Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate

  title={Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate},
  author={Waldy San Sebasti{\'a}n and Adrian Philip Kells and John R. Bringas and Lluis Samaranch and Piotr Hadaczek and Agnieszka Ciesielska and Michael J Macayan and Phillip J Pivirotto and John R. Forsayeth and Sheryl Osborne and J. Fraser Wright and Foad Green and Gregory Heller and Krystof S. Bankiewicz},
  journal={Molecular Therapy. Methods \& Clinical Development},
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately… 

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons

Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

Slow AAV2 clearance from the brain of nonhuman primates and anti-capsid immune response

Surprisingly, convection-enhanced delivery of AAV2 into the thalamus of nonhuman primates (NHPs) resulted in robust staining of neurons with A20 antibody that detected intact A AV2 particles at ∼1.5 months after infusion, which confirmed earlier findings of persistence of intact Aav2 particles in ocular and hepatic tissues.

Direct Intracranial Injection of AAVrh8 Encoding Monkey β-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain.

Most monkeys receiving AAVrh8-cmHexα/β intracranial injection developed dyskinesias, ataxia, and loss of dexterity, with higher dose animals eventually becoming apathetic, and this study demonstrates the variations in safety profiles of AAV rh8-Hex α- and β-subunits among different species, despite encoding for self-proteins.

Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington’s disease

This study suggests that both AAV1-directed and AAV2-directed serotypes are capable of targeting neurons that degenerate in HD, and it sets the stage for the advanced preclinical evaluation of an RNAi-based therapy for this disease.

Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses

This work developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model using an equal mixture of AAVrh8 vectors that encode for the two subunits of HexA into the thalami and lateral ventricle.

Axonal transport of AAV9 in nonhuman primate brain

The data suggest that AAV9 can be axonally transported bi-directionally in the primate brain and has obvious implications to the clinical developing of therapies for neurological disorders like Huntington’s or Alzheimer's diseases.

Targeted Delivery and Tolerability of MRI-Guided CED Infusion into the Cerebellum of Nonhuman Primates.

The potential of real-time MRI-CED to deliver therapeutics into the cerebellum, which has extensive reciprocal connections and may be used as a target for the treatment of neurological disorders, is demonstrated.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

A gene therapy for dopamine transporter deficiency syndrome is developed using patient-derived induced pluripotent stem cell (iPSC) and a mouse model, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

MR-Guided Delivery of AAV2-BDNF into the Entorhinal Cortex of Non-Human Primates

MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorbital cortex and the hippocampus, achieving growth factor distribution through key memory circuits.

AAV viral vector delivery to the brain by shape-conforming MR-guided infusions.



Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum.

The data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease

This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease

These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC.

A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys.

Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys.

AAV2-GDNF gene transfer does not appear to elicit adverse effects, delivers therapeutic levels of GDNF within target brain areas, and enhances utilization of striatal dopamine and dopaminergic nigrostriatal innervation.

Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC.

The present data suggest that the improvement in the L-3,4-dihydroxyphenylalanine (L-Dopa) therapeutic window brought about by AADC gene therapy is pronounced and persistent for many years.

Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain.

This study further validates convection-enhanced delivery (CED) as the preferred method of viral vector delivery to the brain, and supports a Phase I clinical testing of AAV2-hAADC in humans with Parkinson's disease.

A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease.

The findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.

Distribution of AAV2-hAADC-transduced cells after 3 years in Parkinsonian monkeys

The stability of recombinant adeno-associated virus serotype 2 (AAV2) human aromatic L-amino acid decarboxylase (hAADC) gene transfer after 3-year survival time in a non-human primate model of Parkinson's disease is described.