LRRK2 Loss-of-Function Variants: When Less Is More.

Abstract

Gain-of-function variants in leucine-rich repeat kinase 2 (LRRK2) are the most common monogenic cause of Parkinson's disease (PD), albeit with incomplete penetrance, indicating that reduction of LRRK2 kinase activity is a reasonable therapeutic strategy for LRRK2-related PD.1 However, LRRK2 inhibition in animal models was associated with abnormal phenotypes in the lung, kidney, and liver, thus raising safety concerns.2 Resources such as the Genome Aggregation Database or UK Biobank, built on large-scale sequencing projects, represent compelling tools for assessing genetic variant frequency. These were employed by Whiffin and colleagues3 to investigate the frequency of LRRK2 loss-of-function (LoF) variants in humans and their association with specific phenotypes. Among 187,518 individuals in the 2 aforementioned cohorts, they identified 352 carriers of heterozygous LRRK2 LoF variants, implying that approximately 1 in 500 humans harbors such a variant.3 Using genotyping data from the personal genetics company 23andMe, Whiffin and colleagues3 identified an additional 1,103 individuals with LRRK2 LoF variants.3 No reduction in lifespan or overrepresentation of any phenotype affecting the lung, liver, kidney, cardiovascular system, nervous system, immunity, or cancer in carriers of LRRK2 LoF variants was observed.3 In an earlier study, heterozygous LRRK2 LoF variants were identified at comparable percentages of clinically diagnosed patients with PD and controls, suggesting a lack of association between the partial loss of LRRK2 and PD.4 These results collectively suggest that an endogenous decrease of LRRK2 levels and consequently of its activity does not seem to elicit highly penetrant phenotypes, although to date LRRK2 LoF variants have never been investigated specifically in cohorts of patients with unexplained severe manifestations (including those seen in animal models upon LRRK2 inhibition). Thus, the therapeutic administration of compounds intended to decrease LRRK2 enzymatic activity (kinase inhibitors) or levels (antisense oligonucleotides) is not expected to cause harmful effects. Currently, 3 LRRK2-targeted compounds are being tested in phase 1 or 1b clinical trials: the LRRK2 kinase inhibitors DNL151 and DNL201 from Denali Therapeutics Inc., (San Francisco, CA, USA) and the antisense oligonucleotide BIIB094 from Biogen.3 As a caveat, a coinciding loss of both LRRK2 and its functional homolog LRRK1 results in earlier mortality, a loss of dopaminergic neurons, and an increase in α-synuclein in a double-knockout mouse model.5 Hence, targeting LRRK2 may not be safe in individuals with LRRK1 homozygous or heterozygous LoF variants. While it may thus be advisable to exclude the presence of such variants by genetic testing of LRRK1 in individuals prior to the administration of any LRRK2-directed treatment, LRRK2 inhibition is a promising and potentially safe new therapeutic strategy. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the first draft, B. Review and Critique. T.U.: 1A, 1B,1C,2A,2B A.W.:1A,1B,1C,2A,2B T.U. reports the following: employment with University Medical Center Schleswig-Holstein, Campus Lübeck, Germany. A.W. is an advisor for medical writing at CENTOGENE GmbH and reports employment with University Medical Center Schleswig-Holstein, Campus Lübeck, Germany; honoraria from CENTOGENE GmbH; and a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft) Research Unit (FOR2488).