Melpida: Recombinant Adeno-associated Virus (Serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
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|ClinicalTrials.gov Identifier: NCT05518188|
Recruitment Status : Recruiting
First Posted : August 26, 2022
Last Update Posted : November 29, 2023
|Condition or disease||Intervention/treatment||Phase|
|Spasticity, Muscle Microcephaly Intellectual Deficiency Growth Retardation SPG50 Spastic Paraplegia||Biological: MELPIDA||Phase 1 Phase 2|
MELPIDA is a gene therapy product being developed for the treatment of Spastic Paraplegia Type 50 (SPG50), which is one of a group of four genetic disorders (SPG47, SPG50, SPG51 and SPG52) comprising AP-4 related Spastic Paraplegia (AP4-SPG). Inherited in an autosomal recessive pattern, AP-4- SPG is caused by biallelic pathogenic variants in one of 4 genes that encode components of the heterotrimeric adaptor protein complex 4 (AP4). Mutations in any of the components result in disrupted AP-4 function, and result in a common, shared clinical phenotype. Adaptor protein complexes such as AP-4 play key roles in signal-mediated trafficking of integral membrane proteins. They mediate vesicle formation and the cargo contained within these vesicles. While the precise function of the AP-4 complex is not fully understood, recent data suggests it plays an important role in protein sorting through the golgi, including regulation of trafficking of components required for autophagy. Deficiency in AP-4 leads to progressive neurodegeneration.
AP-4-HSP is an ultra-rare autosomal recessive disease with ~156 patients identified worldwide, 59 of which have the SPG50 subtype. There are approximately 9 patients with SPG50 in North America (OMIM #612936), ClinicalTrials.gov Identifier: NCT04712812. SPG50 is caused by biallelic pathogenic variants in the AP4M1 gene.
The AP4-deficiency syndrome (AP-4-HSP) is characterized by progressive spasticity, microcephaly, intellectual deficiency, dysmorphic traits, and growth retardation. Symptoms of AP-4-HSP begin in infancy, though patients are often not correctly identified and diagnosed until age 5 to 10 years. Patients experience progressive spastic paraplegia in the first decade of life, resulting in quadriplegia by adolescence or early adulthood with associated wheelchair dependence. There is also the presence of severe, progressive cognitive impairment. Epilepsy is an important co-morbidity present in the majority of cases. Only a few affected individuals have been identified to survive beyond age 30 year, though the extent of early mortality is yet to be fully elucidated.
Based on an AP-4-HSP natural history study currently in progress at Boston Children's Hospital (BCH), it is evident that disease severity ranges from child to child, but that most children fall into the severely affected (i.e. severe spasticity with paralysis and severe cognitive impairment) category. A small proportion of children, considered least severe, are able to speak in short sentences, walk with an abnormal gait, and have few to no seizures early on in the disease (less than 10 years of age). However, most children in this less severe category still experience progressive decline, ultimately losing the ability to walk and becoming quadriplegic between the ages of 10 and 20 years.
The majority of children with the SPG50 subtype of AP-4-HSP conform to a severe presentation, and are completely non-verbal, have microcephaly, never walk, have epilepsy and are severely cognitively impaired by the age of 10. It is not known how patients are affected later in life as very few have been identified beyond the age of 30. SPG50 is thus a degenerative neurological disease, affecting both cognitive and motor capabilities. Importantly, there is significant care giver burden, as all patients eventually require complete support for all activities of daily living from family and/or caregivers. There are no treatments currently available for patients with SPG50.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||2 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1/2 Open-label Intrathecal Administration of MELPIDA to Determine Its Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by Mutation in the AP4M1 Gene.|
|Actual Study Start Date :||February 15, 2023|
|Estimated Primary Completion Date :||October 1, 2028|
|Estimated Study Completion Date :||October 1, 2030|
Experimental: Treatment Arm
MELPIDA, a gene therapy product
MELPIDA, a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene
- Incidence of unanticipated treatment-related toxicities, Grade 3 or higher in participants with SPG50 [ Time Frame: 60 months ]Incidence of unanticipated treatment-related toxicities, Grade 3 or higher, in participants with SPG50 will be determined from the collection of occurrence and severity of serious adverse events (SAEs). Adverse events will be determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
- Stability or improvement in spasticity in participants with SPG50 as measured by the Modified Ashworth scale (MAS) [ Time Frame: 60 months ]Stability or improvement in spasticity in participants with SPG50 is measured by the Modified Ashworth scale (MAS) which is a muscle tone assessment scale used to assess the resistance experienced during passive range of motion. Possible scores range from 0-4 where lower scores indicate better outcome.
- Stability or improvement in spasticity in participants with SPG50 as measured by the Tardieu scale [ Time Frame: 60 months ]Stability or improvement in spasticity in participants with SPG50 is measured by the Tardieu scale which quantifies muscle spasticity by assessing the response of the muscle to stretch applied at specified velocities. Possible scores range from 0-5 where lower scores indicate better outcome.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05518188
|Contact: Sydney Cooper, MSc||214-250-0174||Sydney.Cooper@UTSouthwestern.edu|
|United States, Texas|
|Children's Medical Center Dallas||Recruiting|
|Dallas, Texas, United States, 75235|
|Contact: SUSAN IANNACCONE, MD 214-456-5220 SUSAN.IANNACCONE@UTSouthwestern.edu|
|Principal Investigator:||Susan T. Iannaccone, MD, FAAN||UT Southwestern Medical Center|