Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease

Paul Wuh-Liang Hwu; Karl Kiening; Irina Anselm; David R Compton; Takeshi Nakajima; Thomas Opladen; Phillip L Pearl; Agathe Roubertie; Thomas Roujeau; Shin-Ichi Muramatsu

doi:10.15252/emmm.202114712

Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease

EMBO Mol Med. 2021 Sep 7;13(9):e14712. doi: 10.15252/emmm.202114712. Epub 2021 Aug 23.

Authors

Paul Wuh-Liang Hwu^{1

2}, Karl Kiening³, Irina Anselm⁴, David R Compton⁵, Takeshi Nakajima^{6

7}, Thomas Opladen⁸, Phillip L Pearl⁹, Agathe Roubertie¹⁰, Thomas Roujeau^{11

12}, Shin-Ichi Muramatsu^{13

14}

Affiliations

¹ Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
³ Division of Stereotactic Neurosurgery, Department of Neurosurgery, University of Heidelberg Medical Center, Heidelberg, Germany.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Preclinical Development (Gene Therapy), PTC Therapeutics, South Plainfield, NJ, USA.
⁶ Department of Neurosurgery, Jichi Medical University, Tochigi, Japan.
⁷ Jichi Medical University Hospital, Rehabilitation Center, Tochigi, Japan.
⁸ Division of Child Neurology and Metabolic Disorders, University Children's Hospital, Heidelberg, Germany.
⁹ Epilepsy and Clinical Neurophysiology, William G. Lennox Chair and Professor of Neurology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
¹⁰ Pediatric Neurology Department, INM, INSERM, CHU Montpellier, University of Montpellier, Montpellier, France.
¹¹ Department of Neurosurgery, Gui-de-Chauliac Hospital, Montpellier University Hospital, Montpellier, France.
¹² Institute of Neurosciences, University Hospital of Montpellier, Montpellier, France.
¹³ Division of Neurological Gene Therapy, Jichi Medical University, Shimotsuke, Tochigi, Japan.
¹⁴ Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l-amino acid decarboxylase (AADC) deficiency and Parkinson's disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno-associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l-DOPA into dopamine in Parkinson's patients.

Keywords: AADC deficiency; aromatic l-amino acid decarboxylase; dopamine; gene therapy; putamen.

MeSH terms

Aromatic-L-Amino-Acid Decarboxylases / genetics
Aromatic-L-Amino-Acid Decarboxylases / metabolism
Carboxy-Lyases*
Genetic Therapy
Humans
Parkinson Disease* / genetics
Parkinson Disease* / therapy
Putamen / metabolism

Substances

Carboxy-Lyases
Aromatic-L-Amino-Acid Decarboxylases

Grants and funding

P50 HD105351/HD/NICHD NIH HHS/United States