Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Sardi, S. Pablo; Cedarbaum, Jesse M.; Brundin, Patrik

doi:10.1002/mds.27414

Cited by 145 publications

(134 citation statements)

References 88 publications

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“…The third approach targets ceramide synthase in order to reduce accumulation of the GCase substrate, glucosylceramide. This strategy is already approved for use in GD patients and is currently in clinical trials for PD . Lastly, we have recently shown that a reduction in ceramide contributes to accumulation of alpha‐synuclein in GCase‐deficient cells .…”

Section: Glucocerebrosidase (Gba1)mentioning

confidence: 89%

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal‐recessive or X‐linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult‐onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Glucocerebrosidase (Gba1)mentioning

confidence: 89%

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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“…Furthermore, genetic studies point to a causal role of α‐syn in PD, as mutations and duplications of the gene coding for α‐syn, SNCA, have been linked to inherited forms of PD. These observations suggest that α‐syn is a promising therapeutic target in PD, and increasing numbers of new therapies targeting α‐syn are in development …”

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confidence: 99%

Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

et al. 2019

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Background Pathological and genetic evidence implicates toxic effects of aggregated α‐synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α‐synuclein is a promising strategy for delaying disease progression. Objective This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human‐derived monoclonal antibody that preferentially binds to aggregated α‐synuclein, in healthy volunteers and participants with Parkinson's disease. Methods A total of 48 healthy volunteers (age 40–65, 19 women) and 18 Parkinson's disease participants (age 47–75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single‐dose cohorts of BIIB054 (range 1–135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α‐synuclein complexes were measured in plasma. Results Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half‐life of BIIB054 was 28 to 35 days; the cerebrospinal fluid–to‐serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α‐synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α‐synuclein complex formation. Conclusions BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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“…As new ideas evolve for therapeutic interventions within the PD brain, there will be further demand for additional ways to traverse the BBB with treatments that might involve fairly large molecules. One of the most recent ideas for modifying the advance of PD has the challenge of targeting several identified genetic mutations causing (or at least facilitating the development of) parkinsonism . For example, PD patients carrying a mutation of the glucocerebrosidase gene are planned to be enrolled in an upcoming clinical trial investigating the administration of the wild‐type gene to “override” the consequences of deficient enzyme production .…”

Section: Focused Ultrasound For Treating Parkinson's Diseasementioning

confidence: 99%

“…For example, PD patients carrying a mutation of the glucocerebrosidase gene are planned to be enrolled in an upcoming clinical trial investigating the administration of the wild‐type gene to “override” the consequences of deficient enzyme production . Similarly, another mechanism of genetic parkinsonism involving various mutations of the leucine‐rich repeat kinase‐2 ( LRRK2 ) gene stands out as a target for genetic modification . In this instance, the goal of suppressing LRRK2 overactivity might be achieved by gene silencing or editing approaches that would require transvascular passage of the therapeutic agents.…”

Section: Focused Ultrasound For Treating Parkinson's Diseasementioning

confidence: 99%

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Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

2019

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The expanding landscape of options for Parkinson's disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high‐energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro‐bubbles can temporarily open the blood–brain barrier at specific brain targets to facilitate real‐time magnetic resonance–guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society

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Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Cited by 145 publications

References 88 publications

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

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