Parkinson’s disease is characterized by the loss of dopamine-producing neurons. The current treatment is oral levodopa, which is taken up by brain neurons and converted to dopamine. But levodopa eventually loses its efficacy as those neurons continue to die. When the medication no longer helps patients, another treatment option is deep brain stimulation. However, this surgical procedure comes with risks that include infection, bleeding in the brain, and stroke.
Although these treatments can do much to relieve the symptoms of Parkinson’s disease, no treatment yet exists to slow the disease’s progression or repair the damage the disease inflicts on the brain—but that may be about to change. New gene and cell therapies are on the horizon to modulate the brain activity that causes the characteristic motor symptoms associated with Parkinson’s disease, heal the damage done to the brain, and even regrow lost neurons.
Autologous cell therapy to replace lost neurons
Because Parkinson’s disease takes time to diagnose, patients may have significant neuron loss before they begin treatment. Aspen Neuroscience is developing an autologous cell therapy to replace these neurons and reestablish the connections that have been lost, potentially reversing the symptoms of the disease.
“Typically, by the time patients are diagnosed with Parkinson’s, 50% of their dopamine neurons are gone, and their neural circuits are disrupted,” says Xiaokui Zhang, PhD, chief scientific officer, Aspen Neuroscience. “The transplanted cells that we are making could fill that gap, reconstruct neural networks, and produce the dopamine that is needed for biological functions.”
Allogeneic cell therapies have the disadvantage that the recipient’s immune system will attack the new cells as foreign, meaning powerful immunosuppressants will have to be administered. Autologous therapies, by contrast, are made from the patient’s own cells and pose no risk of an immune reaction. Aspen Neuroscience starts with skin cells and reprograms them into induced pluripotent stem cells (iPSCs), then differentiates those into dopaminergic neuronal precursor cells. “The cells are not only younger in terms of telomere lengths, but they also have enhanced mitochondrial function,” Zhang asserts. “After transplantation, the neurons can reconstruct the lost neural circuits in the patient.”
The therapy has received IND clearance and Fast Track designation from the FDA. The first cohort has been dosed in a Phase I/IIa trial. PET scans at 6, 12, and 18 months will reveal whether dopamine expression has been restored.
Each lot of cells is characterized using a machine learning algorithm trained on extensive genomic and transcriptomic data to predict clinical efficacy. Clinical data from the trial will also be used to further refine the algorithm. Zhang declares, “Our dream is that we will be able to utilize this algorithm for every patient, to predict whether the patient will actually benefit from our therapy.”
Inducing neuron regrowth
Levodopa, the standard treatment for Parkinson’s disease, is a dopamine precursor that can pass into the brain, where it reduces symptoms by restoring dopamine. But levodopa eventually stops working because it doesn’t slow disease progression. “The brain cells are still dying, so you need more and more levodopa to achieve the same benefit,” says Amber Van Laar, MD, senior vice president, global clinical development, Asklepios BioPharmaceutical (AskBio).
AskBio has developed a gene therapy that could help protect dopaminergic neurons from Parkinson’s-related damage. The therapy, AB-1005, delivers the gene for glial-derived neurotrophic factor (GDNF) directly into the putamen, one of the brain regions damaged by Parkinson’s disease. “This is where a lot of the devastation occurs in Parkinson’s,” Van Laar explains. “However, we’re able to take advantage of the networks that are not injured by Parkinson’s, and we can use these established networks to help distribute our gene therapy beyond the putamen.”
Evidence from animal studies and postmortem brain examinations shows that GDNF stimulates new terminal growth in neurons, boosting the ability of these neurons to make and process dopamine. In this way, GDNF gene therapy not only relieves the motor symptoms associated with the disease but could prolong the usefulness of dopamine-restoring medication.
Phase I data have shown that AB-1005 is safe and well tolerated, and patients with both mild and moderate disease were able to reduce their daily dose of levodopa. Motor symptoms, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) and patient-reported motor diaries, remained stable among the mild cohort and improved considerably among the moderate cohort. “At 36 months, their scores were better than where they were on medication before starting the study,” Van Laar notes. “From a motor standpoint, we’ve turned the clock back and put them into a milder phenotype.”
The FDA has granted Fast Track Designation to AB-1005, and a Phase II, blinded study is currently recruiting.
Reducing hyperactivation of motor neurons
The dopamine deficit in Parkinson’s disease causes hyperactivation of a brain region called the subthalamic nucleus (STN), which also contributes to motor symptoms. The neurotransmitter γ-aminobutyric acid (GABA) can reduce STN hyperactivation and lessen the symptoms, but it can’t be given systemically the way dopamine is—it must be targeted to the STN. A new treatment, a one-time gene therapy called AAV-GAD, has been developed by MeiraGTx. AAV-GAD uses an adeno-associated virus (AAV) capsid to deliver the gene for glutamic acid decarboxylase (GAD) to STN neurons, enabling them to produce GABA. The therapy is infused into the brain using the same surgery that is currently used for deep brain stimulation, which quiets the STN using electricity.
“We address the hyperactivation of the subthalamic nucleus by calming it down and circumventing the need for dopamine in patients who are no longer responding adequately to dopamine,” says Alexandria Forbes, PhD, president and CEO, MeiraGTx.
Phase I and II trials of AAV-GAD have previously shown that the therapy is safe and well tolerated. In October 2024, MeiraGTx reported data from a bridging study using material manufactured at their facilities. “We did this bridging study on the guidance of the FDA to be able to use our material in a Phase III study to support global regulatory filing,” Forbes explains. Patients who received AAV-GAD showed clinically meaningful improvement in their motor symptoms, as reported on the UPDRS, and their quality of life, as measured by the Parkinson’s Disease Questionnaire (PDQ-39).
Forbes points out that the therapy is effective at very small doses, and that the cost to manufacture is quite low. “People tend to think of gene therapy as gene replacement,” Forbes remarks. “We really are using DNA as a delivery device for a biologic therapeutic, in this case a neurotransmitter that changes cell function in a way that we can have a big effect, and the cost of goods is really manageable. We can deliver value for patients that they can’t get through an oral biologic at the moment.”
Delivering gene therapy into the brain without surgery
Voyager Therapeutics has developed a novel gene therapy program in which a GBA1 gene replacement payload is carried by an AAV capsid across the blood-brain barrier, eliminating the need for surgery to deliver the payload. GBA1 encodes a lysosomal enzyme called glucocerebrosidase (GCase). Full inactivation of GBA1 causes Gaucher’s disease, a lysosomal storage disease, and mutations in GBA1 are also found in around 10% of Parkinson’s disease patients. Gaucher’s disease can be treated with enzyme replacement therapy, which restores GCase function in the body, but because of the difficulty delivering large molecules to the brain, this approach can’t address neurological symptoms. Voyager’s capsid discovery platform, TRACER (“Tropism Redirection of AAV by Cell-type-specific Expression of RNA”), applies directed evolution to AAV capsids to find vectors optimized for delivery to the brain and decreased delivery to the liver.
The AAV capsids take advantage of the brain’s natural mechanisms for transporting macromolecules across the blood-brain barrier. “We look for receptors that are responsible for delivery to the brain,” says Todd Carter, PhD, chief scientific officer, Voyager. “We’re piggybacking on a necessary normal function, using that to deliver our therapy across the blood-brain barrier.”
Voyager selects capsids that can cross the blood-brain barrier in multiple species to increase the likelihood they will work similarly in humans. The company then uses human protein and cell assays to show that protein is expressed in the human vascular system and that the capsids bind the human protein. Targeting these receptors enables widespread delivery throughout the brain.
“We are harnessing the massive distribution of the vascular system throughout the central nervous system,” Carter explains. “We are also exploring these receptors for nonviral delivery of other molecules.” Voyager has also designed other families of capsids tuned to different receptors, depending on what type of brain cell is being targeted.
Voyager has partnered with Neurocrine Biosciences to advance the GBA1 gene therapy candidate clinically, and it is progressing toward an anticipated IND in 2025.
Knocking down α-synuclein
A characteristic feature of Parkinson’s disease is buildup in the brain of the protein α-synuclein. Denali Therapeutics has developed an antisense oligonucleotide against α-synuclein and a novel delivery method to get it across the blood-brain barrier.
Antisense oligos can reduce gene expression by binding to mRNA and preventing it from being translated into protein. However, the blood-brain barrier prevents these molecules from entering the brain. Denali has designed a transport vehicle (TV) that carries the antisense oligo into the brain by binding to the transferrin receptor, which is expressed in the vasculature of the brain, to shuttle the iron-carrying protein transferrin into the brain.
“The TV binds to transferrin receptor and essentially hijacks that transport route to bring drugs effectively into the brain,” explains Joe Lewcock, PhD, chief scientific officer, Denali. “It enables systemic administration, higher brain levels, and good brain biodistribution.”
Denali’s TV platform has been clinically validated in a Phase I/II trial of enzyme therapy for lysosomal storage disease. Having shown that TV can deliver replacement enzyme to the brain safely and effectively, the company is now moving forward with IND-enabling studies on the oligonucleotide targeting α-synuclein in Parkinson’s disease.
“Our Parkinson’s program leverages that TV technology to transport the synuclein antisense into the brain, into the right regions of the brain to knock down expression and eliminate α-synuclein-related toxicities,” Lewcock explains. “We’re excited, because we feel it has broad potential to deliver all different types of therapeutics, with this antisense being one of them.”
