A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients

AADC Deficiency Clinical Trial

— AADC  

Official title:

SIngle-Stage, Open-Label, Safety and Efficacy Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase by Magnetic Resonance MR-guided Infusion Into Midbrain in Pediatric Patients With AADC Deficiency

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02852213
• Other study ID #: 2018H0269
• Secondary ID: 1R01NS094292-035
• Status: Recruiting
• Phase: Phase 1
• Start date: July 2016
• Est. completion date: July 2031

Study information

• Verified date: February 2024
• Source: Ohio State University
• Contact: Andrea Davis, MS
• Phone: 614-688-6412
• Email: andrea.hesse[@]osumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC delivered to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children with aromatic L-amino acid decarboxylase (AADC) deficiency.

Description:

The Study will specifically address: - Safety, as measured by adverse events (AEs), safety laboratory tests, brain imaging, and the relationship of AEs to study/surgical procedures or to AAV2 hAADC. - Clinical responses to treatment with AAV2-hAADC. The primary clinical outcomes will reflect the predominant motor deficits of loss of motor function and dystonic movements. Primary Endpoints Safety: Assessment of AE or severe AE (SAE) and its relationship to study surgery, infusion, or treatment effect (graded as definite, probable, possible, unlikely or unrelated). - Adverse Events and Serious Adverse Events - Post-operative MRI and/or CT (with contrast if clinically indicated) - Clinical laboratory assessments (hematology, chemistry, immunology) Biological Activity: Demonstration of effective restoration of AADC function by assays of cerebrospinal fluid (CSF) neurotransmitter metabolites and 18-fluoro-3,4-dihydroxyphenylalanine (F-DOPA) positron emission tomography (PET) imaging. Secondary and Exploratory Endpoints To obtain preliminary data for clinical response by assessing the magnitude and variability of changes in specific outcomes. The principal clinical outcome measures are: - Motor function, as assessed by the Gross Motor Function Measure (GMFM-88) - Frequency of oculogyric episodes, as measured by a Symptom Diary Secondary clinical outcome measures include: • Assessment of subject disability, as assessed using the Pediatric Evaluation of Disability Inventory (PEDI); adaptive behavior, as assessed using Vineland Adaptive Behavior Scale; Patient's Global Impression of Change (PGI-C); and quality of life, as determined using the Pediatric Quality of Life Inventory (PedsQL). Although the investigators recognize that the utility of established developmental and cognitive assessments may be limited because of the study population's severe physical disability, the investigators will use the following: - Peabody Developmental Motor Scales 2nd edition (PDMS-2) - Bayley Scales of Infant Development, 3rd edition.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: July 2031
• Est. primary completion date: July 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 24 Months and older

Eligibility

Inclusion Criteria

1. Definite diagnosis of AADC deficiency, confirmed by at least two of the following three criteria: (1) CSF neurotransmitter profile demonstrating reduced HVA and 5-HIAA, and elevated 3-OMD concentrations; (2) Plasma AADC activity less than or equal to 5 pmol/min/mL; (3) Molecular genetic confirmation of homozygous or compound heterozygous mutations in DDC.

2. Age 24 months and older.

3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6), as judged by presence of residual oculugyric crises and developmental delay.

4. Documented history of motor developmental delay, with inability to walk independently without support by age 18 months.

5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the head for MRI-guided stereotactic targeting.

6. Brain MRI does not show any conditions or malformations that are clinically significant with respect to risks for stereotactic brain surgery.

7. Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the study, including the need for frequent and prolonged follow-up.

8. Both parents (or legal guardians) must give their consent for their child's participation in the study parents unless (i.) one parent is deceased, unknown or incompetent; (ii.) one parent is not reasonably available; or (iii.) one parent has responsibility for the care and custody of the child (if consistent with state law).

9. Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory value ranges, unless in the Investigator's judgment, the out-of-range values are not clinically significant with respect to subject's suitability for surgery. Exclusion Criteria

1. Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe brain atrophy, white matter degenerative changes), which, in the opinion of the study investigators, would confer excessive risk and/or inadequate potential for benefit.

2. Presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk (including congenital heart disease, respiratory disease with home oxygen requirement, history of serious anesthesia complications during previous elective procedures, history of cardiorespiratory arrest), liver or renal failure, malignancy, or HIV positive.

3. Previous stereotactic neurosurgery.

4. Coagulopathy, or need for ongoing anticoagulant therapy.

5. Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI).

6. Receipt of any investigational agent within 60 days prior to Baseline and during study participation.

7. Evidence of clinically active infection with adenovirus or herpes virus on physical examination.

Related Conditions & MeSH terms

• AADC Deficiency
• Amino Acid Metabolism, Inborn Errors

Intervention

Drug:
• AAV2-hAADC
Initially, subjects will be enrolled sequentially into 2 dose groups. 3 subjects will be enrolled in Cohort 1 and treated with a single dose of AAV2 hAADC (1.3x10 11 vg, delivered as infusate volume of up to 160µL of vector at concentration of 8.3x10 11 vg/mL) on Day 0. Enrollment in Cohort 2 may commence after the last subject in Cohort 1 is treated and followed through Month 3 post-op, with approval of the data safety monitoring board (DSMB). Cohort 2 will receive a higher dose (4.2 x 10^11 vg, 160 uL). Upon DSMB review of Cohort 1/2 results, Cohort 3 (4-12 yo) and 4 (aged >/= 13 yo) will be dosed (1.6 x 10^12 vg, 60uL) in 1-2 sites bilaterally in-between the SNc and VTA. Cohort 5 will follow (aged 24-47 months) at 1.3 x 10^12 vg, 500uL. Final safety and clinical outcome assessments will be performed 1 year post-surgery. Follow-up analysis will be performed for 2 years post-op. Subjects will be enrolled in a long-term follow-up study to assess safety and clinical status updates.

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	University of California San Francisco, Benioff Children's Hospital	San Francisco	California

Sponsors (3)

Lead Sponsor	Collaborator
Krzysztof Bankiewicz	National Institute of Neurological Disorders and Stroke (NINDS), University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (46)

Brun L, Ngu LH, Keng WT, Ch'ng GS, Choy YS, Hwu WL, Lee WT, Willemsen MA, Verbeek MM, Wassenberg T, Regal L, Orcesi S, Tonduti D, Accorsi P, Testard H, Abdenur JE, Tay S, Allen GF, Heales S, Kern I, Kato M, Burlina A, Manegold C, Hoffmann GF, Blau N. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010 Jul 6;75(1):64-71. doi: 10.1212/WNL.0b013e3181e620ae. Epub 2010 May 26. Erratum In: Neurology. 2010 Aug 10;75(6):576. Dosage error in article text. — View Citation

Caviness VS Jr, Kennedy DN, Richelme C, Rademacher J, Filipek PA. The human brain age 7-11 years: a volumetric analysis based on magnetic resonance images. Cereb Cortex. 1996 Sep-Oct;6(5):726-36. doi: 10.1093/cercor/6.5.726. — View Citation

Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, VanBrocklin HF, Wright JF, Bankiewicz KS, Aminoff MJ. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009 Nov 17;73(20):1662-9. doi: 10.1212/WNL.0b013e3181c29356. Epub 2009 Oct 14. — View Citation

Dumas HM, Fragala-Pinkham MA, Haley SM, Ni P, Coster W, Kramer JM, Kao YC, Moed R, Ludlow LH. Computer adaptive test performance in children with and without disabilities: prospective field study of the PEDI-CAT. Disabil Rehabil. 2012;34(5):393-401. doi: 10.3109/09638288.2011.607217. Epub 2011 Oct 12. — View Citation

Dumas HM, Fragala-Pinkham MA. Concurrent validity and reliability of the pediatric evaluation of disability inventory-computer adaptive test mobility domain. Pediatr Phys Ther. 2012 Summer;24(2):171-6; discussion 176. doi: 10.1097/PEP.0b013e31824c94ca. — View Citation

Eapen M, Zald DH, Gatenby JC, Ding Z, Gore JC. Using high-resolution MR imaging at 7T to evaluate the anatomy of the midbrain dopaminergic system. AJNR Am J Neuroradiol. 2011 Apr;32(4):688-94. doi: 10.3174/ajnr.A2355. Epub 2010 Dec 23. — View Citation

Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P, Beyer J, Hadaczek P, Bowers W, Park J, Federoff H, Forsayeth J, Bankiewicz KS. Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage. 2009 Aug;47 Suppl 2(Suppl 2):T27-35. doi: 10.1016/j.neuroimage.2008.11.012. Epub 2008 Nov 27. — View Citation

Gill SS, Patel NK, Hotton GR, O'Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003 May;9(5):589-95. doi: 10.1038/nm850. Epub 2003 Mar 31. — View Citation

Haley, S., W. Coster, L. Ludlow, J. Haltiwanger and A. PA (1992). Pediatric Evaluation of Disability Inventory: Development, Standardization and Administration Manual. Boston, MA, Trustees of Boston University.

Hnasko TS, Perez FA, Scouras AD, Stoll EA, Gale SD, Luquet S, Phillips PE, Kremer EJ, Palmiter RD. Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8858-63. doi: 10.1073/pnas.0603081103. Epub 2006 May 24. — View Citation

Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, Snyder RO, Byrne BJ, Tai CH, Wu RM. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012 May 16;4(134):134ra61. doi: 10.1126/scitranslmed.3003640. — View Citation

Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis. 1990;13(3):301-4. doi: 10.1007/BF01799380. No abstract available. — View Citation

Hyland K, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem. 1992 Dec;38(12):2405-10. — View Citation

Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology. 1992 Oct;42(10):1980-8. doi: 10.1212/wnl.42.10.1980. — View Citation

Jernigan TL, Archibald SL, Berhow MT, Sowell ER, Foster DS, Hesselink JR. Cerebral structure on MRI, Part I: Localization of age-related changes. Biol Psychiatry. 1991 Jan 1;29(1):55-67. doi: 10.1016/0006-3223(91)90210-d. — View Citation

Jernigan TL, Tallal P. Late childhood changes in brain morphology observable with MRI. Dev Med Child Neurol. 1990 May;32(5):379-85. doi: 10.1111/j.1469-8749.1990.tb16956.x. — View Citation

Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J, Bankiewicz KS. Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. Hum Gene Ther. 2009 May;20(5):497-510. doi: 10.1089/hum.2008.137. — View Citation

Kells AP, Forsayeth J, Bankiewicz KS. Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. Neurobiol Dis. 2012 Nov;48(2):228-35. doi: 10.1016/j.nbd.2011.10.004. Epub 2011 Oct 14. — View Citation

Kim DS, Palmiter RD, Cummins A, Gerfen CR. Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice. Neuroscience. 2006;137(4):1381-8. doi: 10.1016/j.neuroscience.2005.10.054. Epub 2006 Jan 4. — View Citation

Laske DW, Morrison PF, Lieberman DM, Corthesy ME, Reynolds JC, Stewart-Henney PA, Koong SS, Cummins A, Paik CH, Oldfield EH. Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg. 1997 Oct;87(4):586-94. doi: 10.3171/jns.1997.87.4.0586. — View Citation

Laske DW, Youle RJ, Oldfield EH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med. 1997 Dec;3(12):1362-8. doi: 10.1038/nm1297-1362. — View Citation

Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. 2009 Mar;13(2):135-40. doi: 10.1016/j.ejpn.2008.03.008. Epub 2008 Jun 24. — View Citation

Lonser RR, Schiffman R, Robison RA, Butman JA, Quezado Z, Walker ML, Morrison PF, Walbridge S, Murray GJ, Park DM, Brady RO, Oldfield EH. Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology. 2007 Jan 23;68(4):254-61. doi: 10.1212/01.wnl.0000247744.10990.e6. Epub 2006 Oct 25. — View Citation

Lonser RR, Walbridge S, Garmestani K, Butman JA, Walters HA, Vortmeyer AO, Morrison PF, Brechbiel MW, Oldfield EH. Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg. 2002 Oct;97(4):905-13. doi: 10.3171/jns.2002.97.4.0905. — View Citation

Lonser RR, Warren KE, Butman JA, Quezado Z, Robison RA, Walbridge S, Schiffman R, Merrill M, Walker ML, Park DM, Croteau D, Brady RO, Oldfield EH. Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg. 2007 Jul;107(1):190-7. doi: 10.3171/JNS-07/07/0190. — View Citation

Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia. Dev Med Child Neurol. 2013 Jul;55(7):671-2. doi: 10.1111/dmcn.12108. Epub 2013 Mar 1. No abstract available. — View Citation

Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laass MW, Pritsch M, Wilichowski E, Horster F. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis. 2009 Jun;32(3):371-80. doi: 10.1007/s10545-009-1076-1. Epub 2009 Jan 28. — View Citation

Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE, Zhou S, Wright JF, Jiang H, Pierce GF, Arruda VR, High KA. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood. 2007 Oct 1;110(7):2334-41. doi: 10.1182/blood-2007-03-080093. Epub 2007 Jul 3. — View Citation

Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, Kawakami T, Urabe M, Kume A, Sato T, Watanabe E, Ozawa K, Nakano I. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther. 2010 Sep;18(9):1731-5. doi: 10.1038/mt.2010.135. Epub 2010 Jul 6. — View Citation

Peden CS, Burger C, Muzyczka N, Mandel RJ. Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain. J Virol. 2004 Jun;78(12):6344-59. doi: 10.1128/JVI.78.12.6344-6359.2004. — View Citation

Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol. 1994 Sep;51(9):874-87. doi: 10.1001/archneur.1994.00540210046012. — View Citation

Pons R, Syrengelas D, Youroukos S, Orfanou I, Dinopoulos A, Cormand B, Ormazabal A, Garzia-Cazorla A, Serrano M, Artuch R. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency. Mov Disord. 2013 Jul;28(8):1058-63. doi: 10.1002/mds.25382. Epub 2013 Feb 6. — View Citation

Richardson RM, Gimenez F, Salegio EA, Su X, Bringas J, Berger MS, Bankiewicz KS. T2 imaging in monitoring of intraparenchymal real-time convection-enhanced delivery. Neurosurgery. 2011 Jul;69(1):154-63; discussion 163. doi: 10.1227/NEU.0b013e318217217e. — View Citation

Richardson RM, Kells AP, Martin AJ, Larson PS, Starr PA, Piferi PG, Bates G, Tansey L, Rosenbluth KH, Bringas JR, Berger MS, Bankiewicz KS. Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg. 2011;89(3):141-51. doi: 10.1159/000323544. Epub 2011 Apr 14. — View Citation

Richardson RM, Kells AP, Rosenbluth KH, Salegio EA, Fiandaca MS, Larson PS, Starr PA, Martin AJ, Lonser RR, Federoff HJ, Forsayeth JR, Bankiewicz KS. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease. Mol Ther. 2011 Jun;19(6):1048-57. doi: 10.1038/mt.2011.11. Epub 2011 Feb 22. — View Citation

Russell, D. J., P. L. Rosenbaum, L. M. Avery and M. Lane (2002). The Gross Motor Function Measure (GMFM-66 & GMFM-88) User's Manual. London, Mac Keith Press.

Salegio EA, Streeter H, Dube N, Hadaczek P, Samaranch L, Kells AP, San Sebastian W, Zhai Y, Bringas J, Xu T, Forsayeth J, Bankiewicz KS. Distribution of nanoparticles throughout the cerebral cortex of rodents and non-human primates: Implications for gene and drug therapy. Front Neuroanat. 2014 Mar 17;8:9. doi: 10.3389/fnana.2014.00009. eCollection 2014. — View Citation

Sanftner LM, Suzuki BM, Doroudchi MM, Feng L, McClelland A, Forsayeth JR, Cunningham J. Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV. Mol Ther. 2004 Mar;9(3):403-9. doi: 10.1016/j.ymthe.2003.12.005. — View Citation

Su X, Kells AP, Salegio EA, Salegio EA, Richardson RM, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Forsayeth J, Bankiewicz KS. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther. 2010 Aug;18(8):1490-5. doi: 10.1038/mt.2010.114. Epub 2010 Jun 15. Erratum In: Mol Ther. 2012 Feb;20(2):468. Salegio, Ernesto Aguilar [corrected to Salegio, Ernesto A]. — View Citation

Swoboda KJ, Hyland K, Goldstein DS, Kuban KC, Arnold LA, Holmes CS, Levy HL. Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology. 1999 Oct 12;53(6):1205-11. doi: 10.1212/wnl.53.6.1205. — View Citation

Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54 Suppl 6:S49-55. doi: 10.1002/ana.10631. — View Citation

Szczypka MS, Kwok K, Brot MD, Marck BT, Matsumoto AM, Donahue BA, Palmiter RD. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron. 2001 Jun;30(3):819-28. doi: 10.1016/s0896-6273(01)00319-1. — View Citation

Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001 Aug;39(8):800-12. doi: 10.1097/00005650-200108000-00006. — View Citation

Voges J, Reszka R, Gossmann A, Dittmar C, Richter R, Garlip G, Kracht L, Coenen HH, Sturm V, Wienhard K, Heiss WD, Jacobs AH. Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol. 2003 Oct;54(4):479-87. doi: 10.1002/ana.10688. — View Citation

Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD; CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. doi: 10.1001/jama.2008.929. — View Citation

Ziegler DA, Wonderlick JS, Ashourian P, Hansen LA, Young JC, Murphy AJ, Koppuzha CK, Growdon JH, Corkin S. Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease. JAMA Neurol. 2013 Feb;70(2):241-7. doi: 10.1001/jamaneurol.2013.597. — View Citation

* Note: There are 46 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events related to surgery and gene transfer	Assessment of adverse events related to surgery (including intracerebral hemorrhage or stroke, CNS infection) and gene transfer (including severity of post-operative dyskinesia)	2 years
Primary	CSF neurotransmitter metabolite concentrations	Change in CSF neurotransmitter metabolite concentrations after gene transfer (increase in homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and elevated 3-O-methyldopa (3-OMD) concentrations)	1 year
Secondary	Gross Motor Function Measure	Increase in Gross Motor Function Measure-88 (GMFM-88) score	2 years
Secondary	Symptom Diary created by PI	Decrease in frequency and severity of oculogyric episodes	1 years
Secondary	Fluorodopa PET scan	Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure	Evaluated at 3 months and 2 years