Novel Gene Therapy Promising for Rare Neurologic Disorder

Megan Brooks

August 26, 2021

An investigational gene therapy being developed by PTC Therapeutics is generating hope for children born with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder for which there are no approved disease-modifying therapies.

AADC deficiency is a neurologic disorder that involves debilitating motor and nonmotor dysfunction caused by dopamine deficiencies. In AADC deficiency, the putamen is directly affected by the loss of dopamine synthesis and is therefore a prime target for gene therapy.

The novel gene therapy (AAV2-hAADC, also known as PTC-AADC) restores dopamine synthesis by infusing a functional copy of the human dopa decarboxylase gene, critical to the production of dopamine, directly into the putamen using low doses of adeno-associated viral vector serotype 2.

"We deliver the gene directly to the place in the brain that needs it most using stereotactic neurosurgery. By delivering it directly into where it needs to go, we give a much lower dose than is given in other gene therapies," Matthew Klein, MD, chief development officer for PTC Therapeutics, told Medscape Medical News.

"That's important because one of the things people worry about with gene therapies is high levels of virus vector," Klein added.

The clinical benefits and the safety profile of PTC-AADC have been demonstrated across multiple clinical trials involving 20 children with AADC deficiency. Together, this is the largest cohort of patients with AADC deficiency ever studied.

A commentary describing in detail the gene therapy and clinical trial results was published online August 23 in EMBO Molecular Medicine.

Significant Improvements

The commentary was authored by clinicians from Taiwan, Germany, France, Japan, and the United States, including Irina Anselm, MD, director of the Mitochondrial Program and co-director of the Neurometabolic Program at Boston Children's Hospital.

Prior to receiving gene therapy, nearly all of the children in the reviewed studies had characteristic manifestations of severe AADC deficiency, including hypokinesia, dystonia, oculogyric crisis, emotional instability, and increased sputum. They were also bedridden and had not achieved full head control or more advanced motor functions.

Following the one-time gene therapy, all showed significant improvements in oculogyric crisis symptoms, emotional stability, and motor function, including good or partial head control. Some children were even able to sit and stand with support and began learning to speak.

"What we are seeing is that many years after first being treated, the children have maintenance of dopamine levels and continued improvement of motor function," Klein said.

"The data reported in this article show that the surgical approach of delivering our novel PTC-AADC gene therapy directly to the putamen robustly produces dopamine in the brain that results in sustained and substantial functional improvements in children with AADC deficiency," Stuart Peltz, PhD, chief executive officer of PTC Therapeutics, said in a news release.

As reported by Medscape Medical News, the technique of injecting a gene therapy directly into the putamen has previously been shown to be effective in the treatment of Parkinson's disease.

The novel PTC-AADC gene therapy is currently under review by the Committee for Medicinal Products for Human Use of the European Medicines Agency. An opinion is expected later this year.

The company also plans to seek approval from the US Food and Drug Administration.

EMBO Mol Med. Published online August 23, 2021. Full article

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