Aspiring to make gene therapy for Duchenne muscular dystrophy (DMD) a reality

As a leader in DMD our goal is to develop effective therapies to treat 100% of individuals with this devastating disease. To get to the heart of DMD, it is critical for gene therapy to be delivered to skeletal and cardiac muscle. 1 Sarepta Therapeutics has brought together all of the elements essential for successful development of gene therapy—productive collaborations, unparalleled scientific understanding, and an unwavering sense of purpose.

We’re proud to be working with distinguished pioneers at The Center for Gene Therapy in The Research Institute at Nationwide Children’s Hospital, striving to transform gene therapy’s promise into clinically-proven reality.

Jerry R. Mendell, MD
Important milestones in the gene therapy journey

Louise Rodino-Klapac, PhD
Critical scientific aspects that make gene therapy viable

Kevin M. Flanigan, MD
The wide neuromuscular applicability of surrogate gene therapy


Optimizing solutions to overcome the critical challenges in gene therapy development

In order for the potential of gene therapy to be realized in any therapeutic intervention, three essential components are necessary 2,3:

  1. The right vector must deliver the transgene to target cells with minimal immune response
  2. A specific promoter that drives expression in intended tissues
  3. The transgene must produce a functioning version of the protein of interest

Nationwide Children’s micro-dystrophin vector has been elegantly designed to optimize each component necessary for success. 4


Louise Rodino-Klapac, PhD
Why engineering the right micro-dystrophin vector is key

Selected for efficient transduction to target cells and low pre-existing immunity

A vector is the vehicle used to transport the transgene—the genetic material that will make the protein of interest—to the target cells. Selecting the right vector is critical for 2 main reasons:

AAVrh74 has a robust affinity for muscle cells, making it an ideal choice for delivering the micro-dystrophin transgene. 7 AAVrh74 also has a relatively low level of pre-existing immunity.

People who have been infected naturally with an AAV will develop antibodies to that specific AAV. 8 Patients undergoing gene therapy need to be screened for such pre-existing antibodies, as they may interfere with the success of the treatment. 6

At Nationwide Children’s, researchers explored a number of vectors, including AAVrh74, which was originally isolated from non-human primate material. Low pre-existing immunity rates potentially allow more patients to be successfully treated using the AAVrh74 vector. 4


Designed to maximize gene expression in skeletal and cardiac muscle

Once the vector reaches the muscle cells, an element called the promoter becomes vitally important. The promoter controls expression of the therapeutic transgene, and many promoters have specificity for certain tissues. Using a tissue-specific promoter can limit wasteful expression of the transgene in non-target tissues and enable persistent expression of the transgene where it is needed. 1,5

Cardiomyopathy is the leading cause of early mortality in patients with DMD. 1 The muscle-specific MHCK7 promoter is designed to target skeletal and cardiac muscle. 5 It includes an element to enhance expression in cardiac muscle. In pre-clinical models, MHCK7 has demonstrated nearly 100% cardiac tissue transduction. 5

Jerry R. Mendell, MD
The importance of maximizing
cardiac expression


Optimized to potentially generate dystrophin

The term “transgene” refers to the gene being transferred. 6 The dystrophin gene is one of the largest in the human body with a size of 2.4 megabases and a protein-coding region of approximately 11.5 kilobases. Fitting a full dystrophin gene inside the vector ideal for its delivery would be impossible, as AAV can only carry approximately 5 kilobases of DNA. 6

After a decade of intensive experimentation, the researchers at Nationwide Children’s were able to disassemble the dystrophin gene and reassemble a version consisting only of select regions optimized for protein functionality. These regions include spectrin-like repeats 1, 2, 3, and 24. 9

Preclinical studies in a mouse model of DMD expressing the same micro-dystrophin construct used in Nationwide Children’s AAVrh74 vector have suggested that spectrin-like repeats 2 and 3 are likely required for complete muscle protection. Mice expressing other dystrophin constructs lacking those portions exhibited a loss of muscle force, supporting the potential role for these repeats in modulating force transmission and mechanical vulnerability. 4,10

Preclinical studies have demonstrated that this micro-dystrophin transgene, delivered in the AAVrh74 vector and potentiated with the MHCK7 promoter, can generate gene expression by dystrophin positive fibers as high as 70% in the skeletal muscle and 100% expression of dystrophin in the heart. 4

Systemic delivery of this vector achieved widespread distribution across muscle groups in a mouse model of DMD, and resulted in reduced skeletal myopathy, including substantial improvements in functional measures like muscle strength and stamina. 4


Surrogate gene therapy with broad and exciting potential

The GALGT2 program currently in clinical studies at Nationwide Children’s takes a surrogate approach to gene therapy for DMD. Instead of acting to resupply missing dystrophin, GALGT2 gene therapy fortifies the structural integrity of muscle in ways that compensate for the absence of dystrophin, by increasing expression of proteins not mutated or lost in the disease. 11

GALGT2 offers the potential to treat DMD irrespective of specific dystrophin mutation, as well as having utility in other muscular dystrophies. 11

GALGT2 is expressed in skeletal muscle, highly and specifically concentrated in a small region called the neuromuscular junction, where the motor nerve touches the muscle to transmit the chemo-electrical impulses that drive expansion and contraction. 11

Overexpression of the GALGT2 gene may help muscle cells recruit protective proteins to reinforce the dystroglycan complex, including utrophin, laminin α4, laminin α5, agrin, and plectin 1. 11


It takes bold hearts and outstanding minds to move gene therapy forward. We’re working with the best.

Sarepta Therapeutics is working with several strategic partners under various agreements to research and develop multiple treatment approaches to DMD. In advancing our gene therapy product candidates, we’re proud to be collaborating closely with Nationwide Children’s in Ohio.

Nationwide Children’s is internationally recognized as having been at the forefront of genetic therapy research for over 30 years. We are collaborating with Nationwide Children’s on the advancement of their micro-dystrophin gene therapy program under a research and exclusive license option agreement and also their GALGT2 gene therapy program under an exclusive license agreement. Nationwide Children’s is an ideal partner for Sarepta Therapeutics in that it also designs and manufactures adeno-associated viral vectors (AAVs).

Nationwide Children’s: A SERIES OF FIRSTS 4

Contributions to gene therapy research include the development of the Nationwide Children’s manufacturing capacity to support clinical DMD programs.


Nationwide Children’s Research Institute developed the first AAV vectors using recombinant technology.


First gene therapy trial in DMD using intramuscular delivery of


First successful intramuscular trial for muscular dystrophy using a muscle-specific promoter.


Good Manufacturing Practices (GMP)-accredited facility at Nationwide Children’s manufactures first clinical product.


First intramuscular gene therapy trial, evaluating a muscle enhancement agent.


First vascular delivery safety trial with AAVrh74.

First intravenous delivery trial with AAV for neuromuscular disease.


Second GMP facility opens at Nationwide Children’s quadrupling production capacity.


Initiation of Phase I/IIa trial of systemic micro-dystrophin (AAVrh74.MHCK7) for DMD.


Sarepta’s goal is to build a sustainable gene therapy platform while focusing on speed to market for its current and future gene therapy programs. Toward that end, the Company’s gene therapy manufacturing capabilities were greatly enhanced through its recently announced strategic partnership with Brammer Bio. This partnership will afford Sarepta rapid clinical and commercial manufacturing capacity for its micro-dystrophin Duchenne muscular dystrophy (DMD) gene therapy programs and Limb-girdle muscular dystrophy (LGMD) programs (in the US and globally), while also acting as a manufacturing platform for potential future gene therapy programs.

Sarepta has adopted a hybrid manufacturing strategy in which it is building internal manufacturing expertise relative to all aspects of AAV-based manufacturing, including gene therapy and gene editing supply, while closely partnering with first-in-class manufacturing partners to expedite development and commercialization of its gene therapy programs. The collaboration integrates process development, clinical production and testing, and commercial manufacturing. Brammer Bio will also partner with Sarepta to design and build dedicated state-of-the-art commercial manufacturing suites within their facility.


Duchenne muscular dystrophy is a devastating disease

DMD is a genetic disorder affecting approximately 1 in 3,500 to 5,000 newborn boys. It causes progressive weakness and muscle wasting, robbing sufferers first of their childhood and eventually their lives. 12

DMD is caused by a lack of dystrophin, an essential protein that helps keep muscle cells intact. Muscle weakness becomes increasingly noticeable by age 3 to 5, and most patients use a wheelchair by the time they are 13, having lost the ability to walk. 12,13 During adolescence, cardiac and respiratory muscle deterioration lead to serious, life-threatening complications. 12


Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying DMD drug candidates. Our goal is to develop effective therapies to treat 100% of individuals with DMD. For more information, please visit

In addition to our collaboration with Nationwide Children’s Hospital, we are also working with other institutions world-renowned for purposeful achievements in gene-therapy innovation:

Genethon was the first organization in the world to publish a map of the human genome and remains a leader in gene therapy discovery, design, and development, employing one of the largest research and clinical groups in the world working to advance rare disease therapies. We are collaborating with Genethon on the advancement of their micro-dystrophin gene therapy program under a sponsored research and exclusive license option agreement.

Duke University in North Carolina is at the cutting edge of harnessing gene editing technology to change the lives of patients with DMD. We are collaborating on the advancement of gene editing CRISPR/Cas9 technology for muscular dystrophy under a sponsored research and exclusive license option agreement that grants us rights to certain related intellectual properties.

Forward-Looking Statements:

This website contains forward-looking statements, such as statements regarding Sarepta's goals and the potential benefits of its programs, collaborations and partnerships. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from those forward-looking statements as any and such risk can materially and adversely affect the business, results of operations and the trading price of Sarepta's common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K and quarterly report on Form 10-Q filed with the Securities and Exchange Commission, as well as other Sarepta SEC filings.


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  4. Data on file, Sarepta Therapeutics.
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  11. Chicoine LG, Rodino-Klapac LR, Shao G, et. al. Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin α2 surrogates. Mol Ther. 2014;22(4):713-724.
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