Re-administration of Intramuscular AAV9 in Patients With Late-Onset Pompe Disease
Condition: Pompe Disease
MeSH terms: Glycogen Storage Disease Type II
Study type: Interventional
Phase: Phase 1

Summary: 
      A recombinant AAV vector has been generated to carry the codon-optimized acid
      alpha-glucosidase (coGAA) gene expressed from a human desmin enhancer/promoter (DES). The
      proposed clinical trial is a within-participant, double-blind, randomized, phase I controlled
      study evaluating the toxicology, biodistribution and potential activity of re-administration
      of rAAV9-DES-hGAA injected intramuscularly into the TA. Nine participants (18 to 50-years
      old) who reside within the United States with Late-Onset Pompe Disease (LOPD) will be
      included. The goal of the immune modulation strategy is to ablate B-cells (Rituximab and
      Sirolimus) prior to the initial exposure to the study agent in one leg and the subsequent
      exposure of the same vector to the contralateral leg after four months. At each study agent
      dosing, the contralateral leg will receive excipient. Patients will act as their own
      controls. Repeated measures, at baseline and during the following 3 months after each
      injection, will assess the safety, biochemical and functional impact of the vector.
    

Detailed description: 
      Enrolling in this study will entail participating in 18 months of study-related visits.
      Patients will be asked to come to the Clinical and Translational Research Building at the
      University of Florida for a series of onsite study visits.

      All the visits will be performed as outpatient procedures at the Clinical Research Center
      (CRC) and at other facilities at the University of Florida. Overnight observation will not be
      needed, however, patients will be asked to stay overnight in a hotel near the University of
      Florida. During the first 4 months after each injection, patients will be asked to perform
      outpatient laboratory work at a laboratory facility convenient for them.

      In addition, during this study patients will be asked to take medications that will modulate
      the ability of their immune system to react against foreign agents including the gene
      transfer agent. The purpose of these medications is to improve the activity of the GAA within
      the body. Patients will receive a Rituximab injection 21 days prior to the first injection of
      the study agent and 7 days before each injection of the study agent and the day of the first
      injection. Rituximab will be delivered by infusion that may last 2-6 hours. Patients will
      need to take another medication (Sirolimus) every day starting 7 days before the first
      injection of the study agent until four months after the second injection of the study agent.

      The following discusses what will occur at each visit:

      Baseline Baseline Evaluation and first Rituximab infusion - Day -22/-21/-20

        -  Medical history: Patients will be asked to complete a questionnaire about his/her
           medical history.

        -  Physical exam: The study doctor will perform a general physical exam to evaluate
           patients physical health.

        -  Blood and urine tests: These tests will be used for evaluating the safety of the gene
           transfer agent.

        -  Electrocardiogram (ECG): This test will measure the electrical activity of patient's
           heart to see if it is working properly.

        -  Quantitative Muscle Testing (QMT): This test finds out how strong the patient's leg
           muscles are.

        -  10 Meter Walk Test: Patients will be instructed to walk a set distance (10 meters); time
           will be measured while patient walks the set distance and the distance covered will be
           divided by the time it took to walk that distance.

        -  Gait analysis: Gait will be tested with Gait Mat II, which will record the spatial and
           temporal parameters of his/her walk such as cadence, speed and distance between your
           feet.

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS): MRI and MRS testing will be
           done inside a large magnet that lets the study doctors measure the size and health of
           the patient's muscles. These tests are done at the same time. MRI and MRS testing will
           require the patient to stay very still for up to an hour.

        -  Magnetic stimulation of the common fibular nerve: The common fibular nerve, which is the
           nerve that controls the injected muscle, will be stimulated with a magnetic field to
           test the impact of the gene transfer agent to the nervous system.

        -  The patient will receive the first Rituximab infusion. It might last between 2 and 6
           hours.

      Rituximab infusion - Day -6

        -  The patient will receive the 2nd Rituximab infusion 7 days before the gene transfer
           agent. It might last between 2 and 6 hours.

        -  Patient will begin Rapamycin.

           1st Injection - Day 0/1

        -  The patient will receive the 3rd Rituximab infusion the day before the gene transfer
           agent. It might last between 2 and 6 hours.

        -  Patient will receive the gene transfer agent in 1 injection (a total of about 1
           teaspoon) into the tibialis anterior (TA) muscle of one leg. The other leg will receive
           a pharmacologically inactive solution. An ultrasound will be used to detect the proper
           location of injection. A photograph of the injection at the injection site may be taken.
           If the patient agrees to this, he/she will be asked to sign a consent form for this
           procedure.

      On day 1, blood tests will be done.

      Outpatient lab work - Day 3/7/15/30/60

        -  Blood and urine tests

      Onsite visit - Day 89/90

        -  Medical history

        -  Physical Exam

        -  Blood and urine tests

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Gait analysis

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)

        -  Muscle Biopsy: Tissue samples obtained will be used for evaluation of muscle glycogen
           and GAA activity in the injected muscle.

        -  Magnetic stimulation of the common fibular nerve

      Rituximab infusion - Day 114

        -  The patient will receive the 4th Rituximab infusion, it might last between 2-6 hours.

           2nd Injection - Day 121/122

        -  The patient will receive the second gene transfer agent injection in the leg that
           previously received the inactive solution. The leg that previously received the study
           agent will receive the inactive solution. The injection procedure and the amount of
           study agent injected will be the same as the first injection.

      On day 122, blood tests will be done.

      Outpatient lab work - Day 124/128/135/150/180

        -  Blood and urine tests

      Onsite visit - Day 209/210

        -  Medical History

        -  Physical Exam

        -  Blood and urine tests

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Gait analysis

        -  Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)

        -  Muscle Biopsy

        -  Magnetic stimulation of the common fibular nerve

      Onsite visit - Day 365

        -  Medical history

        -  Physical exam

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Blood and urine tests

      Onsite visit - Day 520

        -  Medical history

        -  Physical exam

        -  Quantitative Muscle Testing (QMT)

        -  10 Meter Walk Test

        -  Blood and urine tests
    

Intervention name(s): Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase; Rapamycin; saline; Rituxan; Diphenhydramine; Acetaminophen; Lidocaine; LMX 4 Topical Cream
Intervention type(s): Genetic; Drug; Other; Drug; Drug; Drug; Drug; Drug
Intervention description(s): The dose selected for this study is a fixed dose of 4.6 x 10^13 vg per TA muscle (range of 7.64 x 10^11 vg/gm to 4.6 x 10^11 vg/gm based on TA weight).; Patients will receive Rapamycin (dose 0.6-2 mg/m^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until four months after second injection.; Same volume as rAAV9-DES-hGAA injection will be used.; Patients will receive Rituxan (dose: 750 mg/m^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m^2.; 25-50mg will be provided before each Rituximab dose.; We will provide 650 mg of tylenol before each dose of Rituximab.; Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.; Topical anesthesia cream will be used prior to gene therapy/saline injection.
Other intervention name(s): rAAV9-DES-hGAA; Sirolimus; Excipient; Rituximab; Benadryl; Tylenol; Xylocaine; Lidocaine 4%
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Sirolimus; Rituximab; Lidocaine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pompe Disease; Gene Therapy; Repeated dosing; Immune modulation