You are viewing a javascript disabled version of the site. Please enable Javascript for this site to function properly.
Go to headerGo to navigationGo to searchGo to contentsGo to footer
In content section. Select this link to jump to navigation

Improved Delivery Methods for Gene Therapy and Cell Transplantation in Parkinson’s Disease


A number of cell transplantation and gene therapy trials have been performed over the last three decades in an effort to restore function in Parkinson’s disease. Much has been learned about optimizing delivery methods for these therapeutics. This is particularly true in gene therapy, which has predominated the clinical trial landscape in recent years; however, cell transplantation for Parkinson’s disease is currently undergoing a renaissance. Innovations such as cannula design, iMRI-guided surgery and an evolution in delivery strategy has radically changed the way investigators approach clinical trial design. Future therapeutic strategies may employ newer delivery methods such as chronically implanted infusion devices and focal opening of the blood brain barrier with focused ultrasound.

A number of cell transplantation and gene therapy trials have been performed over the last three decades in an effort to restore function in those afflicted with neurodegenerative disorders. Parkinson’s disease (PD) has been the most frequently investigated disease thus far, with a number of therapeutic strategies including cell transplantation from a variety of donor sources as well as gene therapy for enzyme replacement or local expression of a neurotrophic growth factor [1–8]. These early human trials were informed by pre-clinical animal work, predominantly using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine nonhuman primate (NHP) model of PD.

The surgical delivery of these therapeutics in the 1990s and early 2000s utilized the widely accepted tools of the day, typically a stereotactic frame such as the Leksell (Elekta, Stockholm, Sweden) or CRW (Integra, Cincinnati, OH). These systems were used to place a delivery cannula blindly into the intended target. For cell transplantation, a “withdraw and deposit” delivery strategy was employed by placing the cannula at the deepest point along the trajectory and withdrawing it several millimeters at the time to intermittently deposit cells [1, 9]. For viral vector gene transfer, the “withdraw and deposit” method with intermittent infusions delivered by hand or a single-point infusion in the center of the target with convection enhanced delivery (CED) were performed using simple cylindrical cannula designs [4, 5]. The determination of the amount of therapeutic to deliver was usually calculated by scaling up volumes used in the pre-clinical animal studies that resulted in a clinical change.

Early phase 2 trials in both cell transplantation and gene therapy for PD had disappointing results, most with failure to reach their primary endpoints and/or emergence of bothersome side effects in placebo-controlled trials [1, 8, 10, 11]. These outcomes may have been related to the biology of the therapeutic material or local host environment (especially in cell transplantation). In gene therapy, the success of a particular therapeutic strategy depends on many factors including the properties of the vector and serotype used, whether they are capable of anterograde and/or retrograde transport (and if this is important to the biological intent), the type of promotor used, how the gene product is expressed and the viability of the therapeutic strategy in the first place. Early gene therapy trials were particularly hampered by suboptimal delivery methods [12]. We now realize that blind infusions of a viral vector using traditional stereotactic methods are subject to multiple sources of off-target delivery (infusate not going to or remaining in the intended target). These include reflux up the cannula, unintentional spread through perivascular spaces and misplacement of infusion cannulas; such events occur even in the hands of very experienced and skilled surgeons [13–17]. Moreover, hand injections with a syringe are far less efficient for delivering infusate over large volumes of tissue than convection enhanced delivery [12]. Indeed, CED for viral vectors has now become the method of choice for achieving predictable, adequate coverage of targets in the basal ganglia [11, 18–22].

For cell transplantation, the delivery considerations appear to be less complicated. Unlike viral vectors, transplanted cells do not need to be distributed over a large area during surgical delivery to potentially produce a therapeutic effect. Cells that survive after transplantation sprout neurites well beyond the localized cell deposits; in one PD patient who underwent postmortem analysis 24 years after fetal cell transplantation, cells deposited along three linear cannula tracts with an entry point near the coronal suture resulted in reinnervation throughout the entire postcommissural putamen [23]. In a double-blind trial of fetal cell transplant in the United States, a more anterior frontal approach with the entry point in the forehead was used to place the cannulas down the long axis of the putamen as close to the axial plane as possible [1]. Since the putamen is an elongated structure in the axial plane, this less-traditional angle of approach increased the efficiency of delivery while using only two needle tracts per putamen.

The emergence of interventional MRI (iMRI)-guided surgery using an FDA approved platform for placing devices in the human brain led to the development of co-infusion of viral vectors with gadoteridol, a gadolinium-based contrast agent (Fig. 1) [24–26]. There has been debate regarding the safety of intraparenchymal infusion of gadoteridol after several studies demonstrated radiographic evidence of contrast accumulation in certain brain regions in patients receiving repeated intravenous administration of gadolinium-based contrast agents (GBCAs) [27, 28]. However, the clinical significance and/or risk of these deposits is unknown. A subsequent in vitro study attempted to determine potential toxicity of such deposits by exposing a cell culture of dopaminergic neurons differentiated from a human neuroblastoma cell line to various GBCAs [29]. The authors did demonstrate mitochondrial and cellular toxicity in the cultured cells after direct exposure to GBCAs; however, these in vitro experiments were quite artificial, and do not replicate the complex environment of the human brain parenchyma.

By contrast, direct intraparenchymal delivery of gadoteridol (either in liposomes or admixed directly with viral vector) has been performed numerous times in the non-human primate, an animal model that does closely replicates the local environment of the human brain parenchyma. Co-infusion of various therapeutics with gadoteridol has been performed in multiple brain targets (including striatum, thalamus, midbrain, brainstem and entorhinal cortex) with varying survival times to sacrifice and histological analysis [26, 30–34]. No tissue or cell toxicity was observed in any of these studies. Many adult and pediatric human subjects have undergone similar intraparenchymal infusions in the basal ganglia, midbrain and brainstem as well as intra-tumoral delivery [35–39]. None of these clinical trials demonstrated any known or suspected toxicity of one-time intraparenchymal administration of gadoteridol. NHP studies of AAV-based gene therapy showed this technique provided a “what you see is what you get” visualization of the infusions. That is, the area of gadoteridol enhancement seen on real-time MR images correlated highly with the area of vector transduction observed on histopathology [32]. This technique was translated to humans simultaneously in two phase 1 clinical trials of intraputaminal AAV gene therapy for PD [38, 39]. These trials started by using the traditional single-point CED infusion strategy of placing the cannula tip stationary in center of the target region. The advantages of real-time visualization during infusions quickly became apparent during the first few procedures. Off-target delivery due to reflux and perivascular spread were seen in almost all of the infusions, and effective coverage of the target was less than anticipated [14, 38, 39].

The gradual evolution in delivery methods for CNS gene therapy infusions was greatly accelerated as these two trials progressed in order to minimize off-target delivery (Table 1). The use of cannulas with two stepwise increases in diameter along the distal end of the device was previously found to resist reflux better than cylindrical or single-step cannulas. The initial dual-step cannula for these trials had a small square step 3 mm above the tip, and a second rounded step 18 mm above the tip. Real-time visualization of the infusions showed that that smaller volumes with lower flow rates usually only reflux to the first step, while increasing flow rates and larger volumes eventually cause reflux to the second step. The 18 mm distance to the second step proved to be too long for the height of some putamen in the coronal plane, so a variety of cannulas with shorter, varied step geometries were developed to tailor the cannula design to individual patients’ anatomy [14].

Table 1

Summary of delivery methods in completed gene therapy clinical trials for Parkinson’s disease as of the time of this writing. AAV2, adeno associated virus serotype 2; GAD, glutamic acid decarboxylase; TH, tyrosine hydroxylase; AACD, amino acid decarboxylase; CH1, GTP-cyclohydrolase-1; GDNF, glial cell-derived neurotrophic factor; STN, subthalamic nucleus; SN, substantia nigra; CED, convection enhanced delivery; iMRI, interventional MRI

Gene therapyPhase, nTargetVolume per targetDual-step CannulaCED, infusion strategyiMRI-guidedClinical outcome summaryYear published or completedReference
AAV2-GADPhase 1, n = 12STN50μLNoYes, single pointNoImproved2007[3]
Phase 2, n = 45 (22 active, 23 sham)STN34.5μLNoYes, single pointNoImproved, but program discontinued2011[15]
AAV2-NeurturinPhase 1, n = 12Putamen40μLNoNoNoImproved2008[5]
Phase 2, n = 58 (38 active, 20 sham)Putamen40μLNoNoNoNo difference active vs sham2010[10]
Phase 1b, n = 6Putamen, SN150μL putamen, 30μL SNNoYes, single pointNoNo improvement2013[21]
Phase 2b, n = 51 (24 active, 27 sham)Putamen, SN150μL putamen, 30μL SNNoYes, single pointNoNo difference active vs sham2015[11]
Lentivirus-TH, AADC, CH1Phase 1/2, n = 15Putamen[Not stated]NoUncertainNoImproved2014[6]
AAV2-AADCPhase 1, n = 10Putamen100μLYesYes, single pointNoImproved2009[4]
Phase 1, n = 15PutamenUp to 450μL or 900μLYesYes, single point, stacked &progressiveYesImproved2019[26]
Phase 1, n = 8PutamenUp to 1800μLYesYes, progressive (posterior approach)Yes[ongoing]2018 (follow up ongoing)n/a
AAV2-GDNFPhase 1, n = 13Putamen450μLYesYes, single point, stacked &progressiveYesNo improvement2019[27]

The single-point CED strategy was found to be inefficient for achieving adequate coverage and minimizing off-target delivery. Once it starts, the only way to stop significant perivascular spread is to move the tip of the cannula away from the offending vessel. CED is most effective when the cannula tip is in contact with intact brain parenchyma, so the cannula should only be advanced during infusion, not withdrawn. If the cannula tip is already at the center of the target and perivascular spread occurs, there is little room to advance the cannula before the distal border of the target is reached. Early advancement of the cannula in this scenario may also compromise coverage in the proximal portion of the target. In addition, once the infusion rate or volume become sufficient to cause reflux beyond the first step, it is advantageous to have advanced the cannula such that the second step is at the proximal border of the target (or even within the target itself). For both of these reasons, it is better to start the infusion at the proximal end of the target and advance the cannula as the infusion is performed. These so-called stacked or progressive infusions have become the standard method for optimizing target coverage in gene therapy, and allow experienced surgeons to shape the infusions to fit the target [14, 40].

Finally, it became apparent that the volume of infusions used in the past were too conservative, and likely resulted in coverage of the target that was below what was needed to see a clinical effect. This is in part a reflection of the cautious approach taken in some earlier trials, which were first-in-human studies of these novel intracranial gene therapies. The concept of the Vd/Vi ratio (volume of distribution/volume of infusion) was developed during NHP gene therapy studies in basal ganglia targets using adeno associated virus, or AAV [26, 32]. If an infusion is optimal with minimal off-target delivery, the Vd/Vi ratio is approximately 3:1 (i.e., to cover 1500 cubic mm of tissue, one must infuse about 500 microliters of vector). As real-world infusions in the human brain frequently do suffer from off-target delivery, a more realistic Vd/Vi ratio is often closer to 2:1. In gene therapy, the Vd/Vi ratio has become a useful tool for predicting the volume of infusate needed to cover a given target. For example, the human putamen has an average volume of approximately 4000 cubic mm. To approach 100% coverage of this target with AAV, one must infuse somewhere between 1333 (Vd/Vi of 3:1) and 2000 (Vd/Vi of 2:1) microliters of vector. This ratio can be used to design future trials as well as predict coverage of prior studies that utilized traditional, blind infusion techniques [14]. In recent human gene therapy trials, volumes of 1800 microliters have been safely and effectively delivered to the human putamen. This is approximately 45 times more volume than was delivered to the putamen in the earlier trials of gene therapy for PD [4, 5, 14].

Most of the recent advances in delivery methods for therapeutics to the brain in PD have focused on intraparenchymal gene therapy. This is largely due to the fact that delivery of a fluid to the brain parenchyma is more unpredictable and more dependent on surgical technique than cell transplantation, at least based on our current understanding. In the aftermath of two negative phase 2 fetal cell transplantation trials, gene therapy has also predominated the clinical trials landscape in PD over the last two decades, and the delivery methods have varied significantly. However, there are a number of exciting cell transplant trials on the horizon at the time of this writing, utilizing novel sources for transplantation such as induced pluripotent stem cells and new strategies to promote cell survival [41]. Several of these trials will be using iMRI-guided surgery for cell delivery, although it is not yet established if this technique will have the same benefits that have been seen with viral vector delivery. Since cell transplantation is not as dependent on coverage of the target as gene therapy, the only advantage that MRI-guided surgery might have is confirmation of cannula placement in the intended target. Many assumptions were made regarding infusions of fluids into the brain that turned out to be incorrect once gene therapy entered the era of iMRI-guided delivery; it will be interesting to see if there are lessons to be learned regarding surgical technique for cell transplantation in the iMRI era.

One important alternative to gene or cell-based strategies in PD is the chronic infusion of proteins directly to the basal ganglia. One recent program used a novel, chronically implanted delivery system consisting of a subcutaneous reservoir and multiple intracranial catheters to perform repeated CED infusions of glial cell line-derived neurotrophic factor as an alternative to intraventricular delivery [42, 43]. Although the study did not reach its primary endpoint, it was an important proof-of-principle study for successful chronic delivery of a protein to the parenchyma. There has not been a role thus far for chronic delivery of cells. Chronic delivery of viral vectors may be inadvisable due to antibody formation to the virus carrying the gene of interest over time. However, for other novel therapies, this may be an important delivery method moving forward.

The future of CNS delivery of cells, viral vectors and other biological agents for PD is bright. There is a movement towards less invasive and more efficient surgical approaches. New surgical tools, such as percutaneously mounted aiming devices and small twist drills, have transformed intraparenchymal delivery into an almost incision-less procedure. Posterior approaches through the occipital region to place laser fibers down the long axis of the hippocampus to treat seizures have been transformative in epilepsy surgery over the last decade. These procedures are now done routinely, and have a bleeding risk comparable to traditional frontal approaches for gene therapy or deep brain stimulation [44–47]. A posterior trajectory along the long axis of the putamen (analogous to the far anterior approach for cell transplantation utilized by Freed et. al. over 20 years ago) have made gene therapy procedures a single-pass affair, with greater efficiency and shorter procedure times [14].

There are newer, more cost effective iMRI-based delivery devices that are capable of performing multiple bilateral simultaneous infusions, and others are sure to follow [48–50]. New routes of administration for novel agents, such as intranasal delivery of antisense oligonucleotides, may provide a non-surgical option for delivery in the future [51]. Finally, recent studies have shown that focused ultrasound can be used to induce focal opening of the blood brain barrier, raising the possibility that an intravenous or systemically-administered agent could be delivered to a brain target without any direct parenchymal penetration [52]. It remains to be seen if adequate concentrations of the therapeutic could be achieved by this means of delivery, or what the implications might be for widespread systemic delivery of a given agent.

These explorations of less invasive options and alternative routes of delivery are encouraging, provided we strike an appropriate balance between safety, efficiency and invasiveness. It is natural to strive towards a non-surgical delivery option to make these potential treatments as safe as possible and attractive for patients. However, we must remember that the most important factor in delivering a biologically-based treatment is getting enough of the therapeutic to the target to produce a clinically meaningful change.


Dr. Larson serves as a consultant for Aspen Neuroscience, Corlieve, Neurocrine Biosciences, and Sanofi; serves on the advisory board of Biogen and Sio (Axovant); and has grants from Brain Neurotherapy Bio, Neurocrine Biosciences, UniQure, and Voyager.



Freed CR , Greene PE , Breeze RE , Tsai WY , DuMouchel W , Kao R , Dillon S , Winfield H , Culver S , Trojanowski JQ , Eidelberg D , Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344, 710–719.


Snow B , Mulroy E , Bok A , Simpson M , Smith A , Taylor K , Lockhart M , Lam BJ , Frampton C , Schweder P , Chen B , Finucane G , McMahon A , Macdonald L (2019) A phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL((R)) [immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease. Parkinsonism Relat Disord 61, 88–93.


Kaplitt MG , Feigin A , Tang C , Fitzsimons HL , Mattis P , Lawlor PA , Bland RJ , Young D , Strybing K , Eidelberg D , During MJ (2007) Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: An open label, phase I trial. Lancet 369, 2097–2105.


Christine CW , Starr PA , Larson PS , Eberling JL , Jagust WJ , Hawkins RA , VanBrocklin HF , Wright JF , Bankiewicz KS , Aminoff MJ (2009) Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73, 1662–1669.


Marks WJ Jr. , Ostrem JL , Verhagen L , Starr PA , Larson PS , Bakay RA , Taylor R , Cahn-Weiner DA , Stoessl AJ , Olanow CW , Bartus RT (2008) Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: An open-label, phase I trial. Lancet Neurol 7, 400–408.


Palfi S , Gurruchaga JM , Ralph GS , Lepetit H , Lavisse S , Buttery PC , Watts C , Miskin J , Kelleher M , Deeley S , Iwamuro H , Lefaucheur JP , Thiriez C , Fenelon G , Lucas C , Brugieres P , Gabriel I , Abhay K , Drouot X , Tani N , Kas A , Ghaleh B , Le Corvoisier P , Dolphin P , Breen DP , Mason S , Guzman NV , Mazarakis ND , Radcliffe PA , Harrop R , Kingsman SM , Rascol O , Naylor S , Barker RA , Hantraye P , Remy P , Cesaro P , Mitrophanous KA (2014) Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: A dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146.


Olanow CW , Koller W , Goetz CG , Stebbins GT , Cahill DW , Gauger LL , Morantz R , Penn RD , Tanner CM , Klawans HL , et al. (1990) Autologous transplantation of adrenal medulla in Parkinson’s disease. 18-month results. Arch Neurol 47, 1286–1289.


Olanow CW , Goetz CG , Kordower JH , Stoessl AJ , Sossi V , Brin MF , Shannon KM , Nauert GM , Perl DP , Godbold J , Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54, 403–414.


Lindvall O , Widner H , Rehncrona S , Brundin P , Odin P , Gustavii B , Frackowiak R , Leenders KL , Sawle G , Rothwell JC , Ourklund AB , Marsden CD (1992) Transplantation of fetal dopamine neurons in Parkinson’s disease: One-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol 31, 155–165.


Marks WJ Jr. , Bartus RT , Siffert J , Davis CS , Lozano A , Boulis N , Vitek J , Stacy M , Turner D , Verhagen L , Bakay R , Watts R , Guthrie B , Jankovic J , Simpson R , Tagliati M , Alterman R , Stern M , Baltuch G , Starr PA , Larson PS , Ostrem JL , Nutt J , Kieburtz K , Kordower JH , Olanow CW (2010) Gene delivery of AAV2-neurturin for Parkinson’s disease: A double-blind, randomised, controlled trial. Lancet Neurol 9, 1164–1172.


Warren Olanow C , Bartus RT , Baumann TL , Factor S , Boulis N , Stacy M , Turner DA , Marks W , Larson P , Starr PA , Jankovic J , Simpson R , Watts R , Guthrie B , Poston K , Henderson JM , Stern M , Baltuch G , Goetz CG , Herzog C , Kordower JH , Alterman R , Lozano AM , Lang AE (2015) Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Ann Neurol 78, 248–257.


Bartus RT , Herzog CD , Chu Y , Wilson A , Brown L , Siffert J , Johnson EM Jr. , Olanow CW , Mufson EJ , Kordower JH (2011) Bioactivity of AAV2-neurturin gene therapy (CERE-120): Differences between Parkinson’s disease and nonhuman primate brains. Mov Disord 26, 27–36.


Krauze MT , Saito R , Noble C , Bringas J , Forsayeth J , McKnight TR , Park J , Bankiewicz KS (2005) Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp Neurol 196, 104–111.


Richardson RM , Bankiewicz KS , Christine CW , Van Laar AD , Gross RE , Lonser R , Factor SA , Kostyk SK , Kells AP , Ravina B , Larson PS (2020) Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease. J Neurol Neurosurg Psychiatry 91, 1210–1218.


LeWitt PA , Rezai AR , Leehey MA , Ojemann SG , Flaherty AW , Eskandar EN , Kostyk SK , Thomas K , Sarkar A , Siddiqui MS , Tatter SB , Schwalb JM , Poston KL , Henderson JM , Kurlan RM , Richard IH , Van Meter L , Sapan CV , During MJ , Kaplitt MG , Feigin A (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10, 309–319.


Krauze MT , Saito R , Noble C , Tamas M , Bringas J , Park JW , Berger MS , Bankiewicz K (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103, 923–929.


Brady ML , Raghavan R , Alexander A , Kubota K , Sillay K , Emborg ME (2013) Pathways of infusate loss during convection-enhanced delivery into the putamen nucleus. Stereotact Funct Neurosurg 91, 69–78.


Yin D , Valles FE , Fiandaca MS , Bringas J , Gimenez F , Berger MS , Forsayeth J , Bankiewicz KS (2011) Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates. Neuroimage 54(Suppl 1), S196–203.


Lieberman DM , Laske DW , Morrison PF , Bankiewicz KS , Oldfield EH (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82, 1021–1029.


Hadaczek P , Kohutnicka M , Krauze MT , Bringas J , Pivirotto P , Cunningham J , Bankiewicz K (2006) Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther 17, 291–302.


Aguilar Salegio EA , Kells AP , Richardson M , Hadaczek P , Forsayeth J , Bringas J , Sardi P , Passini MA , Shihabuddin LS , Cheng SH , Fiandaca MS , Bankiewicz K (2010) MRI-guided delivery of AAV2 to the primate brain for the treatment of lysosomal storage disorders. Hum Gene Ther 21, 1093–1103.


Bartus RT , Baumann TL , Siffert J , Herzog CD , Alterman R , Boulis N , Turner DA , Stacy M , Lang AE , Lozano AM , Olanow CW (2013) Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 80, 1698–1701.


Li W , Englund E , Widner H , Mattsson B , van Westen D , Latt J , Rehncrona S , Brundin P , Bjorklund A , Lindvall O , Li JY (2016) Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A 113, 6544–6549.


Larson PS , Starr PA , Bates G , Tansey L , Richardson RM , Martin AJ (2012) An optimized system for interventional magnetic resonance imaging-guided stereotactic surgery: Preliminary evaluation of targeting accuracy. Neurosurgery 70, 95–103; discussion 103.


Richardson RM , Kells AP , Martin AJ , Larson PS , Starr PA , Piferi PG , Bates G , Tansey L , Rosenbluth KH , Bringas JR , Berger MS , Bankiewicz KS (2011) Novel platform for MRI-guided convection-enhanced delivery of therapeutics: Preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg 89, 141–151.


Su X , Kells AP , Salegio EA , Salegio EA , Richardson RM , Hadaczek P , Beyer J , Bringas J , Pivirotto P , Forsayeth J , Bankiewicz KS (2010) Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 18, 1490–1495.


Kanda T , Nakai Y , Oba H , Toyoda K , Kitajima K , Furui S (2016) Gadolinium deposition in the brain. Magn Reson Imaging 34, 1346–1350.


Kanda T , Ishii K , Kawaguchi H , Kitajima K , Takenaka D (2014) High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: Relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 270, 834–841.


Bower DV , Richter JK , von Tengg-Kobligk H , Heverhagen JT , Runge VM (2019) Gadolinium-based MRI contrast agents induce mitochondrial toxicity and cell death in human neurons, and toxicity increases with reduced kinetic stability of the agent. Invest Radiol 54, 453–463.


Krauze MT , McKnight TR , Yamashita Y , Bringas J , Noble CO , Saito R , Geletneky K , Forsayeth J , Berger MS , Jackson P , Park JW , Bankiewicz KS (2005) Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging. Brain Res Brain Res Protoc 16, 20–26.


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 (2009) Real-time MR imaging of adeno-associated viral vector delivery to the primate brain.T. Neuroimage 47(Suppl 2), 27–35.


Richardson RM , Kells AP , Rosenbluth KH , Salegio EA , Fiandaca MS , Larson PS , Starr PA , Martin AJ , Lonser RR , Federoff HJ , Forsayeth JR , Bankiewicz KS (2011) Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther 19, 1048–1057.


San Sebastian W , Kells AP , Bringas J , Samaranch L , Hadaczek P , Ciesielska A , Macayan M , Pivirotto PJ , Forsayeth J , Osborne S , Wright JF , Green F , Heller G , Bankiewicz KS (2014) Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of non-human primate. Mol Ther Methods Clin Dev 3, 14049.


Nagahara AH , Wilson BR , Ivasyk I , Kovacs I , Rawalji S , Bringas JR , Pivirotto PJ , Sebastian WS , Samaranch L , Bankiewicz KS , Tuszynski MH (2018) MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther 25, 104–114.


Lonser RR , Sarntinoranont M , Morrison PF , Oldfield EH (2015) Convection-enhanced delivery to the central nervous system. J Neurosurg 122, 697–706.


Merola A , Kobayashi N , Romagnolo A , Wright BA , Artusi CA , Imbalzano G , Litvan I , Van Laar AD , Bankiewicz K (2021) Gene therapy in movement disorders: A systematic review of ongoing and completed clinical trials. Front Neurol 12, 648532.


D’Amico RS , Aghi MK , Vogelbaum MA , Bruce JN (2021) Convection-enhanced drug delivery for glioblastoma: A review. J Neurooncol 151, 415–427.


Christine CW , Bankiewicz KS , Van Laar AD , Richardson RM , Ravina B , Kells AP , Boot B , Martin AJ , Nutt J , Thompson ME , Larson PS (2019) Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann Neurol 85, 704–714.


Heiss JD , Lungu C , Hammoud DA , Herscovitch P , Ehrlich DJ , Argersinger DP , Sinharay S , Scott G , Wu T , Federoff HJ , Zaghloul KA , Hallett M , Lonser RR , Bankiewicz KS (2019) Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease. Mov Disord 34, 1073–1078.


Bankiewicz KS , Sudhakar V , Samaranch L , San Sebastian W , Bringas J , Forsayeth J (2016) AAV viral vector delivery to the brain by shape-conforming MR-guided infusions. J Control Release 240, 434–442.


Barker RA , Drouin-Ouellet J , Parmar M (2015) Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurol 11, 492–503.


Whone A , Luz M , Boca M , Woolley M , Mooney L , Dharia S , Broadfoot J , Cronin D , Schroers C , Barua NU , Longpre L , Barclay CL , Boiko C , Johnson GA , Fibiger HC , Harrison R , Lewis O , Pritchard G , Howell M , Irving C , Johnson D , Kinch S , Marshall C , Lawrence AD , Blinder S , Sossi V , Stoessl AJ , Skinner P , Mohr E , Gill SS (2019) Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain 142, 512–525.


Nutt JG , Burchiel KJ , Comella CL , Jankovic J , Lang AE , Laws ER Jr. , Lozano AM , Penn RD , Simpson RK Jr. , Stacy M , Wooten GF , ICV GDNF Study Group. Implanted intracerebroventricular. Glial cell line-derived neurotrophic factor (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60, 69–73.


Drane DL , Loring DW , Voets NL , Price M , Ojemann JG , Willie JT , Saindane AM , Phatak V , Ivanisevic M , Millis S , Helmers SL , Miller JW , Meador KJ , Gross RE (2015) Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy. Epilepsia 56, 101–113.


Waseem H , Vivas AC , Vale FL (2017) MRI-guided laser interstitial thermal therapy for treatment of medically refractory non-lesional mesial temporal lobe epilepsy: Outcomes, complications, and current limitations: A review. J Clin Neurosci 38, 1–7.


Shukla ND , Ho AL , Pendharkar AV , Sussman ES , Halpern CH (2017) Laser interstitial thermal therapy for the treatment of epilepsy: Evidence to date. Neuropsychiatr Dis Treat 13, 2469–2475.


Wu C , Jermakowicz WJ , Chakravorti S , Cajigas I , Sharan AD , Jagid JR , Matias CM , Sperling MR , Buckley R , Ko A , Ojemann JG , Miller JW , Youngerman B , Sheth SA , McKhann GM , Laxton AW , Couture DE , Popli GS , Smith A , Mehta AD , Ho AL , Halpern CH , Englot DJ , Neimat JS , Konrad PE , Neal E , Vale FL , Holloway KL , Air EL , Schwalb J , Dawant BM , D’Haese PF (2019) Effects of surgical targeting in laser interstitial thermal therapy for mesial temporal lobe epilepsy: A multicenter study of 234 patients. Epilepsia 60, 1171–1183.


Sudhakar V , Mahmoodi A , Bringas JR , Naidoo J , Kells A , Samaranch L , Fiandaca MS , Bankiewicz KS (2019) Development of a novel frameless skull-mounted ball-joint guide array for use in image-guided neurosurgery. J Neurosurg 132, 595–604.


Bankiewicz KS , Pasterski T , Kreatsoulas D , Onikijuk J , Mozgiel K , Munjal V , Elder JB , Lonser RR , Zabek M (2020) Use of a novel ball-joint guide array for magnetic resonance imaging-guided cannula placement and convective delivery: Technical note. J Neurosurg, doi: 10.3171/2020.6.JNS201564


Dadey DY , Kamath AA , Smyth MD , Chicoine MR , Leuthardt EC , Kim AH (2016) Utilizing personalized stereotactic frames for laser interstitial thermal ablation of posterior fossa and mesiotemporal brain lesions: A single-institution series. Neurosurg Focus 41, E4.


Alarcon-Aris D , Pavia-Collado R , Miquel-Rio L , Coppola-Segovia V , Ferres-Coy A , Ruiz-Bronchal E , Galofre M , Paz V , Campa L , Revilla R , Montefeltro A , Kordower JH , Vila M , Artigas F , Bortolozzi A (2020) Anti-alpha-synuclein ASO delivered to monoamine neurons prevents alpha-synuclein accumulation in a Parkinson’s disease-like mouse model and in monkeys. EBioMedicine 59, 102944.


McMahon D , O’Reilly MA , Hynynen K (2021) Therapeutic agent delivery across the blood-brain barrier using focused ultrasound. Annu Rev Biomed Eng 23, 89–113.