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Funded Studies

Validation of LRRK2 as a Drug Target for Treatment of Parkinson's Disease Using Antisense Technology

Missense mutations in leucine-rich repeat serine/threonine-protein kinase (Lrrk2) are linked/associated with dominantly inherited, late-onset Lewy body Parkinson's disease (PD). LRRK2 mutations are now the predominant genetic cause of familial parkinsonism. Indeed, in some ethnicities, LRRK2 c.6055G>A (G2019S) is found in up to 30% of patients with seemingly sporadic PD. We plan to directly target wild-type and/or mutant Lrrk2 (allele-specific targeting) reducing their concentration in neuronal cells by means of antisense oligonucleotides (ASOs).

Project Description:
By developing second-generation antisense drug based inhibitors for LRRK2 we plan to assess the safety and efficacy of lowering LRRK2 mRNA in mouse brain. While Lrrk2 protein suppression will interfere and even stop a dominant pathogenic effect, reduction of wild-type Lrrk2 in the context of a mutant allele may not be well tolerated. Thus allele-specific silencing of the G2019S mutant form, the most frequent pathogenic mutation present in familial and sporadic PD, will be explored as an alternative strategy.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The prevailing body of literature suggests that LRRK2 mutations are pathogenic through a “gain-of function”. Hence, reduction in expression of the mutant protein in brain is likely to be of Symptoms & Side Effects and neuroprotective benefit in patients with this prevailing genetic susceptibility. As LRRK2 parkinsonism cannot be distinguished from idiopathic PD similar treatments may be of benefit to all patients with PD.

Anticipated Outcome:
The studies proposed will provide proof-of-concept for ASO as a therapeutic in Lrrk2-parkinsonism and will contribute to our understanding of the normal cellular biology and pathobiology of wild type and mutant Lrrk2.

Progress Report

We have successfully identified second generation ASOs that target both pre-clinical and human LRRK2 to assess the effects of LRRK2 reduction in normal and diseased mice. The ASOs were shown to selectively inhibit the expression of LRRK2 in a pre-clinical model when delivered into the CSF or directly into brain tissue. In addition, we have demonstrated that the ASOs inhibit LRRK2 in peripheral tissues when the mice are dosed systemically. A pre-clinical model treated with LRRK2 ASOs, either locally in CNS or systemically, does not present signs of toxicity (up to 8 weeks of LRRK2 reduction). We have initiated screening for ASOs which will selective inhibit the expression of 6176 G>A (G2019S) mutant allele of LRRK2.  We expect to conclude pharmacological characterization of these molecules within the next year in human LRRK2 pre-clinical models.


  • Alejandro Lloret, PhD

    Carlsbad, CA United States

  • Matthew Farrer, PhD

    Gainesville, FL United States

  • C. Frank Bennett, PhD

    Carlsbad, CA United States

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