Article In Brief
A novel small-molecule modulator, S-181, shows promise in animal studies for the treatment of a familial form of Parkinson's disease, but researchers say S-181 is not yet ready for phase 1 trials in humans.
Mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase), represent the most commonly known genetic risk factor for Parkinson's disease (PD). In animal models of PD, early research suggests that a novel small molecule modulator of GCase offers not only a promising precision medicine pathway for treatment of this subgroup of Parkinson patients, but also a potentially broader treatment option for sporadic, “wild-type” PD.
Dmitri Krainc, MD, chair of the department of neurology and director of the Center for Neurogenetics, and colleagues at Northwestern University Feinberg School of Medicine, reported on the new small-molecule modulator they developed, called S-181, in the October 16 issue of Science Translational Medicine.
He and colleagues suggest that the S-181 looks promising in the animal studies but more work needs to be done before it is ready for early clinical trials.
To study the impact of the small-molecule modulator, the researchers obtained skin fibroblasts from patients with sporadic/non-inherited PD, individuals with low GCase levels, and with mutations in the GBA1, LRRK2, PARK7, or PARKIN genes. The fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated into the neurons.
In vitro treatment of these cells with S-181 increased the activity of wild-type GCase, partially restored lysosomal function, and lowered accumulation of oxidized dopamine, glucosylceramide, and alpha-synuclein in iPSC-derived dopaminergic neurons from both subjects with sporadic PD and those with the GBA variant.
Subsequent in vivo analysis in mice with a mutated GBA1 gene revealed that S-181 could penetrate the central nervous system, enhance wild-type GCase enzyme activity in brain tissue, and reduce accumulation of GCase lipid substrates and alpha-synuclein.
“Modulation of GCase activity may be a promising therapeutic approach for GBA1-linked PD and other forms of PD that exhibit decreased wild-type GCase activity,” the study authors wrote. They also suggested that activating wild-type GCase protein might be therapeutic in multiple types of PD, including sporadic forms of the disease.
S-181 is not yet ready for phase 1 trials in humans, they noted. “Future studies will be needed to fully define the pharmacokinetic and dynamic properties of our GCase modulator S-181 in normal and affected tissues and to develop the most effective analogs for testing in human clinical trials,” they wrote.
Commenting on the study, Gian Pal, MD, MS, an assistant professor in the department of neurological sciences at Rush University Medical Center in Chicago, said GBA mutation carriers with PD tend to have a more aggressive form of the disease than other PD patients.
“They tend to decline faster than non-GBA PD patients from a motor and cognitive standpoint,” said Dr. Pal, who was not involved with the study. “More specifically, GBA-PD subjects are at a higher risk of cognitive impairment and dementia in the long-run compared with their non-GBA PD counterparts.”
GBA-mutation PD is also associated with Gaucher disease, the most common lysosomal storage disease, in which GCase deficiency causes buildup of glucocerebroside, leading to enlargement of the liver and spleen. In fact, this particular form of PD was originally identified by clinicians treating patients with a family history of Gaucher disease.
A 1996 report described six patients with Gaucher disease who had early-onset, severe PD with cognitive decline, and a 2003 study in Molecular Genetics Metabolism associated being a Gaucher carrier with PD risk. Then in 2016, research in Annals of Neurology, involving more than 2,300 patients with PD, found that 10 percent carried one or more defects in copies of the GBA gene, and approximately half of those with the most severe GBA defect, known as a neuronopathic GBA mutation, developed global cognitive impairment within ten years of their Parkinson's diagnosis—compared with only about 20 percent of those without GBA mutations.
“To my knowledge, this is the first small molecule therapeutic modulating this enzyme's activity to reach this stage of research,” said Pamela J. McLean, PhD, associate professor of neuroscience at the Mayo Clinic in Jacksonville, FL, and the director of the neurobiology of disease program at Mayo Graduate School/Mayo College of Medicine. Dr. McLean, whose research focuses on molecular mechanisms underlying neurodegeneration in PD and related disorders, said, “The fact that it is a target not just for patients who have a GBA mutation but could also potentially be useful for people with sporadic or other familial forms of PD makes it that much more interesting.”
Other ongoing trials are also targeting GCase activity in an effort to provide a disease-modifying benefit, noted Valina Dawson, PhD, professor of neurology, neuroscience and physiology in the Solomon H. Snyder department of neuroscience at Johns Hopkins School of Medicine. But, Dr. Dawson said, the agents involved likely would not benefit the particular subgroup of patients whose iPSC-derived neurons formed the basis of the study. These patients have a heterozygous 84GG mutation in GBA1 (GBA-PD), which results in complete loss of mutant GCase. “This mutation causes complete loss of the protein,” she said.
“The authors showed that this molecule, in both the in vitro model using iPSC-derived neurons and in an animal model, can increase the activity of wild-type GCase,” said Roy Alcalay, MD, FAAN, the Alfred and Minnie Bressler associate professor of neurology (in the Taub Institute) and a member of the movement disorders division at Columbia University Irving Medical Center.
“GCase is a very attractive drug target and the science presented in this study is solid. We know that while a symptomatic treatment like levodopa works for almost everyone with PD, the ‘one drug fits all’ approach doesn't work when it comes to disease-modifying therapy, having failed in multiple clinical trials. So the approach of going to the biological pathway that would be relevant to a subset of people makes a lot of sense. It's a very promising start.”
Dr. Pal cautioned, however, that the findings are at the basic science level and further work needs to be done to translate these findings into human clinical trials. “All the biochemical changes they show in iPSC-derived neurons and in mouse brain tissue are very attractive, but we don't yet know whether this will translate into actual functional improvement. An improvement in the biochemical profile of the patient does not necessarily dictate that there will be a meaningful improvement in disease symptoms and/or progression.”
Dr. Dawson agreed. “There's still a good deal of preclinical work to do to determine under what conditions this particular agent or class of agents is going to be useful in treating PD, and then from that point doing all the standard medicinal chemistry and pharmacology to develop something that can be taken into a clinical setting,” she said. “However, it's very provocative and very promising. PD is complex, and I think it's important to have multiple targets. The more drugs available to clinicians, the better off they are in being able to treat and hopefully slow down and prevent the disease.”
“This particular compound does have advantages, with a target population they could take to trials,” said Dr. McLean. “The challenge for all of us comes with trying to take something to trials for a more generalized PD population, because we still don't have good biomarkers and good ways to predict who will develop the non-familial form of the disease. For this agent, you could screen Gaucher families for the mutation and recruit those individuals as potential trial participants.”
Dr. McLean noted that the overall pipeline for PD therapeutics research holds promise along multiple pathways. “We have promising immunotherapy approaches targeting alpha-synuclein, focused on neutralizing the toxic forms of the protein and delaying disease progression. There are also agents being investigated that target LRRK2 mutations, which cause another inherited form of PD. And now we have promising candidates for GBA-linked PD mutations. We should be very encouraged.”
Dr. Krainc is the founder and scientific advisory board chair of Lysosomal Therapeutics Inc. He also serves on the scientific advisory boards of The Silverstein Foundation, Intellia Therapeutics and Prevail Therapeutics and is a Venture Partner at OrbiMed. Dr. Alcalay has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Denali, Prophase, and Genzyme Sanofi. Dr. Pal serves on the scientific advisory board of AbbVie, has consulted for Qessential Medical Market Research, Huron Consulting, and Boston Scientific. Drs. Dawson and McLean and had no competing interests.