Where Are We: Development of Gene and Cell Approaches for Parkinson Disease
According to recent studies and the latest insights provided by experts, early developments in gene and cell therapies show promise for patients living with Parkinson disease, but challenges remain.
According to recent studies and the latest insights provided by experts, early developments in gene and cell therapies show promise for patients living with Parkinson disease, but challenges remain.
In the current realm of treatments for Parkinson disease (PD), clinicians and patients have highlighted the need for more innovative approaches to address the progressive decline in dopamine network function that characterizes the condition. Gene therapy has emerged as a promising avenue to offer the potential for sustained restoration of neuronal function by introducing genetic material that can regulate dopamine levels and improve dopaminergic signaling in PD.1 The current gene therapy clinical trials in progress for PD are primarily aimed towards enhancing dopamine production enzymatically and reinstating the integrity of the nigrostriatal pathway.
Despite the potential of gene therapy for PD, substantial challenges impede its translation into clinical practice. The blood-brain barrier presents an obstacle since it impedes gene delivery into the central nervous system (CNS) unless it is directly administered. Modified vectors, both viral and nonviral, are in development to enhance delivery efficiency to target locations in the CNS; however, the limited number of approved gene therapy approaches for CNS diseases reflect the ongoing safety concerns associated with these viral vectors.2 To combat this, there’s an increasing focus on developing alternative nonviral biomaterial vectors to mitigate these safety risks for CNS disorders such as PD.
Challenges in Parkinson Gene Therapy
Researchers first assessed gene therapy more than 20 years ago, and since have continued to evolve the modality for the potential treatment of neurodegenerative diseases like PD.3 Despite the incremental rate of advancements realized for PD so far, clinicians believe there is hope for the technology. Gene therapy in PD may offer the opportunity to alter dopamine production and neuronal phenotype permanently, which would be a significant therapeutic advancement even if it does not constitute a cure.
In a recent interview with NeurologyLive®, Michael Kaplitt, MD, PhD, a professor of neurological surgery and vice chairman for research in the department of neurological surgery at Weill Cornell Medicine, discussed the regulatory barriers that exist for the approval of gene therapies, and how recent approvals in other neurological disorders have influenced the pathway for treatments in PD. He also touched upon the challenges associated with conducting long-term safety studies for gene therapies compared with how these studies are performed for conventional drugs. In addition, Kaplitt spoke about how patient selection and delivery methods can impact the effectiveness and feasibility of gene therapy for PD.
Progress in Advancing Gene Therapy for PD
AB-1005
AB-1005 (AskBio), an investigational adeno-associated viral vector serotype 2 (AAV2) gene therapy containing the human glial cell line-derived neurotrophic factor (GDNF) transgene, was recently assessed in a phase 1b trial (NCT04167540) for PD. The trial primarily looked at safety and potential clinical effect of AB-1005, with other secondary outcomes that assessed motor and nonmotor function, as well as brain dopaminergic network integrity through DaTSCAN. New data from the phase 1b study showed that the therapy met its primary end point of successful putamen coverage and was safe over an 18-month period.
The study, which follows patients for up to 5 years post administration, scheduled 6-month postoperative MRIs revealed findings of asymptomatic unilateral T1 hypointensity adjacent to 3 of the putaminal infusion trajectories. Although the study was small in scale, with only 11 patients included, those with mild (n = 6) and moderate (n = 5) forms of PD experienced improvements in ON and OFF time with AB-1005.4 According to data presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, neurosurgical delivery of AB-1005 resulted in putamen coverage of 63% (±2%), exceeding the goal of greater than 50% coverage. Bilateral infusions of the agent in the putamen (up to 1.8 mL) were well tolerated, with no serious adverse events associated with the gene therapy or contrast agent.
Russell Lonser, MD, director for the Gene Therapy Institute and chair of the department of neurological surgery at The Ohio State University, discussed the key challenges in optimizing gene therapy for PD, particularly regarding target selection and gene choice, with NeurologyLive. He also spoke about how findings from the recent phase 1b trial further contribute to the understanding of the potential of gene therapy's efficacy and safety in treating PD. In addition, Lonser talked about the potential implications of gene therapy advancements for the future treatment landscape of neurological disorders beyond PD.
The Research Needed to Bring Gene Therapy to PD
In light of the growing interest in gene therapy as a potential modality for treating PD, CGTLive® reached out to Ignacio Mata, PhD, an associate professor of neurology at the Cleveland Clinic Lerner Institute, to get his insight on the obstacles that will need to be overcome to make gene therapy successful in PD. Mata pointed out that PD is not like the monogenic disorders where gene therapy has seen its initial success, but is instead linked to a very large number of different genes. As such, trying to target a specific gene to be “fixed” or replaced is unlikely to be the best approach; instead early success in preclinical research has largely come from inserting genes that simply provide sustained expression of a protein that can help relevant neurons stay alive. Mata also emphasized the need for innovative delivery methods to target the gene therapy to the brain and the need to determine appropriate timing in terms of disease progression to deliver such treatments.
He also gave his view that because PD is such a complex order, it will likely be helpful for researchers to think of PD as a group of related diseases rather than a single disease. He highlighted the need for more research into the pathophysiology of PD itself, as grouping of patients into appropriate subgroups for treatment has likely been a barrier for pursuing gene therapy in PD.
Potential of Cell Therapy in Parkinson
Other than gene therapies, another treatment approach being investigated in movement disorders within recent decades are cell-based strategies which focus on replacement or protection of dopaminergic neurons. These treatment strategies are comprised of neural progenitor cells, fetal stem cells, bone marrow mesenchymal stem cells, retinal pigment epithelial cells, or induced pluripotent stem cells.5 In a recent report from GlobalData, using data from BlueRock Therapeutics’ phase 1 study (NTC04802733) assessing bemdaneprocel, an investigational allogenic stem cell derived cell therapy, and other clinical trials for PD, findings suggest that cell therapies in development may address the motor and nonmotor symptoms of patients with PD with minimal adverse effects.6
Bemdaneprocel
BlueRock Therapeutics recently presented positive 18-month data on bemdaneprocel from the phase 1 study at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held March 5-9, in Lisbon, Portugal. Conducted by lead author Claire Henchcliffe, MD, chair of the Department of Neurology, UCI School of Medicine, University of Califorina, Irvine, and colleagues, the results showed that the agent was safe and well tolerated, with treated patients demonstrating improvements in ON and OFF state time over that time.7
"The results are encouraging, however as a phase 1 study which was not powered to measure statistical significance against a control group, bemdaneprocel’s true clinical potential is likely to be demonstrated in future later phase trials,” Lorraine Palmer, PhD, a pharma analyst at GlobalData, told NeurologyLive when asked about her reaction to these recently presented findings. "The results from the phase 1 study do not have significant implications for patients with PD at the moment because of the early stage of bemdaneprocel. The present results suggest survivability of the transplanted cells and an improvement in both motor and nonmotor symptoms. However, conclusions cannot be drawn until further trials are carried out."
The multicenter, open-label, nonrandomized, noncontrolled trial enrolled 12 patients with PD, who received surgical transplantation of 1 of 2 different dose levels of bemdaneprocel cells to the postcommissural putamen bilaterally. The patients were also treated with an immunosuppression regimen for 1 year. Using the Hauser Diary, those in the high-dose cohort demonstrated a mean increase of 2.7 hours in ON state time compared with baseline following 18 months of treatment. Additionally, this patient group demonstrated a mean reduction of 2.7 hours in time spent in the OFF state.
In the 2 cohorts, patients on high-dose bemdaneprocel (n = 7) received a dose of 2.7 million cells per putamen whereas those in the low-dose group (n = 5) received a dose of 0.9 million cells per putamen. The initial 12-month data from the trial, presented at the 2023 International Congress of Parkinson’s Disease and Movement Disorders, held August 27-31, in Copenhagen, Denmark, highlighted the efficacy and safety of this treatment. At 1 year, the participants in the high-dose cohort displayed a reduction of 13.0 points in MDS-UPDRS-III scores compared with baseline. Additional findings were less pronounced in the low-dose cohort, with reductions of 7.6 points in MDS-UPDRS-III scores after 1 year.
Imaging analysis using 18F-DOPA PET, a technique used to visualize and assess dopaminergic activity, revealed evidence of cell survival and engraftment in both the high and low dose cohorts. At 1-year follow-up investigators observed no reports of serious adverse events (AEs) attributable to bemdaneprocel; however, they did note 2 unrelated serious AEs of seizure attributed to the surgical procedure and 1 COVID case, all of which resolved without sequelae.
At the 2024 AAN Annual Meeting, NeurologyLive sat down with PD expert Daniel Kremens, MD, JD, an associate professor of neurology and codirector of the Parkinson’s Disease and Movement Disorders Center at Thomas Jefferson University, to discuss some of the top data being presented at the meeting on novel approaches in development for the treatment of the movement disorder. Kremens discussed these various presentations, offering his perspective on the clinical landscape. In this segment, Kremens discussed new data from an early-stage trial assessing bemdaneprocel in patients with PD. He gave his reaction to the findings presented at AAN and how they will impact clinical care going forward.
"The current medications used for the treatment of PD are limited to those providing symptomatic relief of motor symptoms, leaving ample opportunities for new entrants into the PD market," Palmer commented when asked about the current state of care for PD. "The need for disease-modifying therapies that can slow or modify the disease course is one of the highest unmet needs and was consistently highlighted in KOL discussions with GlobalData."
GlobalData highlighted 2 other neuronal progenitor stem cell therapies that have completed phase 1 or above trials in PD and disclosed results.6 These other therapies include ISC-hpNSC (Cyto Therapeutics) and HSCfPD (Celavie Biosciences). Similar to the trial assessing bemdaneprocel, Cyto Therapeutics reported improvement in nonmotor symptoms in its phase 1/2a trial (NCT02452723) with ISC-hpNSC. In addition, Celavie Biosciences noted minor improvements in nonmotor symptoms in its phase 1 trial (NCT02780895) with HSCfPD. "It is worth noting that the highest stage of development for PD cell therapies undertaken so far is a phase 2a trial. So while they show promise, it is still too early stage for any firm conclusions to be drawn," Palmer added.
There are 5 other neuronal progenitor stem cell therapies being investigated in phase 1 and phase 2 trials for PD, all currently have no published results. It was noted in the report that only 2 companies have disclosed estimated publication dates for its trial data: NN-9001 (Novo Nodisk AS) anticipates publication in 2025 and TED-A9 (S.Biomedics) anticipates publication in 2026. Palmer noted, “Therefore, the next few years will be crucial in determining the full potential of neuronal stem cell therapies for the treatment of PD, including replacing lost dopaminergic neurons and the treatment of nonmotor symptoms.”
TED-A9
In February 2024, S.Biomedics announced successful completion of the brain transplant of cell therapy TED-A9 for its phase 1/2a study in PD.8 The trial was conducted on 12 patients, between the ages of 50 and 75 years, who had been diagnosed with PD for over 5 years and showed complications such as the drug wearing-off, freezing of gait, or dyskinesia. In the study, TED-A9 was administered to 6 patients in the low-dose group (3.15 million cells) and to another 6 patients in the high-dose group (6.30 million cells).
Initially, a cohort of 3 patients were enrolled at a low dose to investigate the safety of TED-A9, which included dose-limiting toxicity evaluation up to 3 months posttransplantation. In this time frame, investigators observed no reports of safety concerns and because of this, an additional 3 patients were enrolled at a high dose for evaluation over another 3 months posttransplantation. Since there continued to be no safety issues reported in the extended period, the trial added another 3 patients to each of the low-dose and high-dose groups, totaling 12 patients. Overall, none of the 12 participants had any adverse events, complications, or unusual adverse reactions following the transplantation of TED-A9.
"PD is characterized by progressive degeneration of the neurons of the substantia nigra pars compacta, which reduces the levels of dopamine available for neurotransmission in the corpus striatum. As such, cell therapies could have the potential to replace the loss of dopaminergic neurons in PD patients," Palmer told NeurologyLive when questioned about cell therapies in PD. "Early clinical trials of stem cell transplantation in idiopathic PD patients have shown a reduction in motor symptoms and nonmotor symptoms. However, the sample size of these clinical trials have been small and were not powered to measure statistical significance. Moving forward, large scale pivotal trials are required to investigate the efficacy of stem cell therapy on functional improvement (including the assessment of motor and nonmotor PD symptoms), the safety profile, and the ability of stem cells to restore dopaminergic neurons in patients with PD."
SNK01
NKGen’s autologous natural killer (NK) cell therapy SNK01 was recently cleared by the FDA for a phase 1/2a clinical trial in patients with PD on April 30, 2024.9 SNK01, which is the subject of a collaboration between NKGen Biotech and the Parkinson’s Foundation minted in November 2022, is comprised of autologous NK cells that are not genetically engineered, but have enhanced cytotoxicity and activating receptor expression.9,10 The cell therapy was previously approved for a compassionate use administration to a patient with PD in February 2023.11 SNK01 is also being evaluated in a phase 2 clinical trial in people with Alzheimer disease (AD).12
Following the investigational new drug application clearance for the PD trial, CGTLive reached out to Paul Y. Song, MD, the chairman and chief executive officer of NKGen to learn more about the challenges of cell therapy in PD and the development of SNK01 so far. In the May 2024 interview, Song discussed the experience of the patient treated in the compassionate use case, who happens to also be a personal friend of Song. Song noted that the patient shows symptoms that his doctors consider to be early signs of AD in addition to his PD symptoms, and as such SNK01 is effectively being tested as a treatment for both diseases in this patient. Song pointed out that the patient has experienced dramatic improvement after treatment with SNK01 that helped to provide a rationale for going forward with the phase 1/2a trial in PD.
Where We Are Now
The opportunity that gene and cell therapies possess in the field of Parkinson disease can potentially lead to an impactful outcome, improving symptoms among patients and enhancing their quality of life. Currently, there are several clinical trials assessing these therapeutics, most in their early stages but show promising results thus far. Experts have shared their excitement in regard to these ongoing studies and provided their insight into how these treatments can address unmet needs among patients. Based on what has been gathered in conversation from the experts and presented in the recent data from trials, there is still a lot of research that needs to be done and obstacles to overcome in order to get these treatments approved for this patient population.
In a conversation between CGTLive and Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, a clinical research services organization, Phippard expressed optimism for the future of gene therapy in PD, but did not discount the fact that many challenges still need to be overcome. She drew attention to the need to scale up manufacturing and bring down costs of production to accommodate the large number of patients with PD if these therapies are successful. Phippard also noted the need to have feasibly measurable end points for PD gene therapy trials and corroborated Mata’s view on the continued need to better understand PD pathophysiology.
“I always joke that gene therapy truly takes a village,” Phippard concluded. “We need more work on biomarkers, we need more work on clinical endpoints, we need help from the regulatory agencies—what do we have to do to be able to get a gene therapy approved?... We're at a good inflection point for this research. Phase 1/2 trials have started. So yes, it's very exciting, but I think we still have a long way to go to treat these patients."
