BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the fields of medicine, neurobiology, and genetics. More particularly, it concerns identifying Parkinson's disease patients who are likely to benefit from Deep Brain Stimulation (DBS) Therapy.

2. Description of Related Art

Oral levodopa and deep brain stimulation of the subthalamic nucleus (STN DBS) are the mainstay pharmacological and surgical therapies for Parkinson's disease (PD). The introduction of levodopa often leads to a brief period of dramatic efficacy known as the ‘honeymoon’ phase. This honeymoon rapidly ends with increasing medication requirements and the onset of motor fluctuations, beginning after four to six years of levodopa treatment for about 40% of patients (Ahlskog and Muenter, 2001). During mid- and late-stage PD, some patients elect to undergo STN DBS and often experience a marked improvement in motor function, quality of life and motor fluctuations referred to by some as a ‘second honeymoon’ (Tanner, 2013). Although generally effective in treating PD motor symptoms, clinical response is highly variable for both of these therapies. For example, early-stage PD subjects receiving equivalent levodopa dosages experience a magnitude of response ranging from a 100% improvement to a 242% worsening as assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III, motor sub score) (Hauser et al., 2009). In one of the largest clinical trials of STN DBS, late-stage PD subjects experienced improvements in UPDRS-III that ranged from 3% to 63% improvement (Weaver et al., 2012). In addition, in a recent clinical trial in mid-stage PD subjects comparing STN DBS to medical therapy, UPDRS-III scores in the STN DBS treatment group ranged from an 83% improvement to a 7% worsening, whereas in the medication arm UPDRS-III scores ranged from a 50% improvement to a 42% worsening (Schuepbach et al., 2013. These reports underscore the heterogeneity in patient response to therapies and confirm that the clinical phenomenology of PD is extremely variable and patient-specific within each disease stage.

Preclinical studies show that both chronic levodopa administration and STN DBS result in alterations in brain-derived neurotrophic factor (BDNF) levels (Guillin et al., 2001; Spieles-Engemann et al., 2011; Fischer et al., 2014). These findings raise questions regarding whether BDNF levels contribute to patient response to antiparkinsonian therapies. A relatively common and functional single nucleotide substitution in the gene Bdnf (G>A results in Val66Met substitution in the protein BDNF; reference cluster ID: rs6265) has a prevalence of 40.6% in the human population (Val/Met 35.4%, Met/Met 5.2%, allelic frequency assuming Hardy-Weinberg) (dbSNP). Both the heterozygous major allele (Val/Met) and homozygous minor allele (Met/Met) of the Bdnf variant rs6265 result in disrupted packaging and release of activity-dependent BDNF (Chen et al. 2006). Since the majority of BDNF in the brain is released from neurons via this regulated secretory pathway, the Val/Met or Met/Met genotypes exhibit a significant decrease in available BDNF.10However, there is no information on whether BDNF rs6265 SNP genotype confers a differential response to either optimized drug therapy (ODT) or STN DBS plus medication (DBS) in early PD subjects.

SUMMARY OF THE INVENTION

Thus, in accordance with the present disclosure, there is provided a method of identifying a Parkinson's disease patient as a long-term responder to optimized drug therapy (ODT) and deep brain stimulation (DBS) therapy comprising (a) subjecting a nucleic acid-containing sample from a Parkinson's disease patient to sequence analysis; (b) determining the presence or absence of a single nucleotide polymorphism resulting in a Val→Met substitution in the brain derived neurotrophic factor (BDNF) gene coding for residue 66; and (c) identifying a patient as a long-term responder to both ODT and DBS when said nucleic acid-containing sample exhibits a Val/Val profile, and identifying a patient as a non-long-term responder to ODT when said nucleic acid-containing sample exhibits a Val/Met or met/met profile.

The method may further comprise treating said subject with ODT or DBS when said nucleic acid-containing sample exhibits a Val/Val profile, and/or may further comprise treating said subject with DBS when said nucleic acid-containing sample exhibits a Val/Met or met/met profile, and/or may further comprise treating said subject with ODT and DBS when said nucleic acid-containing sample exhibits a Val/Val profile. The patient may be an early stage Parkinson's disease patient. The long-term responder may be responding to ODT at 24 months following initiation of ODT.

The nucleic acid-containing sample may be a DNA sample, or an RNA sample. The nucleic acid-containing sample may be a tissue sample including, but not limited to, urine, cerebrospinal fluid, saliva, serum, skin, biopsy, biopsy of any organ, blood, semen, stool, ova, hair, hair follicle, or a mucosal cell. The sequence analysis may comprise PCR, comprises primer extension, site specific amplification, site specific hybridization, site specific cleavage, ligation, pyrosequencing, SNP microarray, mini-sequencing, RNA seq, real time sequencing, ion or torrent pH sensing. The method further comprise preparing a report corresponding to step (c), or as an alternative step (c).

In another embodiment, there is provided a method of identifying a Parkinson's disease patient as a long-term responder to optimized drug therapy (ODT) and deep brain stimulation (DBS) therapy comprising (a) subjecting a protein-containing sample from a Parkinson's disease patient to sequence analysis; (b) determining the presence or absence of a Val→Met substitution in brain derived neurotrophic factor (BDNF) at residue 66; and (c) identifying a patient as a long-term responder to both ODT and DBS when said protein-containing sample exhibits a Val/Val profile, and identifying a patient as a non-long-term responder to ODT when said protein-containing sample exhibits a Val/Met or Met/Met profile.

The method may further comprise treating said subject with ODT or DBS when said protein-containing sample exhibits a Val/Val profile, and/or further comprise treating said subject with DBS when said protein-containing sample exhibits a Val/Met or Met/Met profile, and/or further comprise treating said subject with ODT and DBS when said protein-containing sample exhibits a Val/Val profile. The patient may be an early stage Parkinson's disease patient. The long-term responder may be responding to ODT at 24 months following initiation of ODT.

The protein-containing sample may be a tissue sample including, but not limited to, urine, cerebrospinal fluid, saliva, serum, skin, biopsy, biopsy of any organ, blood, semen, stool, ova, hair, hair follicle, or a mucosal cell. The sequence analysis may be an antibody-based assay. The sequence analysis may comprise mass spectrometry. The method further comprise preparing a report corresponding to step (c), or as an alternative step (c).

In still a further embodiment, there is provided a kit comprising a first nucleic acid probe, primer or primer pair for determining the presence or absence of an rs6265 Met allele. The kit may further comprise one or more of a polymerase, a ligase, a restriction enzyme, a buffer, instructions for use of said kit, or a label. Another embodiment involves a kit comprising an antibody for determining the presence or absence of a Val→Met substitution at residue 66 of brain derived neurotrophic factor. The kit may further comprise one or more of a support, a third antibody for detection of said first and/or second antibody, a buffer, instructions for use of said kit, or a label. Finally, there is provided a probe or primer having a sequence that hybridizes to or adjacent to an rs6265 Met allele or a rs6265 Val allele, and an antibody that binds selectively to an epitope comprising residue 66 of brain derived neurotrophic factor. The kits may also comprise instructions on how to perform the methods above, and may include appropriate positive and negative control reactants.

For the purpose of this application, early stage Parkinson's disease patients are defined as having idiopathic Parkinson's disease, on anti-parkinsonian medications less than four years, and without a history of motor fluctuations and/or dyskinesias.”

As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” As used herein “another” may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

