The Next Frontier in Parkinson Disease Care: Exploring Gene and Cell Therapies

Cell and gene therapies are emerging as key players in the treatment of Parkinson disease (PD), offering innovative strategies to slow or stop disease progression by targeting genetic mutations, neurotrophic factors, and protein aggregation. Among the most promising therapies in development are PR001, a gene therapy aimed at patients with PD GBA1 mutations, and AB-1005, which leverages glial cell line-derived neurotrophic factor (GDNF) to support dopaminergic neuron regeneration. UB-312, an active immunotherapy targeting pathological α-synuclein, is also showing promising early results, while other therapies like bemdaneprocel and AAV-GAD explore stem cell- and gene-based approaches to restore brain function.

In this feature, NeurologyLive^® will provide an in-depth look at these groundbreaking therapies, highlighting the latest clinical trial updates, safety profiles, and potential impacts on patient outcomes. Readers can expect detailed insights into these therapies' mechanisms of action, as well as expert perspectives on what lies ahead in the development of these cutting-edge treatments. Stay tuned for comprehensive coverage of the agents that may redefine how we approach PD care.

Pipeline Overview

PR001 (Prevail Therapeutics/Eli Lilly) - PD with GBA1 mutations

PR001, also known as LY3884961, is an investigational adeno-associated virus serotype 9 (AAV9) vector-based gene therapy currently being evaluated in a phase ½ trial dubbed PROPEL (NCT04127578) in patients with PD who have at least 1 mutation in the GBA1 gene. Currently, it is estimated that up to 10% of people with PD carry a mutation in 1 copy of GBA1 that reduces enzyme activity and affects lysosomal function.

PROPEL, initiated in 2020, is estimated to enroll 20 patients total, completing in mid-2029. The trial assesses both low- and high-dose PR001 in separate cohorts, with each patient receiving a single PR001 administration alongside six IV pulses of methylprednisolone over three months; sirolimus may be used if methylprednisolone is not tolerated. Over the 5-year study period, investigators will assess cumulative number of treatment-emergent adverse events and serious AEs, as well as incidence of procedure AEs or TEAEs as measured via brain MRI, spine MRI, and nerve conduction study.

Other secondary and exploratory end points include blood and cerebrospinal fluid measures of glucocerebrosidase, glycolipid metabolism, α-synuclein and neurofilament light chain, PR001 immunogenicity, measures of clinical and daily function, and MRI and dopamine imaging. In August 2020, the study was temporarily halted after a serious AE occurred in the first treated patient. The unspecified events were reportedly resolved with immunosuppressive treatment, and the study protocol was thus changed to an open-label design with no sham injection arm, and with concomitant administration of the immunosuppressants prednisone and sirolimus.^1,2

AB-1005 (AskBio) - Idiopathic PD

Earlier this year, AskBio announced the initial patient dosing for its phase 2 REGENERATE-PD trial (NCT06285643) testing AB-1005, a glial cell line-derived neurotrophic factor (GDNF) investigational gene therapy for the treatment of moderate-stage PD. This gene therapy, based on adeno-associated viral vector serotype 2 (AAV2), is an innovative new approach that will test the GDNF hypothesis in PD by getting this neurotrophic factor to degenerating nigrostriatal neurons in a potentially more clinically relevant fashion.

REGENERATE-PD is a phase 2, randomized, double-blind, sham-controlled study testing efficacy and safety of AB-1005 in patients aged 45-75 years with moderate-stage PD. The study, expected to include 87 participants, is conducted across sites in the United States, Germany, Poland, and the United Kingdom.

Prior to REGENERATE-PD, the therapy demonstrated efficacy and safety in a phase 1b, 18-month trial. Although the study included only 11 patients with mild (n = 6) and moderate (n = 5) forms of PD, the therapy met its primary end point, with improvements observed in ON and OFF time among treated patients. Overall, treatment with the agent resulted in putamen coverage of 63% (±2%), exceeding the goal of greater than 50% coverage. In terms of safety, bilateral infusions of the gene therapy within the putamen were well tolerated, with no serious adverse events associated with the gene therapy or contrast agent.³

At the 2024 International Congress of Parkinson’s Disease and Movement Disorders, 36-month data from phase 1b of that study continued to reinforce AB-1005's safe and tolerable profile. In terms of efficacy, the moderate PD cohort showed trends for improvement or stability on several motor scales at 36 months, including Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and motor diaries, and trends in reductions in PD medications, such as levodopa-equivalent daily dose (LEDD)..Overall, most participants in the mild PD cohort showed a stable clinical status with little change in MDS-UPDRS, the self-reported PD motor diary, or LEDD.⁴

UB-312 (Vaxxinity) - Synucleinopathies

UB-312 is an active immunotherapy medicine targeting pathological α-synuclein designed to slow or stop PD progression by addressing the root cause of the disease. Considered a vaccine, this unique treatment is designed to induce antibodies against oligomeric and fibrillar α-synuclein. To date, the therapy has shown promising results in a phase 1 study of PD andis expected to enter next-stage trials in the near future.

Published in Nature Medicine, the phase 1 study comprised 20 patients with PD who were randomized 7:3 to placebo (n = 6), UB-31 300/100/100 ug (n = 7), or UB-312 300/300/300 ug (n = 7) treatment groups for a 44-week period. The trial included two parts: Part A assessed safety, tolerability, and immunogenicity in 50 healthy participants, with 23 receiving all three intramuscular doses (40–2000 μg) at weeks 1, 5, and 13; Part B evaluated two doses of UB-312 vs placebo in 20 age-matched patients with early PD over 20 weeks, followed by a 24-week observation period. Overall, the data showed that the therapy was safe and well tolerated, with headache, local pain after lumbar puncture, and fatigue as the most common treatment-emergent AEs.

In exploratory analyses, investigators observed stable scores on the Montreal Cognitive Assessment and MDS-UPDRS Part II and III, with no significant differences between the treatment and placebo groups. However, patients with detectable CSF antibody titers showed a statistically significant improvement from baseline on MDS-UPDRS Part II compared to those without detectable titers (F = 12.94, 95% CI: 1.569–24.32; P = 0.0004), with a notable treatment-by-time interaction (F = 4.739; P = 0.016). Additionally, immunologic analysis using postimmunization immunoglobulin fractions from healthy volunteers in Part A revealed strong binding to aggregated α-synuclein and minimal binding to recombinant monomeric α-synuclein.⁵

BIIB122 (Denali Therapeutics) - Early-Stage PD

BIIB122 is a selective and brain-penetrant small molecular inhibitor of leucine-rich repeat kinase 2 (LRRK2) that may reduce lysosomal dysfunction and potentially slow disease progression inPD. The investigational therapy is currently being assessed in the phase 2b double-blind, placebo-controlled, LUMA study (NCT05348785) in patients with early-stage PD between the ages of 30 and 80 years with or without a LRRK2 mutation.⁶

In the study, participants are randomly assigned to either 225 mg of oral BIIB122 or placebo once daily for a minimum of 48 weeks and a maximum of 144 weeks. To understand whether BIIB122 slows the worsening of symptoms, investigators are evaluating patients on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts 2 and 3.In addition to MDS-UPDRS, other outcomes investigators will key in on include treatment-emergent adverse events (AEs) and serious AEs, and time to confirmed worsening in Schwab and England Activities of Daily Living Scale (SEADL).

In 2 early-phase, placebo-controlled trials, the LRRK2 inhibitor BIIB122 was reported as safe and well tolerated in both healthy participants and patients with mild to moderate PD. Published inMovement Disorders, the drug demonstrated strong central nervous system penetration and achieved substantial, dose-dependent reductions in key biomarkers related to LRRK2 activity and lysosomal pathway engagement. These previously published findings support theagent’s continued development as a potential treatment for PD.⁷

Bemdaneprocel (BlueRockTherapeutics) - Idiopathic PD

Bemdaneprocel, otherwise known as BRT-DA01, is a stem cell approach in which neuron precursors are implanted into the brain of a patient with PD through a surgical procedure. When transplanted, these neuron precursors have the potential to reform neural networks that have been severely impacted by the disease and to potentially restore motor and nonmotor function to patients.To date, the investigational product has received fast track and regenerative medicine advance therapy designations from the FDA.

This investigational cell therapy will be assessed in a phase 3 registrational trial dubbed exPDite-2 (NCT06944522) which is anticipated to begin in the first half of 2025.⁸ The study, the first such phase 3 trial testing an allogeneic pluripotent stem cell therapy in PD, is expected to be a randomized, sham surgery-controlled double-blind trial featuring approximately 102 patients with moderate levels of the disease. In an attempt to build on positive phase 1 data, the study will use change in PD diary measure of ON time without troublesome dyskinesia, adjusted for a 16-hour walking day, over a 78-week period as the primary end point.

Bemdaneprocel first showed promising outlook in the phase 1 exPDite trial, a multicenter, open-label, nonrandomized, noncontrolled study of 12 patients with PD. In the study, patients received surgical transplantation of 1 or 2 different doses of the cell therapy to the post-commissural putamen bilaterally, along with administration of a 1-year immunosuppression regimen. In the high dose cohort, patients demonstrated a mean reduction of 21.9 points in UPDRS Part III compared with baseline while the low dose cohort demonstrated mean decreases of 8.3 points. Furthermore, at this time point, there was a mean reduction of 3.4 points and 2.0 points in the high and low-dose cohorts, respectively, on MDS-UPDRS Part II, a measure of activities of daily living.⁹

AAV-GAD (MeiraGTx) - Idiopathic PD

AAV-GAD is an experimental gene therapy aimed at restoring proper brain circuit function in all forms of PDby promoting localized production of GABA, a neurotransmitter that helps regulate cellular activity. It is administered through a 1-time, minimally invasive infusion using MeiraGTx’s proprietary device, which delivers a small amount of the therapy directly into the subthalamic nucleus, a critical brain region involved in movement control.

The company noted that the therapy is phase 3 ready¹⁰ and has an ongoing long-term follow-up study assessing AAV-GAD in participants for atotal of 5 years posttreatment (NCT05894343) who completed the clinical bridging MGT-GAD-025 study (NCT05603312).MGT-GAD-025 is a 6-month, 3-arm, randomized, double-blind, sham-controlled study investigating AAV-GAD among participants who had idiopathic PD, a history of levodopa responsiveness for at least 12 months, and a UPDRS Part 3 score of at least 25 points in the "OFF" state. Participants were randomized to receive either AAV-GAD infused bilaterally into the STN (low dose group, 7.0×1010 vg; high dose group, 21×1010 vg or a sham procedure in a blinded fashion. The primary objective was to assess the safety and tolerability of the gene therapy while exploratory efficacy end points included the mean change in MDS-UPDRS Part 3 scores in the “OFF” state and the Parkinson’s Disease Questionnaire (PDQ-39) score.

In topline data from MGT-GAD-025, findings showed that over a 26-week period, patients with PD treated with the agent displayed significant improvement in motor function.Among all the participants in the trial (n = 14), the high-dose AAV-GAD group (n = 5) had a statistically significant 18-point average improvement from baseline in the UPDRSPart 3 “OFF” medication score (P = .03) at week 26, with no significant changes observed by researchers in the sham or low-dose groups (n = 4; n = 5; respectively). Notably, investigators also reported that AAV-GAD demonstrated safety and was well tolerated, with no serious adverse events related to the treatment observed among the participants.¹¹

REFERENCES
1. Phase 1/ 2a Clinical Trial of PR001 (LY3884961) in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL). Clinicaltrials.gov. Website. Accessed April 29, 2025. https://www.clinicaltrials.gov/study/NCT04127578
2. LY3884961. Alzforum. Updated February 3, 2023. Accessed April 29, 2025. https://www.alzforum.org/therapeutics/ly3884961
3. AskBio presents 18-month phase 1b trial results of AB-1005 gene therapy for patients with Parkinson disease. News release. AskBio. April 16, 2024. Accessed April 29, 2025. https://www.globenewswire.com/news-release/2024/04/16/2863581/0/en/AskBio-presents-18-month-Phase-Ib-trial-results-of-AB-1005-gene-therapy-for-patients-with-Parkinson-s-disease.html
4. First participants randomized in AskBio Phase II gene therapy trial for Parkinson’s disease. News release. AskBio. January 14, 2025. Accessed April 29, 2025. https://www.bayer.com/en/us/news-stories/phase-ii-gene-therapy-trial-for-parkinsons-disease
5. Eijsvogel P, Misra P, Concha-Marambio L, et al. Target engagement and immunogenicity of an active immunotherapeutic targeting pathological a-synuclein: a phase 1 placebo-controlled trial. Nature. Published online June 20, 2024. doi:10.1038/s41591-024-03101-8
6. Denali Therapeutics and Biogen announce initiation of phase 2b study of LRRK2 inhibitor in Parkinson disease. News release. Biogen. May 31, 2022. Accessed April 29, 2025. https://investors.biogen.com/news-releases/news-release-details/denali-therapeutics-and-biogen-announce-initiation-phase-2b
7. Jennings D, Huntwork-Rodriguez S, Vissers MFJM, et al. LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease. Mov Disord. 2023;38(3):386-398. doi:10.1002/mds.29297
8. BlueRock Therapeutics advances investigational cell therapy bemdaneprocel for treating Parkinson’s disease to registrational Phase III clinical trial. News release. BlueRock Therapeutics. January 13, 2025. Accessed April 29, 2025. https://www.bluerocktx.com/bluerock-therapeutics-advances-investigational-cell-therapy-bemdaneprocel-for-treating-parkinsons-disease-to-registrational-phase-iii-clinical-trial/
9. BlueRock Therapeutics’ investigational cell therapy bemdaneprocel for Parkinson’s disease shows positive data at 24-months. News release. BlueRock Therapeutics. September 27, 2024. Accessed April 29, 2025. https://www.bayer.com/media/en-us/bluerock-therapeutics-investigational-cell-therapy-bemdaneprocel-for-parkinsons-disease-shows-positive-data-at-24-months/
10. MeiraGTx Enters into a Strategic Collaboration with Hologen AI to Expedite Phase 3 Development of AAV-GAD for Parkinson’s Disease and Industrialize MeiraGTx’s Proprietary Manufacturing Process. News Release. MeiraGTx. Published March 13, 2025. Accessed April 29, 2025. https://investors.meiragtx.com/news-releases/news-release-details/meiragtx-enters-strategic-collaboration-hologen-ai-expedite
11. MeiraGTx Announces Positive Data from Randomized, Sham-controlled Clinical Bridging Study of AAV-GAD for the Treatment of Parkinson’s Disease. News Release. MeiraGTx. Published October 15, 2024. Accessed April 29, 2025. https://investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-positive-data-randomized-sham-controlled