In recent years, a growing number of companies have started to look for ways to stem the progression of Parkinson’s disease. One approach targets glucocerebrosidase (GBA), the leading genetic risk factor for sporadic PD and dementia with Lewy bodies (DLB). Defects in this lysosomal enzyme cause a buildup of α-synuclein, as well as of the glycolipid glucosylceramide that GBA normally cleaves (see Jun 2011 news; Jul 2011 news). Parkinson’s patients with GBA mutations, who make up about 7 percent of cases, decline faster and have more severe symptoms than idiopathic PD patients.

At the annual Society for Neuroscience conference, held November 12-16 in San Diego, Pablo Sardi of Sanofi Genzyme, Framingham, Massachusetts, announced the launch of a Phase 2 study in Parkinson’s patients who carry GBA mutations. The company will test its small-molecule inhibitor of glucosylceramide synthesis, GZ/SAR402671, which turns off production of this key GBA substrate. Because glucosylceramide stabilizes α-synuclein oligomers, its buildup is believed to contribute to α-synuclein toxicity. Also known as ibiglustat, GZ/SAR402671 can be taken by mouth and enters the brain well, Sardi noted. The Sanofi trial will be the largest attempt so far to target treatment to this genetically defined Parkinson’s population. “I think of this as precision medicine for Parkinson’s,” Sardi wrote to Alzforum.

At SfN, Sardi detailed preclinical findings with the closely related compound GZ667161. The researchers fed this compound to PD model mice, which carry the homozygous GBA mutation D409V, from the ages of six to 13 months. Compared with untreated, age-matched controls, GZ667161 slashed hippocampal α-synuclein deposits in the aged mice to less than half, below the amount present when treatment began at six months. Memory in a contextual fear-conditioning test improved. While untreated mice froze only 5 percent of the time in a location where they had previously received a shock, treated animals froze 30 percent of the time, nearing the wild-type recall of 50 percent. Sardi expects to publish these findings soon.

A Phase 2 trial has been approved by the Food and Drug Administration and will begin enrolling this month, with completion scheduled for 2022, Sardi said. The study will enroll about 230 people who have Parkinson’s and a GBA mutation. Although this initial trial only includes mutation carriers, the researchers believe the strategy may work to rein in α-synuclein in other forms of PD as well. Supporting this idea, GZ667161 also suppressed pathology and boosted cognition in the PrP-A53T-SNCA mouse model, which overexpresses α-synuclein but has wild-type GBA, and did so with a similar efficacy to that seen in the D409V mice, Sardi reported.

Michael Schlossmacher at Ottawa Hospital Research Institute, Ontario, Canada, who collaborated with Sardi on the preclinical studies of GZ667161, told Alzforum he is cautiously optimistic that the strategy might help sporadic PD patients, as well as people with DLB. As many as 25 percent of the latter carry GBA mutations, and they typically progress faster than PD patients, so their need for treatment is great, Schlossmacher noted. Sardi said his company will wait to analyze results from the PD genetic cohort before considering whether to test the compound in other groups.

GZ/SAR402671 is currently in a Phase 2 trial for the lysosomal storage disorder Gaucher’s disease, as well as Phase 2 for the related disorder Fabry’s disease. It has been fast-tracked by the Food and Drug Administration for the latter disorder.

Schlossmacher noted that these Gaucher studies provided proof of principle that GZ/SAR402671 can lower accumulation of glucosylceramide in peripheral organs.

Meanwhile, many other companies, including Pfizer and the biotech company Lysosomal Therapeutics in Cambridge, Massachusetts, are developing drugs for Parkinson’s that target GBA. Researchers in Canada recently evaluated the ability of the chaperone ambroxol to stimulate GBA activity in a small Phase 2 Parkinson’s study, and a similar trial of ambroxol is starting up in London. Amicus Therapeutics, Cranbury, New Jersey, is developing the small-molecule GBA chaperone AT3375 for both Gaucher’s and Parkinson’s diseases.—Madolyn Bowman Rogers


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News Citations

  1. Feedback Loop—Molecular Mechanism for PD, Gaucher’s Connection
  2. Targeting α-Synuclein, Glucocerebrosidase May Work for LBD

External Citations

  1. Phase 2
  2. Phase 2 
  3. Phase 2
  4. fast-tracked
  5. Phase 2
  6. trial
  7. AT3375

Further Reading