BIIB122 for Parkinson's Disease
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Denali Therapeutics Inc.
Disqualifiers: Stroke, Dementia, Atypical parkinsonism, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.
How does the drug BIIB122 differ from other Parkinson's disease treatments?
BIIB122 (DNL151) is unique because it targets the FBXO7 protein, which is involved in maintaining brain neurons and is linked to the pathogenesis of Parkinson's disease. This approach is different from traditional treatments that primarily focus on managing symptoms rather than addressing underlying cellular mechanisms.12345
Research Team
DJ
Danna Jennings, MD
Principal Investigator
Denali Therapeutics
Eligibility Criteria
This trial is for people aged 30-80 with Parkinson's Disease who carry a specific genetic change (LRRK2 variant) that increases LRRK2 activity. They must meet the clinical criteria for PD diagnosis and have verified genetic test results showing they have this mutation.Inclusion Criteria
I am between 30 and 80 years old with a specific genetic mutation.
I am 30 years or older with a specific genetic mutation.
My genetic test shows I have a LRRK2 mutation.
See 1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either BIIB122 225 mg or a matching placebo once daily for 12 weeks
12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Open-label extension (optional)
Participants may opt into continuation of treatment long-term
Treatment Details
Interventions
- BIIB122 (Kinase Inhibitor)
Trial OverviewThe study tests BIIB122, a potential new treatment for Parkinson's Disease, against a placebo. Participants are randomly assigned to receive either BIIB122 or a fake pill without active ingredients, in order to compare effects over 12 weeks.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: BIIB122 225 mgExperimental Treatment1 Intervention
Oral 225 mg dose, once daily (QD)
Group II: BIIB122 Matching PlaceboPlacebo Group1 Intervention
Oral BIIB122 matching placebo, once daily (QD)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Inland Northwest ResearchSpokane, WA
Parkinson's Disease and Movement Disorders CenterBoca Raton, FL
Evergreen Health LaboratoryKirkland, WA
Beth Israel Deaconess Medical CenterBoston, MA
More Trial Locations
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Who Is Running the Clinical Trial?
Denali Therapeutics Inc.
Lead Sponsor
Trials
24
Patients Recruited
1,900+
Biogen
Industry Sponsor
Trials
655
Patients Recruited
468,000+
References
Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15). [2021]Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.
FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. [2013]Mutations in the gene encoding the F-box only protein 7 (FBXO7) cause PARK15, an autosomal recessive form of juvenile parkinsonism. Although the brain pathology in PARK15 patients remains unexplored, in vivo imaging displays severe loss of nigrostriatal dopaminergic terminals. Understanding the pathogenesis of PARK15 might therefore illuminate the mechanisms of the selective dopaminergic neuronal degeneration, which could also be important for understanding idiopathic Parkinson disease (PD). The expression of FBXO7 in the human brain remains poorly characterized, and its expression in idiopathic PD and different neurodegenerative diseases has not been investigated. Here, we studied FBXO7 protein expression in brain samples of normal controls (n = 9) and from patients with PD (n = 13), multiple system atrophy (MSA) (n = 5), Alzheimer disease (AD) (n = 5), and progressive supranuclear palsy (PSP) (n = 5) using immunohistochemistry with 2 anti-FBXO7 antibodies. We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. There were no major differences between normal and PD brains overall, but FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions), where it colocalized with α-synuclein in PD and MSA cases. By contrast, weak FBXO7 immunoreactivity was occasionally detected in tau-positive inclusions in AD and PSP. These findings suggest a role for FBXO7 in the pathogenesis of the synucleinopathies.
A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism. [2014]Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.
Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease. [2013]Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in α-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in α-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified α-synuclein species in vivo. For this purpose, we used two mutated forms of human α-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type α-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the α-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type α-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A α-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D α-synuclein appeared earlier than the other two forms of α-synuclein. Conversely, S129A α-synuclein showed significantly larger pathological α-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of α-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three α-synuclein forms resulted in pathological accumulations of α-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of α-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state.
The loss of inhibitory C-terminal conformations in disease associated P123H β-synuclein. [2018]β-synuclein (βS) is a homologue of α-synuclein (αS), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to αS, βS does not form fibrils, mitigates αS toxicity in vivo and inhibits αS fibril formation in vitro. Previously a missense mutation of βS, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of βS is able to convert βS from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of αS in vivo. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of αS, βS and P123H-βS, and the effects on fibril formation of coincubation of αS with βS, and with P123H-βS. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of βS renders it more flexible C-terminal to the mutation site and more αS-like. In vitro Thioflavin T fluorescence experiments show that P123H-βS accelerates αS fibril formation upon coincubation, as opposed to wild type βS that acts as an inhibitor of αS aggregation. When P123H-βS becomes more αS-like it is unable to perform the protective function of βS, which suggests that the extended polyproline II motif of βS in the C-terminus is critical to its nontoxic nature and to inhibition of αS upon coincubation. These studies may provide a basis for understanding which regions to target for therapeutic intervention in Parkinson's disease.