J Neurol (1998) 245 [Suppl 3] : P35P42

Springer-Verlag 1998

Richard Grondin
Don M. Gash

R. Grondin (Y)
Department of Anatomy and Neurobiology,
University of Kentucky Medical Center,
800 Rose Street, MN 224, Lexington,
KY 405360084, USA
Tel.: +1-606-257-5036,
Fax: +1-606-323-5946
D. M. Gash
Department of Anatomy
and Neurobiology Center
for Magnetic Resonance Imaging
and Spectroscopy, University of Kentucky,
College of Medicine, Lexington,
KY 40536, USA

Glial cell line-derived

neurotrophic factor (GDNF):
a drug candidate for the treatment
of Parkinsons disease

Abstract Considerable effort has

been devoted to the search for molecules that might exert trophic influences on midbrain dopamine neurons, and potentially be of therapeutic value in the treatment of Parkinsons disease. One such candidate is
glial cell line-derived neurotrophic
factor (GDNF). GNDF is distantly
related to the transforming growth
factor- superfamily and is widely
expressed in many neuronal and nonneuronal tissues. GDNF uses a multisubunit receptor system in which
GFR-1 and Ret function as the ligand-binding and signalling components, respectively. In addition to its
effects on cultured fetal midbrain
dopamine neurons, GDNF promotes
recovery of the injured nigrostriatal
dopamine system and improves motor functions in rodent and nonhuman primate models of Parkinsons
disease. Intraventricular, intrastriatal
and intranigral routes of administration are efficacious in both models.
In parkinsonian nonhuman primates,

Introduction
Parkinsons disease (PD) is characterized by a progressive
degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons that innervate the striatum. The loss
of striatal dopamine (DA) and the consequent dysfunction
of the nigrostriatal pathway lead to the cardinal symptoms
of PD, namely, resting tremor, cogwheel rigidity, difficulty in initiating movement (bradykinesia) and loss of
postural reflex. Current treatment strategies for PD aim at

GDNF treatment improves bradykinesia, rigidity and postural instability. In this model, adult midbrain dopamine neurons stimulated by GDNF
show increased cell size, neuritic extent, and expression of phenotypic
markers. The neurorestorative effects
of a single administration of GDNF
last for at least a month and can be
maintained in rhesus monkeys by
monthly injections. GDNF also induces neuroprotective changes in
dopamine neurons, which are active
within hours following trophic factor
administration in rodents. The powerful neuroprotective and neurorestorative properties of GDNF seen in
preclinical studies suggest that trophic factors may play an important
role in treating Parkinsons disease.
Key words 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)
Nonhuman primates Dopamine
Parkinson Glial cell line-derived
neurotrophic factor (GDNF)

pharmacologically augmenting striatal DA using the DA

precursor levodopa or DA receptor agonists, or both. Such
treatments provide symptomatic relief, but do not slow or
halt continued degeneration of nigral dopaminergic neurons. Consequently, interventions that slow or reverse the
progression of neuronal degeneration are currently under
investigation. One such approach involves trophic factor
administration.
Neurotrophic factors are required for development,
guidance and maintenance of the developing and adult

P36

nervous system [32]. Classically, a neurotrophic factor is

produced and secreted by targets cells, be they nerve cells
or other cells, and then taken up by the innervating nerve
terminals to exert both local effects and, via retrograde axonal transport, trophic effects in the nerve cell bodies
[42]. Considerable effort has been devoted to the search
for neurotrophic factors with survival-promoting activities on dopaminergic neurons of the SNc that could potentially be of therapeutic value in the treatment of PD.
One such candidate is glial cell line-derived neurotrophic
factor (GDNF). In the paragraphs to follow, we will review much of the literature on GDNF from its discovery
to its trophic effects in nonhuman primates.

Identification and characterization

GDNF was isolated and purified from the conditioned
medium of cultured rat glial cells from the B49 cell line
[36]. It consists of 134 amino acids whose sequence is almost identical in rats and humans. GDNF is a heparinbinding, basic protein, which is heterogenously glycosylated and has an apparent molecular mass of 3345 kDa
[37]. This disulfide-bonded homodimer contains seven
conserved cysteine residues found in the same relative
spacing across the members of the transforming growth
factor- (TGF-) superfamily [36]. However, GDNF
shares less than 20% homology with any of the known
TGF- proteins and, thus, is sufficiently different to warrant classification in a new TGF- subfamily.
Consistent with this possibility, Kotzbauer et al. [30]
recently described the purification and cloning of a new
neurotrophic factor, termed neurturin, structurally related
to GDNF. The amino-acid sequence of mature neurturin
shares about 42% similarity with mature GDNF. Sequence alignments suggest that neurturin, like GDNF, is
also a distant member of the TGF- superfamily. The discovery of neurturin has established the existence of a new
family of neurotrophic factors structurally similar to TGF. The isolation of other members should now be feasible
by methods based on amino-acid sequences conserved between neurturin and GDNF.

Distribution
GDNF mRNA expression has been found in many regions
of the central nervous system (CNS). Using in situ hybridization, Strmberg et al. [52] reported detectable levels of GDNF mRNA in embryonic and newborn rat striatum, but not in adult rats. However, subsequent studies,
using reverse transcriptase-polymerase chain reaction
(RT-PCR), have demonstrated GDNF mRNA expression
in the striatum in adult rats [14, 51] and in adult humans
[51]. In situ hybridization is not as sensitive as RT-PCR,
which likely explains why GDNF mRNA was not de-

tected in the adult striatum using the former method. In

addition, GDNF mRNA levels have been decteted using a
nuclease protection assay in adult mice striatum throughout postnatal development and maturity [6]. GDNF may
also affect other CNS neurons, as expression of GDNF
mRNA has been demonstrated in many other brain regions. These include the thalamus, hippocampus, cerebellum, cortex and spinal cord of embryonic and newborn
rats [14, 52] as well as the hippocampus, cortex, cerebellum and spinal cord of adult rats [14, 51] and adult humans [51].
GDNF expression is not limited to the CNS. Indeed,
GDNF mRNA is widely expressed in peripheral tissues,
suggesting possible additional roles for GDNF outside the
CNS. GDNF mRNA expression has been detected in
many organs of the developing rats, including kidney,
lung, gonad [14, 53, 59], gut [14], bone, liver, heart [53],
skeletal muscle and adrenal gland [59].

GDNF-deficient mice
Several groups have investigated the role of GDNF during
development by generating a null mutation in the murine
GDNF locus [39, 45, 47]. Such GDNF-null mice show
kidney agenesis or dysgenesis, defective enteric innervation and die shortly after birth. Analysis failed to reveal
overt differences in distribution, density or tyrosine hydroxylase (TH) staining properties between SNc DA neurons in newborn GDNF/ mutant mice and the GDNF+/+
controls. Similarly, significant reduction is not seen in the
number and size of locus ceruleus noradrenergic neurons
in these mutant mice [39].
Although the number of central catecholaminergic
neurons at birth seems to be preserved in GDNF/ mice,
these studies do not rule out the possibility that, in the
adult brain, GDNF is a physiological survival factor for
these CNS neurons. The effects of deleting GDNF on the
postnatal survival and maturation of DA and noradrenergic neurons remains to be determined, as this issue cannot
be addressed in the GDNF-deficient mice because of their
premature death. Also, it is possible that GDNF-like molecules such as neurturin can compensate for the lack of
GDNF function in the mutant brain. Consistent with this
possibility, Klein et al. [29] found that neurturin prevents
the death of embryonic dopaminergic neurons and motor
neurons in cell culture.

GDNF receptors
The proto-oncogene Ret encodes a receptor protein-tyrosine kinase [54]. Targeted disruption of the Ret protooncogene in mice results in renal agenesis or severe dysgenesis and lack of enteric neurons throughout the digestive tract [50]. The striking similarity in phenotype be-

P37

tween the GDNF-deficient mice described above and Retdeficient mice raised the possibility that these two proteins function in the same signalling cascade. Four groups
came to the conclusion that Ret is indeed a functional receptor component for GDNF. However, they disagreed
about the details of the receptor complex. On the one
hand, Trupp et al. [57] and Durbec et al. [16] have suggested that GDNF exerts its biological activity solely by
binding to and causing phosphorylation of Ret. On the
other hand, Jing et al. [26] and Treanor et al. [56] showed
that a novel glycosyl-phosphatidylinositol (GPI)-anchored
membrane protein, termed GDNFR-, was required for
Ret to bind and be activated by GDNF. Because all receptors for members of the TGF- superfamily characterized
so far are receptor serine-threonine kinase, the ability of
GDNF to interact with a receptor tyrosine kinase indicates
further functional divergence from other members of the
TGF- superfamily [57].
Northern blot, PCR and in situ hybridization analysis
detected mRNA for GDNFR- in many GDNF-responsive regions of the embryonic and adult rat nervous system, including DA neurons and spinal motoneurons [56].
Consistent with the finding that the kidney and the enteric
nervous system fail to develop in GDNF-deficient mice,
high levels of GDNFR- mRNA are present in striated
and smooth muscles adjacent to the enteric nervous system and in developing nephrons of the kidney [56]. In situ
hybridization analysis also shows high levels of c-Ret
mRNA expression in dopaminergic neurons of the adult
rat SNc. Accordingly, c-Ret mRNA expression was
markedly reduced in the lesioned SNc 1 day after 6-hydroxydopamine (6-OHDA) treatment and nearly absent 5
days after the lesion [57]. Similarly, high levels of Ret immunoreactivity are detected in the SNc, which are significantly reduced in adult rats with 6-OHDA lesions of the
medial forebrain bundle [1]. High c-Ret mRNA expression was also found in the adult rat spinal cord, pons,
medulla, hypothalamus, thalamus, and cerebellum [57]. It
is also of interest to note that some neuronal populations,
such as in the subthalamic nucleus, express Ret but not
GDNFR-. Conversley, GDNFR- is expressed in regions in which Ret expression is absent, including the superior colliculus and extensive regions of the cerebral cortex [58]. Clearly, our understanding of the normal biology
of GDNF trophic actions mediated via the Ret/GDNFR-
receptor complex is at an early stage, and much remains
to be learned about it.
Like GDNF, neurturin signals via a multicomponent
receptor system formed by a recently cloned GPI-linked
ligand binding subunit (the component) and the receptor tyrosine kinase Ret as a signalling (i.e., ) subunit. This novel GPI-linked lingand binding subunit,
structurally related to GDNFR-, has been alternatively
named Trn-2 [3], NTNR- [9, 29] and RETL2 [48]. The
finding that neurturin can activate Ret may help explain
why some neuronal populations appear unperturbed in the

GDNF knockout mice. Common receptor components

such as Ret are economical, as they allow multiple factors
to share the same signal-transduction receptor subunits. It
was recently proposed [19] to use the abbreviated name
GFR-X (for GDNF family receptor alpha-X), where
X denotes an arabic numeral to be assigned based on
the date of publication of the receptor. Thus, GDNFR-
will become GFR-1, while NTNR-/TrnR-2/RETL2
will be GFR-2.

GDNF effects in cultures

GDNF was originally identified based on its properties to
promote the survival and morphological differentiation of
dopaminergic neurons in embryonic mesencephalic cells
grown in culture [36, 37]. The effects of GDNF on DA
neurons in midbrain cultures are potent (EC50 40 pg/ml)
and relatively specific as GDNF increases DA cell number, DA uptake, cell size and neurite length, without affecting -aminobutyric acid (GABA) and serotonin uptake
or overall number of glia (astrocytes, oligodentrocytes),
which are also present in these cultures. Further studies
have since confirmed the effects of GDNF in culture. In
dissociated cultures of embryonic rat mesencephalon developing under normal conditions, GDNF at 1 ng/ml optimally improved the survival and stimulated the growth of
dopaminergic neurons [24]. Additionally, in cultures exposed to 1-methyl-4-phenylpyridinium ion (MPP+), GDNF
protects dopaminergic neurons against continuous cell
death and promotes regrowth of damaged dopaminergic
fibers after removal of MPP+ [24].
Although most of the initial studies have examined the
effects of GDNF on the dopaminergic system, several reports also demonstrate the trophic effects of GDNF on
other types of neurons in vitro. GDNF was demonstrated
to be an extremely potent survival factor for embryonic
rat and chicken motoneurons in culture [21, 22, 43].
GDNF can also promote the survival and morphological
differentiation of cultured Purkinje cells, the efferent neurons of cerebellar cortex [40].

GDNF effects in rodents

Behavioral and immunocytochemical data suggest that a
single intracranial injection of GDNF adjacent to the SNc
elicits profound and long-lasting upregulation of the midbrain dopaminergic system in normal rats [25]. The infusion of GDNF was seen to produce significant increases
in spontaneous locomotor activity 1 week following treatment. Immunocytochemical studies performed 3 weeks
after GDNF injections showed sprouting of TH+ neurites
towards the injection site and increased TH immunoreactivity of the ipsilateral striatum, suggesting that GDNF
can induce neuritogenesis in adult midbrain DA neurons.

P38

Follow-up studies have reported both protective and regenerative effects using rodent models of PD.
Neurorestoration
Most of the studies on the restorative effects of GDNF
have used rodent models with 6-OHDA- or 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the nigrostriatal DA system. With a 4-week interval between the 6-OHDA lesion and GDNF treatment,
Hoffer et al. [23] demonstrated a significant decrease in
apomorphine-induced rotational behavior by 1 week after
a single injection of 100 g GDNF into the supranigral region. In addition, DA levels in the SNc were 3 times
higher 5 weeks after trophic factor administration. Subsequent studies have shown that a number of morphological
and functional features of the midbrain DA neurons are
restored by GDNF. Trophic factor treatment significantly
increases the number of neurons expressing TH, the number of TH+ neurites, and TH activity levels [7, 35]. In
mice with degeneration of nigrostriatal DA neurons and
processes induced by systemic MPTP treatment, Tomac et
al. [55] found that either striatal or nigral administration
of GDNF begun a week after the lesion improved motor
performance and promoted recovery of midbrain DA levels when measured 18 days later.
Aged F344 rats have long been used as a model for
age-related dysfunctions of the dopaminergic pathway. The
ability of GDNF to have a positive trophic influence on
aged DA neurons in rats has also been reported [34]. Most
effects of GDNF have been described for the midbrain
dopaminergic neurons. Recently, a more widespread spectrum of GDNF activities has been reported. In addition to
DA neurons, GDNF has been found to exert in vivo trophic
effects on other CNS neurons of several different phenotypic origins, including motor neurons [22, 43], forebrain
cholinergic neurons [61], and locus ceruleus noradrenergic neurons [2].
Neuroprotection
In addition to its neurorestorative effects, GDNF also exhibits neuroprotective properties. In adult rats, GDNF
protects midbrain DA neurons against intranigral and intrastriatal injections of 6-OHDA [28], neurotoxic doses of
methamphetamine [11], as well as axotomy-induced degeneration of the medial forebrain bundle [4]. Protective
effects have also been reported against MPTP neurotoxicity in mice [55]. To follow up on initial reports on the neuroprotective properties of GDNF, our group has conducted a series of experiments in which the timing between GDNF infusion into the SNc before a 6-OHDA lesion was varied from 0 to 24 h [27]. Significantly increased survival of nigral DA neurons was found in male
F344 rats receiving 10 g of GDNF at either 6, 12 or 24 h

before an intranigral 6-OHDA lesion. GDNF pretreatment

was most effective at the 6-h time point, with virtually
100% of the neurons surviving the subsequent 6-OHDA
lesion. These results imply that protective mechanisms
are operating at the 624 h time points. Taken together, the
above studies suggest that GDNF has profound effects on
normal, aged and lesioned nigrostriatal DA systems.

GDNF effects in nonhuman primates

Normal animals
Based on the rodent data, our group has carried out an extended series of experiments to analyze the effects of
GDNF in rhesus (Macaca mulatta) monkeys. All of the
procedures performed on nonhuman primates were in
strict accordance with the NIH Guide for the Care and
Use of Laboratory Animals and were approved by institutional animal care and use committees. In the first experimental series [17], the effects of GDNF were analyzed in
normal adult female monkeys. The animals were evaluated prior to and 34 weeks after a single injection of either 150 g human recombinant GDNF or vehicle into the
right SNc using stereotaxic procedures guided by magnetic
resonance imaging (MRI). The study included whole animal behavior, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal DA system. In the adult
rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic DA neurons. In the SNc ipsilateral to GDNF administration, DAneuron perikaryal size was significantly increased, along
with a significant increase in TH+ axons and dendrites,
which lasts for weeks. Most but not all of the GDNFtreated monkeys showed increased activity levels.
Neurorestorative properties in hemiparkinsonian animals
Because GDNF can upregulate normal primate DA neurons, the next step was to determine whether or not it can
similarly upregulate dopaminergic functions in nonhuman
primate models of PD. All animals received right intracarotid artery infusions of MPTP to induce continuously
expressed parkinsonian features using procedures described in detail elsewhere [44]. MPTP is a neurotoxin
that produces behavioral, neurochemical and neuropathological changes in both human and nonhuman primates
similar to those observed in idiopathic PD [10, 31].
In the second experimental series [18], sterile MRIguided stereotaxic procedures were used to deliver a single injection of human recombinant GDNF into the right
side of the brain of rhesus monkeys by one of three routes:
intranigral (150 g), intracaudate and intracerebroventricular (450 g). Testing was continued on the ventriculartreated animals to assess the ability of the animals to re-

P39

spond to three repeated dosings 4 weeks apart. Behavioral

parameters associated with motor function were assessed
using a primate parkinsonian scale [44] patterned after the
human Unified Parkinsons Disease Rating Scale (UPDRS). Values of the primate rating scale range from 0
(normal) to 22 (severely unilaterally disabled monkey)
and are scored in the following categories: rigidity,
bradykinesia, posture, balance, tremor, and food acquisition test. Immunohistochemical staining for TH, the ratelimiting enzyme in DA synthesis, was used to identify
neuritric processes and cell bodies of surviving DA neurons, and multiple tissue punches were taken from the
basal ganglia and midbrain to measure levels of DA using
high-performance liquid chromatography. GDNF recipients showed significant functional improvements after all
three routes of administration by 2 weeks after treatment,
which continued for the remainder of the 4-week test period. In this and subsequent experiments, improvements
were found in three of the cardinal features of PD: bradykinesia, rigidity, and postural stability. GDNF administered every 4 weeks maintained functional recovery. On
the lesioned side of GDNF-treated animals, DA levels in
the midbrain and globus pallidus were twice as high, and
nigral DA neurons were 20% larger on average, with an
increased fiber density.
Follow-up experiments have provided additional details about the antiparkinsonian actions of GDNF. Dosedependent improvements in movement functions were
seen in MPTP-induced parkinsonian rhesus monkeys receiving monthly ventricular injections of 1001000 g
GDNF [62]. The minimal efficacious dose to produce a
significant improvement in behavioral parameters was determined to be 300 g. After trophic factor treatment was
discontinued, the parkinsonian features in most animals
began to return to baseline levels within 60 days. In this
and the other studies on nonhuman primates, side effects
from GDNF injections were limited to a transient weight
loss. At no time did any of the animals appear to be malnourished or unhealthy. Rather, in post hoc analysis of the
GDNF-recipients, they appeared to be more active, alert
and better-groomed than vehicle-treated controls. The observed accumulation of [125I]GDNF label around the hypothalamus as well as the observed increase in hypothalamic DA levels may be in part responsible for the inhibition of weight gain, considering the established role of the
hypothalamus in the regulation of body weight [33]. Further studies are required to test whether altered hypothalamic DA neurotransmission is involved in the GDNF
modification of feeding behavior.
Levodopa-GDNF interactions
in hemiparkinsonian monkeys
Levodopa is currently the most widely used drug for treating PD. However, parkinsonian patients given levodopa

therapy frequently develop motor complications, such as

dyskinesias, after many years of treatment. The mechanisms underlying levodopa-induced dyskinesia remain
obscure. Thus, our group has also evaluated potential interactions between levodopa and GDNF in MPTP-treated
hemiparkinsonian monkeys [38].
At baseline, each animal was tested for its dose-reponse to levodopa treatment. Levodopa alone produced
dose-dependent improvements in parkinsonian features,
but at higher levels typical levodopa-induced dyskinesias
were prominent. Then, the animals received two monthly
injections of 300 g GDNF or vehicle in the right lateral
ventricle, which were followed by a second levodopa
dose-reponse test. This study shows that 300 g of GDNF
infused into the lateral ventricle produces an improvement
in parkinsonian features of the same magnitude as levodopa. In addition, the behavioral effects of combined
GDNF-levodopa treatment are clearly additive, as five- to
six-fold lower doses of levodopa in GDNF-treated monkeys were required to produce equivalent reductions in
behavioral deficit scores. Not only were parkinsonian features reduced, but levodopa-induced dyskinesias were significantly ameliorated.
Several observations in humans [41] and in nonhuman
primates [8, 49] point to the importance of extensive nigrostriatal damage for the development of dyskinesia.
GDNF effects are evident in the nigra, where DA levels
are increased and the number of dopaminergic processes
(using TH as a marker) are enhanced [17, 18]. Thus, the
trophic actions of GDNF on the nigrostriatal dopaminergic system may explain the attenuation of levodopa-induced dyskinesias. In parkinsonian monkeys, GDNF also
increases DA levels in the globus pallidus [18], which
may play a role in the reduction of dyskinesias. In addition, GDNF was shown to prevent the chemically induced
death of noradrenergic neurons in the locus ceruleus and
to promote their fasciculation and sprouting in whole animals [2]. Thus, the actions of GDNF could also be mediated by this or other neurotransmitter systems affected by
GDNF. Consistent with this possibility, treatments aimed
at pharmacologically augmenting noradrenergic transmission produce antidyskinetic effects without impairing the
levodopa antiparkinsonian response in PD patients [46]
and in MPTP-treated monkeys [20].

Future directions
Little is known about the long-term effects of trophic factor treatment on the mature nervous system. One of the
challenges in future studies will be to define dosing protocols and delivery systems for GDNF that optimize its actions. These may require chronic or timed infusion of
GDNF into specific brain sites. In addition to the direct
stereotaxic protein injection approach, several studies using novel methods for chronic delivery of GDNF into the

P40

nigrostriatal pathway have already been reported in rodents.

Tseng et al. [60] implanted encapsulated baby hamster
kidney cells, genetically engineered to produce approximately 5 ng GDNF/capsule per day, adjacent to the median forebrain bundle/SNc in adult female Wistar rats.
The implant preserved many TH+ DA neurons in the SNc
following a subsequent medial forebrain bundle transection. Another approach has utilized adenovirus vectors to
transfect cells in adult rats to produce GDNF. When rats
with nigral cells transfected to produce GDNF were challenged with an intranigral 6-OHDA injection a week later,
75% of the striatal projecting neurons in the SNc survived
compared with 2530% in controls animals [15]. When
cells in the striatum were transfected via adenoviral vectors and 6-OHDA later injected into the striatum, approximately 60% of TH+ neurons were preserved in the nigra
of GDNF-transfected rats versus approximately 40% in
control animals [5]. One novel method to deliver GDNF
in the CNS for prolonged local release is to incorporate it
in a biodegradable biomaterial such as fibrin glue [12,
13]. New approaches for the treatment of PD may also be
developed by targeting GDNF receptors or the signalling
pathway that is initiated when these receptors are activated. Moreover, simultaneous delivery of multiple
growth factors might produce a more substantial recovery
than seen with single factor delivery. It will be important
to determine whether these or other methods of providing

chronic levels of GDNF are also effective in preserving or

restoring motor functions in nonhuman primates, and if
so, seeing how they might be extended into treating PD.

Summary
GDNF is a glycosylated, disulfide-bonded homodimer
distantly related to the TGF- superfamily. It is synthesized by many cell types throughout the body and effects
the survival and development of a diverse set of neuronal
and non-neuronal cells. A multicomponent receptor system is known for GDNF, which consists of a membranebound subunit that can bind GDNF and facilitate its
interaction with the tyrosine kinase Ret receptor subunit. Collectively, in vitro and in vivo data, in both the rodent and nonhuman primate, provide strong support for a
role for GDNF in treating PD. The powerful stimulatory
actions of GDNF increase cell size, neuritric extent, and
expression of phenotypic markers in adult midbrain DA
neurons. This restoration of the nigrostriatal system correlates well with functional recovery. Clearly, GDNF shows
considerable promise for continued investigation as a
drug candidate for the treatment of PD.
Acknowledgements The work in the authors laboratory discussed in this review was supported by contracts with AMGEN
Inc., California. Richard Grondin holds a postdoctoral fellowship
from the Fond de la Recherche en Sant du Qubec (FRSQ).

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