AAV2-GDNF for Advanced Parkinson s Disease

Objective:

While medications can temporarily alleviate the symptoms of Parkinson s disease (PD), they do
not influence the degenerative process. Progressive loss of nigral dopaminergic (DA) neurons
(the pathological hallmark of PD) results in progressive neurologic dysfunction and death.
Glial cell line-derived neurotrophic factor (GDNF) was first identified based on its ability
to promote the survival of embryonic DA neurons in vitro, and research has demonstrated
beneficial effects of GDNF in animal models of PD. Preliminary clinical trials of GDNF
infusions have yielded inconclusive results. Observed problems with tolerability and efficacy
in these studies may have been related to the methods of delivery. Recent evidence indicates
that gene transfer via direct delivery of viral vectors may represent a superior approach for
the treatment of PD with GDNF.

Study population:

Twenty-four adult male and female subjects with advanced Parkinson s disease, who are
candidates for surgical treatment for Parkinson s disease and who meet all Inclusion and
Exclusion Criteria.

Design:

We propose a Phase 1 single-center, open-label, dose escalation, safety and tolerability
study of adeno-associated virus, serotype 2 vector (AAV2) containing human GDNF complementary
DNA. Bilateral catheters will be placed surgically through the skull and into the brain and
the vector will be delivered by convection-enhanced delivery (CED) to both putamina (450
microliters per hemisphere) of 24 patients with advanced PD. An additional 76 subjects will
be allowed for screening failures. Four escalating dose levels will be evaluated in the
following dose cohorts (6 patients per cohort): Cohort 1 = 9 x 10(10)vg, Cohort 2 = 3 x
10(11)vg, Cohort 3 = 9 x 10(11)vg and Cohort 4 = 3 x 10(12)vg.

Outcome measures:

To assess the safety, tolerability, and potential clinical effects of CED of AAV2-GDNF in
advanced PD patients, we will use defined clinical evaluations of PD (Unified Parkinson s
Disease Rating Scale, Modified Schwab and England Activities of Daily Living scale, Hoehn and
Yahr Staging, Lang and Fahn Dyskinesia Rating Scale, On-Off Patient Diary, Quality of Life,
Modified Rankin Scale, Adverse Event Log and neurologic examinations), laboratory studies
(hematologic, immunologic and chemistry), neuropsychological testing (Mattis Dementia Rating
Scale, Beck Depression Inventory II and Parkinson Psychosis Questionnaire) and neuroimaging
(magnetic resonance imaging and positron emission tomography).

- INCLUSION CRITERIA:

Greater than 18 years of age.

Diagnosed with Idiopathic PD.

- Bradykinesia and

- At least 3 of the following clinical features: resting tremor, cogwheel rigidity,
bradykinesia, postural reflex impairment.

The above clinical features must not be due to trauma, brain tumor, infection,
cerebrovascular disease, other known neurological disease (e.g., hereditary form of PD,
multiple system atrophy, progressive supranuclear palsy, striatonigral degeneration,
Huntington s disease, Wilson s disease), or to known drugs, chemicals or toxicants.

Disease duration of > 5 years.

Hoehn and Yahr Stage III or IV off medication.

Disability present despite optimal antiparkinsonian medication therapy. Disability will be
operationally defined as a Modified Schwab and England Activities of Daily Living Scale
score of 80% or lower (during the off state).

Unified PD Rating Scale (UPDRS) (Fahn et al., 1987) total motor score greater than or equal
to 30 in the defined off state.

Unequivocal responsiveness to levodopa, based on the single-dose levodopa test (as
described in the CAPIT and CAPSIT guidelines). A 30% or greater improvement in the UPDRS
total motor score will be required to establish unequivocal responsiveness to levodopa.

Able to provide proper Informed Consent.

Laboratory values at screening visit (unless other visit specified):

- Platelets >100,000/mm3 (transfusion independent)

- PT/PTT in normal range and INR less than or equal to 1.3 (on day prior to surgery, if
taking anti-coagulants)

- Absolute neutrophil count (ANC) >1500/mm3

- Hemoglobin >10.0 g/dL (transfusion allowed)

- Aspartate aminotransferase or alanine aminotransferase <2.5 times ULN

- Total bilirubin <2.5 mg/dL

- Serum creatinine <1.5 mg/dL

- Serum anti-AAV2 total antibody titer <1000.

EXCLUSION CRITERIA:

Presence of prominent oculomotor palsy, cerebellar signs, vocal cord paresis,mean standing
blood pressure below 75mmHg, pyramidal tract signs or amyotrophy.

Genetic PD disorders or with a strong family history of PD.

Presence of dementia (Montreal Cognitive Assessment less than or equal to 25).

Received an anti-dementia drug for treatment of cognitive impairment within 30 days of
their screening for protocol eligibility.

Presence or history of psychosis, including if induced by anti-PD medications at doses
required to improve motor symptoms.

Presence of untreated or suboptimally treated depression (Hamilton Depression Scale score
>10) or a history of a serious mood disorder (i.e., requiring psychiatric hospitalization
or a prior suicide attempt).

Presence of substance (drug, alcohol) abuse.

Contraindication to MRI and/or gadolinium.

Presence of normal striatal uptake on PET.

Coagulopathy, anticoagulant therapy, low platelet count, or inability to temporarily stop
any antithrombotic medication.

Prior brain surgery, including GDNF, NTN, GAD, AADC therapy or deep brain stimulation.

Male or female with reproductive capacity who is unwilling to use barrier contraception
throughout the study.

History of stroke or poorly controlled cardiovascular disease.

Uncontrolled hypertension or diabetes or any other acute or chronic medical condition that
would increase the risks of a neurosurgical procedure.

History of malignancy (cerebral or systemic) other than treated cutaneous squamous cell or
basal cell within the prior 5 years.

Clinically active infection, including acute or chronic scalp infection.

Received investigational agent within 12 weeks prior to screening.

Unable to comply with the procedures of the protocol, including frequent and prolonged
follow-up.

Chronic immunosuppressive therapy (e.g., chronic steroids, TNF antagonists, chemotherapy)

Pregnancy or lactation.