PPMD’s Gene Therapy Initiative

In early 2017 PPMD launched our Gene Therapy Initiative, a long-term concept that seeks to accelerate the potential of gene therapy as a therapeutic for Duchenne. Our early strategy was to bring attention to and fund key questions that must be answered in order for the technology to progress towards approvals.

Additionally, the Gene Therapy Initiative intentionally contains an educational component as, while promising, gene therapy is new and presents different questions and considerations than those of previous therapies.

What is gene therapy in Duchenne?

Gene therapy for Duchenne is centered on the goal of successfully introducing a smaller, but efficient version of dystrophin into the muscle cell. The most logical protein to introduce is dystrophin, the protein that is missing in Duchenne. Because dystrophin is such a large protein, smaller versions, referred to as micro-dystrophins are inserted into the delivery vehicle which is typically a virus. Other muscle stabilizing proteins, such as follistatin, GALGT2, biglycan, and others can also be introduced through gene therapy with the aim of compensating for the missing dystrophin.

Scientists had to find a way to deliver these proteins into muscle cells. This was challenging because our bodies are made up of so many muscles, many of which are difficult to reach. Scientists finally found a way to do this, by harnessing nature’s own delivery system – a virus.

In nature, viruses are designed to enter the cell nucleus, essentially “infecting” it, and depositing their own genetic code to start producing more virus. Over many years of painstaking research, scientists have found a virus that infects muscle cells. They removed the qualities or genes that make humans sick ( a term known as gutting the virus).  Researchers today are using an adeno-associated virus, often referred to as AAV, as viruses have evolved over time to deposit their own genetic code into cells. Viral delivery harnesses the virus’s natural ability to deposit genetic material right to the muscle cell nucleus. The result of this viral “infection” would be the successful recoding of each muscle cell in the patient’s body.

While this may seem simple, this is a big moment for gene therapy, even outside of the Duchenne community. The FDA’s recent approval of Kymriah (a gene therapy that treats an aggressive type of leukemia) in August of 2017, Luxturna (a gene therapy for a certain type of vision loss) in October of 2017, and Dr. Jerry Mendell’s recent success with gene therapy in Spinal Muscular Atrophy, are great examples of why it is one of the most promising therapeutic approaches out there.

Another promising gene therapy, one that uses the viral delivery system, is Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR as it is commonly called. In this strategy, a bacterial defense system (or molecular scissors) that can cut DNA is guided to specific spots of DNA, where it cuts the DNA. The DNA then heals, and a modified dystrophin production is restored. This is often thought of as permanent exon skipping.

PPMD Funding

PPMD has announced the following awards as part of the Gene Therapy Initiative launch:

Clinical Intramuscular Gene Transfer Trial of rAAVrh74.MCK.Micro-Dystrophin to Patients with Duchenne

The first award marked PPMD’s largest single research investment to date, a $2.2 million, milestone-driven award to Dr. Jerry Mendell and Dr. Louise Rodino-Klapac of Nationwide Children’s Hospital to explore a microdystrophin gene transfer via AAV delivery in Duchenne.

This investment is to carry out a Phase 1 clinical trial designed to explore several issues confronting gene transfer such as systemic delivery of the virus (vector that carries the micro-dystrophin) and questions around antibodies to the virus (whether the immune system has seen this virus and developed resistance)  or to the microdystrophin in order to maximize our knowledge of safety and to broadly apply learnings to individuals with Duchenne. To date, only a few patients have been dosed.

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Using CRISPR/Cas9 Genome Editing to Correct Muscle Abnormalities Associated with Duchenne

PPMD’s initial investment in the laboratory of Dr. Eric Olson at UT Southwestern was to further research the potential of CRISPR/Cas9 in Duchenne and build on his previous work. This grant brought focus to essential questions that have to be examined.

CRISPR/Cas9 has the potential for off-target effects as it works through the precision of the molecular signposts, or guidewires, pinpointing where to deliver.  In other words, to ensure safety, we have to make sure the molecular scissors targets only the dystrophin gene.

Through this grant, Dr. Olson examined the stability and functionality of edited forms of dystrophin, assessing possible off-target effects in mouse models, developed for this specific question, in order to determine the safety of this approach.

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Effect of immunomodulatory treatments on immune response after gene correction in Duchenne

PPMD awarded Dr. Kanneboyina Nagaraju and his team at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences a $329,000 grant to continue his work examining the immune response to the production of new dystrophin protein, resulting from exon skipping and gene therapy treatments. This is an important next step in our exploration of both gene therapy and exon skipping as potential treatments for Duchenne.

To better understand the role of the immune system on dystrophin restoration, Dr. Nagaraju will explore the combination of exon skipping or micro-dystrophin gene therapy with an immunosuppressive treatment, using one of the following drugs:

  • Treatment with rituximab to block antibodies to newly produced dystrophin.
  • Treatment with abatacept CTLA4ig to halt an anti-dystrophin immune response.
  • Treatment with either prednisolone, vamorolone, or eplerenone to test the respective reduction in inflammatory and anti-dystrophin immune response.
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Educational Efforts

As the community enters the era of gene therapy, many new concepts, terms and issues arise, ones that families have not had to consider before. As part of PPMD’s gene therapy initiative, we have conducted five webinars on different aspects of gene therapy:

[Webinar] A Closer Look at the Potential of CRISPR/Cas9 in Duchenne – December 2016

 [Webinar] Gene Therapy for Duchenne – August 2017

[Webinar] PART 2: Gene Therapy for Duchenne – Nationwide Children’s Hospital – September 2017

[Webinar] Understanding Gene Therapy, Part 3 – Galgt2 and Dup2 – December 2017

[Webinar] Gene Therapy: A Closer Look – March 2018

The Future of Gene Therapy Initiative

PPMD continues to evaluate opportunities to further the promise of gene therapy for Duchenne, such as the development of a virally delivered exon skipping therapy for exon 2 duplications, and virally delivered GALGT2, a protein that compensates for the lack of dystrophin. As with all of our investments, we believe it is essential to accelerate options for all individuals diagnosed and invest in work across approaches, targets, and methodologies. At this early stage, it is prudent to diversify and invest in other gene therapy strategies in order to develop options for all.