Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy

Jerry R. Mendell3 enrolled

Overview

The proposed clinical trial is an outgrowth of the safety record and functional improvement seen in the BMD follistatin gene therapy trial. In this study the investigators propose to inject AAV1.CMV.huFS344 at a total dose of 2.4E12 vg/kg to six DMD patients. This dose will be divided between gluteal muscles, quadriceps and tibialis anterior. This is a wider distribution of vector than given to BMD patients, who overall improved the distance walked on the 6MWT without adverse events related to viral transduction into a single muscle.

The primary objective of this study is safety and endpoints will include hematology, serum chemistry, urinalysis, immunologic response to rAAV1 and follistatin, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcomes and include the distance walked on the 6MWT, functional tests by PT, life quality questionnaire, MRI, EIM, and muscle biopsy. Subject will have follow up visits on days 7, 14, 30, 45, 60, 90, 180 and 9,12, 18 and 24 months post-gene transfer.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Duchenne Muscular Dystrophy

Interventions

Eligibility

Sex: MALEMin age: 7 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 7 or older * Confirmed DMD gene mutations * Impaired muscle function based on clinical evidence including difficulty climbing stairs, getting from the floor (Gowers' sign), and weakness of individual muscles of extremities * Males of any ethnic group will be eligible * Ability to cooperate with study procedures including muscle testing. * Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception * Subjects must be on stable dose of prednisone for three months at time of enrollment or be started on oral dose of daily prednisone regimen for 30 days prior to gene transfer. Study participants will continue prednisone post gene transfer unless there is adverse event that warrants prednisone taper or withdrawal. Exclusion Criteria: * Active viral infection based on clinical observations. * The presence of a DMD gene mutation without weakness or loss of function * Symptoms or signs of cardiomyopathy, including: * Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs * Echocardiogram with ejection fraction below 40% * Serological evidence of HIV infection, or Hepatitis A, B or C infection * Diagnosis of (or ongoing treatment for) an autoimmune disease * Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer * Subjects with rAAV1 binding antibody titers \> 1:50 as determined by ELISA immunoassay * Abnormal laboratory values for liver, kidney, CBC, in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory

Outcomes

Primary Outcomes

Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.

Dose limiting toxicity (DLT) is defined as any adverse event that is possibly, probably, or definitely related to the study agent. This would include any grade 3 according to the classification given above. Study enrollment will be halted by the investigators when any subject experiences a Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the study drug. Only those adverse events requiring treatment will qualify as DLT. The classification for adverse events to be used is the following: 1. Mild adverse event; did not require treatment 2. Moderate adverse event; resolved with treatment 3. Severe adverse event; inability to carry on normal activities; required professional medical attention 4. Life-threatening or permanently disabling adverse event 5. Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.

Time frame: DLT Adverse events will be recorded from the date of dosing and through the time of the subject's last study visit. Serious adverse events will be recorded from the date of dosing and for up to 2 years after gene therapy administration.

Secondary Outcomes

Muscle Function Measured by Six-minute Walk Test (6MWT)

Number of subjects with increased distance walked in meters on the Six Minute Walk Test. The participant was asked to walk a set course of 25 meters for 6 minutes (timed) and the distance walked in meters was recorded. Increases from baseline in 6MWT distance are indicative of improvement and decreases from baseline indicate worsening.

Time frame: 2 years

Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue

Muscle biopsies on quadriceps muscles a muscle biopsy on one leg at baseline screening visit and the post gene transfer biopsy on the opposite leg at day 180. Muscle tissue obtained at biopsy will also be assessed for viral DNA (qPCR), and follistatin transgene expression. Measured in CMV.FS344 Gene Copy Number in Genomic DNA (Copies/ug DNA)

Time frame: 180.days

Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)

Overall Improvement in North Star Ambulatory Assessment The activities are graded as follows: 2 - "Normal" - no obvious modification of activity 1 - Modified method but achieves goal independent of physical assistance from another 0 - Unable to achieve independently This scale is ordinal with 34 as the maximum score indicating fully-independent function.