BACKGROUND:Glial cell line-derived neurotrophic factor (GDNF) is required for development and survival of dopaminergic neurons. A previous trial evaluating lower-dose adeno-associated virus serotype 2-GDNF (AAV2-GDNF) bilateral intraputaminal infusion in participants with advanced Parkinson's disease (PD) achieved 26% mean putaminal coverage and was associated with stable motor features with no unexpected adverse events (AEs) over 60 months. OBJECTIVE:We assessed safety and preliminary clinical outcomes of optimized bilateral intraputaminal infusion of a single, higher dose of AAV2-GDNF (product code AB-1005) for PD after 18 months. METHODS:This phase 1b single-arm, open-label clinical trial enrolled participants with mild (Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III off score ≤ 32) and moderate (MDS-UPDRS Part III off score of 33-60) PD. The primary outcome was safety. Clinical outcomes were assessed using PD-specific clinical measures. RESULTS:Eleven participants were enrolled (n = 6 mild; n = 5 moderate). Mean (±SE) putaminal coverage of AAV2-GDNF was 63% (±2%). All participants experienced treatment-emergent AEs (63 events); most were transient and perioperative. Six serious AEs in three participants were unrelated to AAV2-GDNF. At 18 months posttreatment, the mild cohort exhibited numerically stable MDS-UPDRS, motor diary, Unified Dyskinesia Rating Scale (UDysRS) scores, and levodopa equivalent daily dose (LEDD). The moderate cohort demonstrated numerical improvements in mean (±SE) MDS-UPDRS Part III off scores (-20.4 [±4.5]), motor diary off time (-1.7 [±1.1] hours), and UDysRS scores (-2.2 [±1.9]) and reduced LEDD (-257.6 [±162.2] mg). CONCLUSIONS:Bilateral intraputaminal AAV2-GDNF gene therapy was well tolerated and associated with numerical stability (mild cohort) and improvement (moderate cohort) in clinical assessments at 18 months posttreatment. © 2025 AskBio Inc and The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Parkinson's disease (PD) is characterized by loss of dopaminergic neurons and subsequent motor features. Adeno-associated virus serotype 2 glial cell line–derived neurotrophic factor (AAV2-GDNF; AB-1005), an investigational gene therapy, has shown promising results in pre-clinical models of PD. In a phase 1 study, participants with advanced PD showed increased [18F]DOPA values at 6 and 18 months post-infusion of AAV2-GDNF. This phase 1b study used alternate dopaminergic imaging to assess participants with mild or moderate PD who received AAV2-GDNF.

To assess safety and preliminary efficacy of adeno-associated virus vector serotype 2 containing glial cell–derived neurotrophic factor (AAV2-GDNF), AB-1005, in participants with mild or moderate Parkinson's disease (PD) administered using magnetic resonance imaging (MRI)-monitored, one-time bilateral, convection-enhanced delivery (CED).

Huntington's disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene comprising an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat sequence that results in a pathogenic huntingtin protein. Adeno-associated viral (AAV) gene therapy containing a primary artificial microRNA (pri-amiRNA) specifically targeting HTT messenger RNA (mRNA) has the potential to provide long-lasting therapeutic benefit, through durable reduction of mutant HTT expression after a single administration. The efficiency and precision of processing of the pri-amiRNA precursor to the mature guide (G) strand by transduced cells are critical for specific and potent HTT mRNA lowering. The selection of the optimized pri-amiRNA comprised a series of in vitro studies followed by in vivo studies in small and then large mammals. Our studies demonstrate the predictivity of certain cell culture systems and rodent models for nonhuman primates with respect to some, but not all key features of pri-amiRNA processing. In addition, our results show that the processing of pri-amiRNAs to the mature guide strand can differ greatly across different scaffolds and sequences while providing the same levels of target lowering. Importantly, our data demonstrate that there is a combinatorial effect of guide and passenger (P) strand sequences, together with the scaffold, on pri-amiRNA processing, with different guide and passenger strand sequences within the same scaffold dramatically altering pri-amiRNA processing. Taken together, our results highlight the importance of optimizing not only target lowering but also the efficiency and precision of pri-amiRNA processing in vitro, in rodents and in large mammals to identify the most potent and selective AAV gene therapy that harnesses the endogenous microRNA (miRNA) biogenesis pathway for target lowering without perturbing the endogenous cellular miRNA profile. The optimized pri-amiRNA was selected with this focus on efficiency and precision of pri-amiRNA processing in addition to its pharmacological activity on HTT mRNA lowering and general tolerability in vivo.

Ribs and vertebrae of 8 children and young adults aged from 17 months to 24 years with juvenile-onset diabetes mellitus, 4 with diabetes secondary to cystic fibrosis and 2 with diabetes secondary to thalassemia major, were analyzed for osteoporosis by a point-count morphometric method. The mean ratio of bone spicule to marrow space in cancellous bone of ribs of patients with juvenile-onset diabetes mellitus or with diabetes mellitus secondary to cystic fibrosis or thalassemia was 55% that of 10 control patients. The lengths of the zones of proliferating and mature cartilage cells in costal epiphyses of patients with juvenile-onset diabetes mellitus were also below normal. The ratio of bone spicule to marrow space of vertebrae of the diabetic patients was not significantly different from control values. The data confirm clinical reports that osteoporosis is a regular feature of juvenile-onset diabetes mellitus and suggest that the degree of bone matrix and mineral deficiency in such patients is greater than is usually considered.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.

May 5, 2019April 9, 2019Free AccessPD-1102: A Phase 1 study of VY-AADC01 Administered Using a Posterior Approach in Patients with Parkinson’s Disease and Motor Fluctuations (P1.8-017)Amber Van Laar, Mark Richardson, Chadwick Christine, Stewart Factor, Robert Gross, Sandra Kostyk, Russell Lonser, … Show All … , Marc de Somer, Alex Sedkov, Bernard Ravina, Adrian Kells, Krystof Bankiewicz, and Paul Larson Show FewerAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P1.8-017 Letters to the Editor

Objective To understand the safety, putaminal coverage, and enzyme expression of adeno‐associated viral vector serotype‐2 encoding the complementary DNA for the enzyme, aromatic L‐amino acid decarboxylase (VY‐AADC01), delivered using novel intraoperative monitoring to optimize delivery. Methods Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY‐AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 10 11 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10 11 vg); cohort 2 received the same concentration (8.3 × 10 11 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10 12 vg); and cohort 3 received 2.6 × 10 12 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10 12 vg). (18)F‐fluoro‐L‐dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. Results MRI‐guided administration of ascending VY‐AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of –15%, –33%, and –42%, respectively, at 6 months. At 12 months, there were dose‐related improvements in clinical outcomes, including increases in patient‐reported ON‐time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. Interpretation Novel intraoperative monitoring of administration facilitated targeted delivery of VY‐AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704–714

OBJECTIVE Successful convection-enhanced delivery of therapeutic agents to subcortical brain structures requires accurate cannula placement. Stereotactic guiding devices have been developed to accurately target brain nuclei. However, technologies remain limited by a lack of MRI compatibility, or by devices’ size, making them suboptimal for direct gene delivery to brain parenchyma. The goal of this study was to validate the accuracy of a novel frameless skull-mounted ball-joint guide array (BJGA) in targeting the nonhuman primate (NHP) brain. METHODS Fifteen MRI-guided cannula insertions were performed on 9 NHPs, each targeting the putamen. Optimal trajectories were planned on a standard MRI console using 3D multiplanar baseline images. After cannula insertion, the intended trajectory was compared to the final trajectory to assess deviation (euclidean error) of the cannula tip. RESULTS The average cannula tip deviation was 1.18 ± 0.60 mm (mean ± SD) as measured by 2 independent reviewers. Topological analysis showed a superior, posterior, and rightward directional bias, and the intra- and interclass correlation coefficients were > 0.85, indicating valid and reliable intra- and interobserver evaluation. CONCLUSIONS The data demonstrate that the BJGA can be used to reliably target subcortical brain structures by using MRI guidance, with accuracy comparable to current frameless stereotactic systems. The size and versatility of the BJGA, combined with a streamlined workflow, allows for its potential applicability to a variety of intracranial neurosurgical procedures, and for greater flexibility in executing MRI-guided experiments within the NHP brain.