Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency by MR-Guided Direct Delivery of AAV2-AADC to Midbrain Dopaminergic Neurons

Pearson, Toni S.; Gupta, Nalin; Sebastián, Waldy San; Imamura-Ching, Jill; Viehoever, Amy; Grijalvo-Perez, Ana; Fay, Alex J.; Seth, Neha; Lundy, Shannon; Seo, Youngho; Pampaloni, Miguel Hernandez; Hyland, Keith; Smith, Erin M.; deOliveiraBarbosa, Gardenia; Heathcock, Jill C.; Minnema, Amy J.; Lonser, Russell R.; Elder, J. Bradley; Leonard, Jeffrey R.; Larson, Paul; Bankiewicz, Krystof

doi:10.21203/rs.3.rs-73870/v1

Cited by 5 publications

(16 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When available, imaging data showed more prominent increase in radiotracer uptake in regions that correlate with areas of infusions. FMT-PET putaminal uptake ( 33 ) or 18F-DOPA PET midbrain, putaminal, and caudate uptake ( 34 ) passed from absent to bilaterally present with high signal intensity, after up to 2-year follow-up, while in the study from Hwu and coll ( 31 ) three out of four participants showed an increased 18F-DOPA uptake, as compared to pre-treatment imaging ( Table 6 ). CSF catechol analysis demonstrated levels that trended toward increased dopamine metabolites across these studies, but degree of change in serotonin metabolites and levodopa varied significantly across individuals both before and after treatment.…”

Section: Resultsmentioning

confidence: 98%

“…Out of the 1,437 studies derived from the initial searching strategy ( Figure 1 ), 27 published articles met full criteria ( 8 – 34 ) ( Tables 1 – 6 ) and underwent data extraction and assessment for individual risk of bias. There were 21 studies focusing on PD ( 8 – 28 ), two on HD ( 29 , 30 ), and four on AADC deficiency ( 31 – 34 ).…”

Section: Resultsmentioning

confidence: 99%

“…There were 25 studies investigating intraparenchymal gene therapy delivery using Adeno-Associated Virus type 2 (AAV2; n = 19 PD studies, and n = 4 AADC deficiency study) ( 8 – 17 , 20 – 28 , 31 – 34 ) or lentivirus (LV; n = 2 PD studies) ( 18 , 19 ), 1 study of direct ventricular implantation of polymer-encapsulated cells in HD ( 29 ), 1 study of ASO intrathecal infusion in HD ( 30 ).…”

Section: Resultsmentioning

confidence: 99%

“…Twenty-seven participants (14 males and 13 females) received AAV2-AADC through intraputaminal bilateral infusions ( n = 20) or SN and ventral tegmental area (VTA) ( n = 7), in 2 phase I/II open-label studies, one phase I open-label study, and one compassionate use study, and were followed-up for 9–38 months ( 31 – 34 ) ( Tables 2 , 5 , 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…Three serious AEs were reported: one asymptomatic subdural hemorrhage related to the surgical procedure ( 33 ), one life-threatening hyperpyrexia ( 32 ), and one transient increase of apneic episodes ( 31 ). Two deaths due to Influenza B encephalitis ( 32 ) or to unknown cause ( 34 ) were considered unrelated to treatment. All participants experienced transient choreic movements weeks to months after surgery to varying degrees and most were managed with medication adjustments similar to what has been seen in the PD AAV2-AADC studies ( Table 6 ).…”

Section: Resultsmentioning

confidence: 99%

See 4 more Smart Citations

Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials

et al. 2021

Self Cite

View full text Add to dashboard Cite

Introduction: We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit.Methods: We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers).Results: We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers).Conclusion: Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

et al. 2022

View full text Add to dashboard Cite

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adenoassociated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

show abstract

An Introduction to Minimally Invasive Pediatric Epilepsy Surgery

Riviello

Curry

Weiner

2022

Journal of Pediatric Epilepsy

View full text Add to dashboard Cite

The field of minimally invasive surgery has evolved over the past 50 years, including neurosurgery, with an evolution to “minimally invasive neurosurgery” when feasible. Epilepsy surgery has followed this trend, with a transition from standard neurosurgical techniques to minimally invasive techniques in all phases of neurosurgical involvement. These include the diagnostic intracranial electroencephalogram with a subdural exploration to stereoelectroencephalography, the actual resection from an open craniotomy to a less destructive technique, or the multiple modalities of neuromodulation instead of a destructive surgery.The influence of these minimally invasive techniques has resulted in a change in the overall philosophy of pediatric epilepsy surgery. The expectations of what is considered “successful” epilepsy surgery has changed from total seizure control, in other words, a “cure,” to palliative epilepsy surgery with a decrease in the targeted seizures, especially “disabling seizures.” This has led to an overall greater acceptance of epilepsy surgery. This article summarizes the major reasons behind the explosion of minimally invasive pediatric epilepsy surgery, which are amplified in the subsequent articles. Some of this chapter includes the authors' opinions.

show abstract

Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency by MR-Guided Direct Delivery of AAV2-AADC to Midbrain Dopaminergic Neurons

Cited by 5 publications

References 29 publications

Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials

Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

An Introduction to Minimally Invasive Pediatric Epilepsy Surgery

Contact Info

Product

Resources

About