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Clinical Vector Core Supports Life-Changing Gene Therapy After AADC Diagnosis

Post gene therapy to treat her AADC deficiency, Rian Rodriguez-Pena is thriving, becoming stronger every day. (Photo courtesty of Shillann Rodriguez-Pena)
In 2019, after nearly five years of waiting and hoping, Rian Rodriguez-Pena received the gene therapy that would begin to turn her life with aromatic l-amino acid decarboxylase (AADC) deficiency around.
"I thought about gene therapy a thousand times a day," Rian's mother, Shillann Rodriguez-Pena, said. "It hadn't even come to trial yet, but we were keeping her alive until she could access it."
In addition to helping make possible the gene therapy products to treat AADC deficiency, the Clinical Vector Core (CVC) at CHOP Research Institute has manufactured 178 vector products that supported the development of treatments for 39 unique clinical indications. Rian is one of more than 800 patients globally who have benefitted from the vector products developed by researchers all over the world that were manufactured at the CVC. That number continues to grow.
Embedded in the heart of CHOP's medical campus, the CVC played key roles in the first-ever FDA-approved gene therapies. While currently a powerhouse in nonprofit adeno-associated virus (AAV) and lentivirus (LV) manufacturing, CHOP's CVC emerged from humble beginnings when it was founded in 2005 as part of the Raymond G. Perelman Center for Molecular Therapeutics (CCMT), now directed by Beverly Davidson, PhD, Chief Scientific Strategy Officer of CHOP Research Institute.
Director of Quality Olga Zelenaia, PhD, is coming up on her 20th anniversary at the CVC, beginning in process development when she joined in 2005. Back then, the CVC was just starting the process of figuring out their procedures and the true extent of what treatments they could make possible. She recalled a small staff of only three dedicated people.
"What drives almost every single individual in this team, then and now, is their passion for seeing the kind of impact they can have on children's lives," Dr. Zelenaia said. "Most of us have dreamed of this since we were teenagers, and that passion helped us become one of the first facilities to begin to manufacture clinical vectors."
Today, the CVC boasts a $35 million state-of-the-art current Good Manufacturing Practices (cGMP) facility with five cleanroom suites compliant with US Food and Drug Administration (FDA), Medicines and Healthcare Products Regulatory Agency, and European Medicines Agency GMP regulations. Since its inception, the CVC has placed a special emphasis on developing products to treat rare and ultra rare diseases such as AADC deficiency.
"Our team works very hard on a daily basis, and we're grateful to receive stories like Rian's back from physicians that show us these miracles as they happen," said Core Director Johannes van der Loo, PhD.
Worry, Advocacy, and Anticipation
Around the world, approximately 150 children are currently diagnosed with AADC deficiency, which is a genetic disorder that affects the brain's ability to produce dopamine and serotonin — two neurotransmitters crucial for relaying information to other cells. Symptoms, such as muscle weakness, usually appear within one to six months of age as babies fail to reach major physical milestones. They have trouble sitting up, learning to stand, and developing fine motor control needed for play. They also experience feeding difficulties that may require a feeding tube and debilitating developmental delays.
The disorder's rarity makes it difficult to screen for, and for patients like Rian, born in October 2014 and diagnosed with AADC deficiency just before her first birthday, these blood draws, muscle biopsies, spinal taps, and whole exome sequencings required to obtain an official diagnosis are only the first intensive steps down a long, uncertain road to treatment.
"I've often said that the day Rian was born was the happiest day of my life because it's the only day I haven't worried about her," Shillann said. "The worrying started the day after."
Once Shillann received a workable diagnosis from the Hospital for Sick Children in Toronto, Canada, she went home and connected with the AADC Research Trust, a charity organization based in England that promotes disease awareness and funds research in gene therapy. Although Rian was on medications to ease the more autonomic symptoms of her disease, her physical development had not progressed beyond that of an infant in over four years. Intent on being her daughter's best advocate, Shillann learned more about gene therapy, attending conferences and contacting doctors from all over the world.
With help from Lisa Flint, a pivotal member of the AADC Research Trust who connected families with new clinical trials, Shillann and her family placed their hope in Krystof Bankiewicz, MD, PhD, a neurologist at The Ohio State University College of Medicine specializing in pediatric neurotransmitter deficiencies, who happened to have a longstanding relationship with CHOP and the CVC.
Helping Investigators Bring Their Products to Clinic
Gene therapies are administered via viral vectors, and viral vector production — which takes anywhere from eight to nine months between growing the cells to final shipping — by nature requires a close, continuous relationship between scientists in the CVC and the investigators who need a gene therapy product.
Usually after years of testing and research, investigators bring their results to the CVC in the form of a DNA sequence that is then copied into a viral particle by CHOP scientists. The particles contain the corrected gene that in a genetic disease would be defective or missing. CHOP also has the capacity to do in-house testing for purity, safety, and efficacy.
CHOP was the first institution to have two vectors in clinical trials by 2007. Through the Gene Therapy Resource Program, the National Heart, Lung, and Blood Institute selected CHOP as the designated manufacturer for AAV for clinical use from 2007 to 2017, which directed researchers like Dr. Bankiewicz to CHOP for their clinical vector needs.
Since working together on their first project in 2007, Dr. Zelenaia and her colleagues have fostered a long, successful relationship with Dr. Bankiewicz that has led to the manufacturing of several AAV vectors over the years, including the vector that would change Rian's life.
"We recognize how special and rewarding our role is in helping investigators bring their products to clinic, especially for projects such as Dr. Bankiewicz's where a single treatment completely changes a life," said Dr. van der Loo, who brings over 22 years of GMP viral vector manufacturing experience and is coming up on his 10th anniversary with the CHOP CVC. "We have such gratitude for the institution for believing in our vision and continuing to support gene therapy programs."
'We'll Show Them All What You Can Do'

The left picture depicts Rian one month before receiving gene therapy; the right picture shows her incredible growth one year after receiving gene therapy. (Photo courtesty of Shillann Rodriguez-Pena)
On Sept. 3, 2019, Dr. Bankiewicz delivered the therapy in a Warsaw hospital in his native Poland that had agreed to treat international children out of compassionate care. Rian was his 12th patient, and since 2019, he has gone on to treat many more children with AADC deficiency.
"I feel drawn to post updates about Rian's journey to provide hope for other families," Shillann said. "Gene therapy is on the rise for many different conditions, so we have families who have children with rare diseases from all over the world following along who thank us for taking away their sense of hopelessness, even for a moment."
Rian's progress began subtly but steadily. Soon after gene therapy, she could hold her head up on her own. Suddenly she was using her hands to play; she could eat and drink without support. She learned to sit, then to stand. From being completely immobilized by her disease only two years prior, Rian was riding roller coasters with her dad and loving every thrill-bound second as a 7-year-old. But despite gaining new skills every month and getting stronger every day, there are times when Rian becomes frustrated over the words and feelings she still has difficulty expressing.
"For years I've been telling her, 'You will walk, and you will talk, and all the world will be in shock. We'll show them all what you can do, and that God's miracles do come true,'" Shillann said. "There's no reason for me to put a cap on what Rian will be able to accomplish as she grows."
To learn more about Rian and her experience with cell and gene therapy, watch this YouTube video.