Rare Disease Report

Gene Therapy in Patients with DMD Demonstrates Outstanding Preliminary Results

JUNE 22, 2018
Krista Rossi
Positive preliminary results from the Sarepta Therapeutics, Inc. phase 1/2a gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin vector in individuals with Duchenne muscular dystrophy (DMD) were announced this week by the study’s principal investigator, Jerry Mendell, MD, of Nationwide Children’s Hospital.  

“I have been waiting my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin,” said Dr Mendell in a recent statement. “Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD. I look forward to treating more patients in the clinical study to generate the data necessary to bring this therapy to patients with DMD, with the goal of dramatically changing the course of the disease.”

In the study, all patients exhibited a robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma as measured by immunohistochemistry. Compared with the normal control, 74.5% was the mean intensity of the fibers, and 76.2% was the mean gene expression, as measured by percentage of micro-dystrophin positive fibers.  

In addition, all post-treatment biopsies exhibited robust levels of micro-dystrophin, as measured by Western blot, with a mean of 38.2% compared with normal utilizing Sarepta’s method, or 53.7% compared with normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue appeared. In patients, a mean of 1.6 vector copies per cell nucleus was measured and found to be consistent with the high micro-dystrophin expression levels observed. 

With a mean reduction of CK over 87% at Day 60, all patients displayed significant reduction of serum creatine kinase (CK) levels, which are enzyme levels associated with muscle damage. Patients with DMD typically exhibit high levels of CK, and, as such, these elevated levels are oftentimes used as a preliminary diagnosis tool for the disease; genetic testing is then performed to confirm.

No serious adverse events (SAEs) were noted in the study, and 2 patients who experienced elevated gamma-glutamyl transferase (GGT) corrected within a week and returned to baseline levels through increased steroid intake. Furthermore, during the first week of treatment, patients experienced transient nausea which correlated with increased steroid dosing.

Dr Mendell teamed up with Louise Rodino-Klapac, PhD, to empirically optimize the AAVrh74.MHCK7 treatment so that it would be specific for DMD.

Without promiscuously crossing the blood, the AAVrh74 vector can be systemically and robustly delivered to skeletal, diaphragm, and cardiac muscle. This function makes it an ideal candidate for the treatment of neuromuscular diseases.

In addition, AAVrh74 is a rhesus monkey-derived AAV vector and appears to show lower immunogenicity rates in existing early-stage clinical studies than expected with other human AAV vectors.

Since DMD patients often die from pulmonary or cardiac complications, the MHCK7 promoter has been chosen for its ability to robustly express in the heart. Micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels displayed in skeletal muscles in preclinical models. 

Since maintenance of spectrin-like repeats 2 and 3 have been reported keys in maintaining the protective functional characteristics of dystrophin, the transgene was engineered to upkeep spectrin-like repeats 2 and 3.

Additionally, with support from supplemental Duchenne foundations and families, Parent Project Muscular Dystrophy’s (PPMD) committed $2.2 million to the trial.

“While these are early days and work remains to fully understand the full potential of gene therapies, these first signals are encouraging,” commented Pat Furlong, Parent Project Muscular Dystrophy’s (PPMD) founding president and chief executive officer. “We remain hopeful that this will lead to a viable treatment for Duchenne.”

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