function and/or complement gene mutation(s).
History of systemic lupus erythematous, Still's disease, rheumatoid arthritis, and/or other severe autoimmune conditions per judgment of the Investigator.
Any known history of thrombotic microangiopathy (TMA)/microangiopathic hemolytic anemia, or hypercoagulable conditions including, but not limited to, disseminated intravascular coagulation (DIC), deep venous thrombosis, and pulmonary embolism.
Current therapy with high dose immunosuppressants.
Prior or current treatment with an investigational drug within 6 months or 5-half-lives of the hospital admission whichever is longer.
Prior treatment with an antisense oligonucleotide within 1 year of hospital admission.
A history of gene therapy administration.
Any contraindication to ICM administration procedure, including contraindications to imaging, contrast use, anesthesia, or any condition that would increase the risk of adverse outcomes from the ICM procedure.
Any contraindication to glucocorticoid use
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cedars-Sinai Medical Center | Los Angeles | California | 90048 | United States | ||
| Rush University Medical Center |
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| ID | Term |
|---|---|
| D017204 | Angelman Syndrome |
| ID | Term |
|---|---|
| D009069 | Movement Disorders |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D000015 | Abnormalities, Multiple |
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| From Baseline to Week 104 |
| Change in developmental milestones as assessed by the Bayley Scale of Infant and Toddler Development, Fourth Edition (Bayley-4) | The Bayley-4 is a performance-based assessment of developmental functioning across communication, cognition, and motor skills. The total raw score reflects the sum of all the item scores within a subdomain, with higher scores reflecting greater ability. | From Baseline to Week 104 |
| Change in adaptive behaviors as assessed by Vineland Adaptive Behavior Scale (VABS-3) | The VABS-3 assesses adaptive behaviors across multiple domains through a clinician-directed interview of a caregiver of an individual with AS. The total raw score reflects the sum of all the item scores within a subdomain, with higher scores reflecting greater ability. | From Baseline to Week 104 |
| Change in Symptoms by the Angelman Severity Assessment (ASA) | The ASA is a clinician-reported outcome measure for Angelman syndrome. The clinicians rate their overall impression of the improvement in disease-related symptoms utilizing a 7-point scale, ranging from "very much improved" to "very much worse". | From Baseline to Week 104 |
| Change in behaviors as assessed by the Aberrant Behavior Checklist-Community (ABC-C) | The ABC-C is a caregiver-rated questionnaire that evaluates key domains in behavior. Items are assessed on a 4 point scale ranging from "not at all a problem" to "the behavior is a severe problem". | From Baseline to Week 104 |
| Change in ambulatory ability as assessed by the wearable device (Syde®) | The Syde is a wearable device that collects continuous data on the ambulatory ability of participants with AS. | From Baseline to Week 104 |
| Change in sleep parameters as assessed by a sleep diary | The sleep diary is a caregiver-reported measure of sleep in individuals with AS. | From Baseline to Week 104 |
| Change in health-related quality of life as assessed by Quality of Life Inventory-Disability (QI-Disability) | The QI-Disability is a caregiver-reported outcome assessment of the health-related quality of life for children and adolescents with intellectual disabilities. Item are rated on a 5-point scale, ranging from "never" to "always ". | Baseline to Week 104 |
| Change in viral deoxyribonucleic acid (vDNA) levels in CSF and blood | Baseline to Week 104 |
| Change in viral DNA levels in urine and feces | From Baseline to Week 104 |
| Change in relevant Electroencephalogram (EEG) parameters (delta power, epileptiform activity) | From Baselien through Week 104 |
| Chicago |
| Illinois |
| 60612 |
| United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |
| D000096803 | Imprinting Disorders |