The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
The authors’ full names, academic de-
grees, and affiliations are listed in the Ap-
pendix. Dr. Bönnemann can be contact-
ed at ­carsten​.­bonnemann@​­nih​.­gov or at
the Neuromuscular and Neurogenetic
Disorders of Childhood Section, National
Institute of Neurological Disorders and
Stroke, National Institutes of Health, 35
Convent Dr., Rm. 2A-116, Bethesda, MD
20814.
*The members of the GAN Trial Team are
listed in the Supplementary Appendix,
available at NEJM.org.
Drs. Todd and Saade contributed equally
to this article.
This article was updated on March 21,
2024, at NEJM.org.
N Engl J Med 2024;390:1092-104.
DOI: 10.1056/NEJMoa2307952
Copyright © 2024 Massachusetts Medical Society.
CME
at NEJM.org
1092
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
Intrathecal Gene Therapy
for Giant Axonal Neuropathy
D.X. Bharucha‑Goebel, J.J. Todd, D. Saade, G. Norato, M. Jain, T. Lehky,
R.M. Bailey, J.A. Chichester, R. Calcedo, D. Armao, A.R. Foley, P. Mohassel,
E. Tesfaye, B.P. Carlin, B. Seremula, M. Waite, W.M. Zein, L.A. Huryn, T.O. Crawford,
C.J. Sumner, A. Hoke, J.D. Heiss, L. Charnas, J.E. Hooper, T.W. Bouldin, E.M. Kang,
D. Rybin, S.J. Gray, and C.G. Bönnemann, for the GAN Trial Team*​​
A BS T R AC T
BACKGROUND
Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic,
neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the
gene encoding gigaxonin.
METHODS
We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-com-
plementary adeno-associated virus–based gene therapy containing the GAN trans-
gene) in children with giant axonal neuropathy. Safety was the primary end point.
The key secondary clinical end point was at least a 95% posterior probability of
slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total
percent score at 1 year after treatment, as compared with the pretreatment slope.
RESULTS
One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 partici-
pants — 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4),
1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7
months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever)
was possibly related to treatment; 129 of 682 adverse events were possibly related to
treatment. The mean pretreatment slope in the total cohort was −7.17 percentage
points per year (95% credible interval, −8.36 to −5.97). At 1 year after treatment,
posterior mean changes in slope were −0.54 percentage points (95% credible in-
terval, −7.48 to 6.28) with the 3.5×1013–vg dose, 3.23 percentage points (95% credible
interval, −1.27 to 7.65) with the 1.2×1014–vg dose, 5.32 percentage points (95% cred-
ible interval, 1.07 to 9.57) with the 1.8×1014–vg dose, and 3.43 percentage points
(95% credible interval, −1.89 to 8.82) with the 3.5×1014–vg dose. The corresponding
posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to
44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99),
which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90).
Between 6 and 24 months after gene transfer, sensory-nerve action potential am-
plitudes increased, stopped declining, or became recordable after being absent in
6 participants but remained absent in 8.
CONCLUSIONS
Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was
associated with adverse events and resulted in a possible benefit in motor function
scores and other measures at some vector doses over a year. Further studies are
warranted to determine the safety and efficacy of intrathecal AAV-mediated gene
therapy in this disorder. (Funded by the National Institute of Neurological Disor-
ders and Stroke and others; ClinicalTrials.gov number, NCT02362438.)
n engl j med 390;12 nejm.org March 21/28, 2024
The New England Journal of Medicine
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy
G
iant axonal neuropathy is a rare,
rapidly progressive, monogenic, neuro-
degenerative disease that has been iden-
tified in more than 75 families currently known
to the study team.1 The disorder is caused by
biallelic pathogenic loss-of-function variants in
GAN (16q23.2), which encodes gigaxonin, a ubiq-
uitously expressed Cul3 ubiquitin ligase adaptor
protein.2 Gigaxonin is a low-abundance protein
that regulates intermediate filament turnover
in the central and peripheral nervous systems.3
When functional gigaxonin is absent, pathologic
accumulation of intermediate filaments results
in cellular inclusions and abnormal axonal
swellings termed “giant axons,”4 which give the
disease its name.
A prototypical, early-onset, progressive giant
axonal neuropathy phenotype and a later-onset,
slower-progressing axonal Charcot–Marie–Tooth
disease–like giant axonal neuropathy phenotype
have been described5 as having a common genetic
mechanism of pathogenic biallelic GAN variants.
Peripheral axonal loss in giant axonal neuropa-
thy causes progressive sensorimotor neuropathy,
as indicated on electrophysiological testing and
histologic analysis of the peripheral nerves. Giant
axonal neuropathy typically manifests with ad-
ditional features of dry, tightly curled hair and
sensory ataxia in the first few years of life. The
disease course includes progressive, nerve length–
dependent, sensorimotor neuropathy; cerebellar
dysfunction; loss of unassisted independent am-
bulation by 8 to 10 years of age; vision loss; and
secondary systemic complications.5,6 Deficits in
motor function are reflected by a uniform de-
cline in score on the 32-item Motor Function
Measure (MFM-32) across varying ages and am-
bulatory statuses.7,8 The disorder is typically fatal,
often because of pulmonary complications, by
the third decade of life.1,9
Intrathecally administered adeno-associated
viral (AAV) vectors can transduce neurons and
glia.10-12 We developed a self-complementary AAV
serotype 9 (scAAV9) vector that carries a codon-
optimized human GAN transgene with expres-
sion controlled by the minimal synthetic recom-
binant JeT promoter consisting of five elements
(see the Supplementary Appendix, available with
the full text of this article at NEJM.org).13 The
agent, scAAV9/JeT-GAN, was tested intrathecally in
preclinical proof-of-concept, dose-ranging, toxicol-
ogy, and biodistribution studies in Gan-knockout
n engl j med 390;12
The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
and phenotypically normal control animals (het-
erozygous littermates).11,13-15 No dose-limiting
toxic effects were observed through the highest
dose tested in rats (6.6×1011 total vector genomes
[vg] per animal). The construct successfully
transduced murine dorsal-root ganglia, decreased
formation of intermediate filament aggregates,
reduced peripheral-nerve pathologic features,
and rescued rotarod performance deficits in
Gan-knockout mice.
Intrathecal AAV9-mediated gene transfer is
primarily intended to target cell bodies of spinal
cord motor neurons in the anterior horn and
sensory neurons in the dorsal-root ganglia,
which would in turn affect their axons in the
peripheral nerves and the central extension of
the dorsal-root ganglia. We present data from a
phase 1 clinical study in which participants with
giant axonal neuropathy received a single intra-
thecal dose of scAAV9/JeT-GAN.
Me thods
Study Oversight
This ongoing, investigator-initiated, phase 1 study
began on February 13, 2015. Natural history
data for giant axonal neuropathy were obtained
in an observational study of various childhood
genetic nerve and muscle disorders (ClinicalTri-
als.gov number, NCT01568658). The protocols
for the natural history study and the current
clinical study were approved by the National
Institutes of Health (NIH) intramural institu-
tional review board. Written informed consent
and assent were obtained before study proce-
dures were initiated. An independent data and
safety monitoring board oversaw the safety of
the study participants and adjudicated dose es-
calation. Hannah’s Hope Fund, a 501(c)(3) public
charity, supported scAAV9/JeT-GAN manufactur-
ing at the University of North Carolina Vector
Core facility–Bamboo Therapeutics. The National
Institute of Neurological Disorders and Stroke was
the regulatory sponsor through August 2022,
after which Taysha Gene Therapies assumed
regulatory sponsorship.
The first and second authors and the last
(senior) author cowrote the first draft of the
manuscript with subsequent input from the co-
authors and without commercial editorial assis-
tance. Commercial entity–affiliated authors pro-
vided support in statistical analyses and assay
nejm.org March 21/28, 2024 1093
 The n e w e ng l a n d j o u r na l of m e dic i n e

development and had confidentiality agreements The participants received a single lumbar in-
with Taysha Gene Therapies. The NIH academic trathecal infusion of scAAV9/JeT-GAN (total vol-
authors collaborated with Taysha Gene Thera- ume, 10.5 ml) at one of four dose levels: 3.5×1013
pies through a clinical trial agreement, which vg, 1.2×1014 vg, 1.8×1014 vg, or 3.5×1014 vg, as
included confidentiality terms. The NIH re- determined by means of reverse-transcriptase–
tained autonomy over the ability to submit the polymerase-chain-reaction assay, which was di-
study data for publication. All the investigators luted in 1× phosphate-buffered saline containing
were responsible for the design and implemen- 5% sorbitol to generate a total volume of 12 ml
tation of the study, which was conducted in (including overfill). Certificates of analysis for
accordance with the Good Clinical Practice the investigational product are provided in the
guidelines of the International Council for Har- Supplementary Appendix. All the participants
monisation, and the collection, analysis, and received concomitant immunomodulation with
interpretation of the data. The authors vouch for transient glucocorticoids (methylprednisolone
the accuracy and completeness of the data and and prednisone), and a subgroup also received
accurate reporting of adverse events and for the rapamycin. The participants who were predicted
fidelity of the study to the protocol, available at to be negative for CRIM received rapamycin and
NEJM.org. tacrolimus to mitigate the potential for T-cell–
mediated antitransgene immune response. Fur-
Participants and Study Procedures ther immunosuppression details are provided in
Participants older than 6 years of age with ge- Figure S1 and Table S1 in the Supplementary
netically confirmed giant axonal neuropathy Appendix.
were enrolled from April 2015 through August
2020. All the participants were first recruited to End Points
the observational natural history study after re- The primary safety end point was the incidence
ferral by a clinician or a parent or guardian and of serious adverse events during the safety ob-
were subsequently invited to participate in the servational period that were at least possibly re-
current study. Mean rates of change during the lated to scAAV9/JeT-GAN, as determined by the
natural history study, which were used for com- principal investigator (the last author) and re-
parison with the post-treatment values, were viewed by the data and safety monitoring board
determined from data collected from 17 study and an independent medical monitor. Discon-
visits across the participants. Among the par- tinuation criteria were the occurrence of the
ticipants, the duration of the natural history of same or similar unexpected serious adverse
the disease that was studied ranged from 3.7 to event that was at least possibly related to
31.5 months before dose administration. scAAV9/JeT-GAN in two or more participants or
The clinical study cohort included persons the occurrence of the same or similar unex-
who were predicted to have no residual gigaxo- pected grade 3 or higher adverse event that was
nin protein expression (cross-reactive immuno- at least possibly related to scAAV9/JeT-GAN in
logic material [CRIM] negative) and were thus three or more participants. Adverse events were
more likely to have an antibody response after assessed by means of physical examinations,
scAAV9/JeT-GAN treatment on the basis of GAN interim medical histories, magnetic resonance
genotype and persons who were AAV9 seroposi- imaging, and laboratory testing.
tive (serum neutralizing antibody titer, ≥1:5) or The key secondary efficacy end point at 1 year
seronegative at baseline, as confirmed by labora- after gene transfer was at least a 95% Bayesian
tory testing. Full eligibility criteria and methods posterior probability of slowing the rate of
are provided in the protocol. The number of change (referred to here as slope) in the MFM-32
participants recruited was based on feasibility total percent score, as compared with the mean
considerations owing to the rarity of the disor- slope during the pretreatment period, which was
der and availability of scAAV9/JeT-GAN. Doses determined in the entire cohort during the natu-
were administered to the participants sequen- ral history study. All the participants completed
tially after the safety of each dose level was the MFM-32 (for persons >6 years of age), which
adjudicated by the data and safety monitoring comprises three subdomains (standing and stand-
board. ing transfers, axial and proximal motor function,

1094 n engl j med 390;12 nejm.org March 21/28, 2024

The New England Journal of Medicine

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy
and distal motor function tested in lying, sitting,
and standing positions).5,7,8 Each item is scored
on a 4-point Likert scale from 0 (inability to
perform) to 3 (performing a task fully without
assistance), for a total score ranging from 0 to
96. Results of the MFM-32 are reported as the
total percent score, which is calculated as the
percentage of achieved points in all subdomains
divided by the maximum obtainable score of 96
points, with higher scores indicating better mo-
tor function. Physical therapists conducted the
MFM-32 at screening; at months 3, 6, 9, 12, and
18; and annually thereafter.
Other secondary end points included the score
on the modified Friedreich Ataxia Rating Scale
(mFARS; range, 0 to 93, with higher scores indi-
cating worse function) and the Neuropathy Im-
pairment Score (range, 0 to 244, with higher
scores indicating more impairment). Exploratory
end points included compound motor-action
potential (CMAP) and sensory-nerve action po-
tential (SNAP) amplitudes in the upper extremity
(arms, wrists, and hands) and lower extremity
(legs, ankles, and feet); findings from a histo-
pathological analysis of regenerating cluster
density in the superficial radial sensory nerve16;
immune responses (white-cell counts, AAV9 neu-
tralizing antibody titer, gigaxonin and AAV9
reactive T-cell counts, and findings from shed-
ding studies), and scAAV9/JeT-GAN biodistribu-
tion in postmortem nervous system and periph-
eral tissue specimens from one participant.
Further details regarding the study end points
are provided in the Supplementary Appendix.
Statistical Analysis
Safety and efficacy populations included all par-
ticipants. Bayesian efficacy analyses, stratified
according to dose group, were conducted 1 year
after dose administration. Hierarchical models
for repeated measures were used to estimate
posterior distributions for the change in slope
with respect to the key secondary and other ef-
ficacy end points at each dose level, as compared
with the mean pretreatment slope across the
dose groups. Pre- and post-treatment slopes
were estimated within a Bayesian framework
with the use of Markov chain Monte Carlo com-
putational methods. The Bayesian hierarchical
model included coefficients for the mean pre-
treatment slope across the dose groups and the
change in the slope after treatment in each dose
n engl j med 390;12
The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
group. Our slope estimates are shown as the
means of these posterior distributions derived
from the observed data. Results are presented as
Bayesian posterior probabilities and 95% credi-
ble intervals. There was no prespecified plan for
adjustment of the widths of credible intervals
for multiple comparisons of outcomes across the
four dose groups or for secondary end points,
and no inferences can be drawn from these data.
Exploratory data are reported as individual re-
sponses and are described with summary statis-
tics, as applicable. Analyses were performed with
R software, version 4.2.0, with the use of Open-
BUGS through the BRugs package. Additional
details are provided in the Supplementary Meth-
ods in the Supplementary Appendix. The statisti-
cal analysis plan is available with the protocol.
R e sult s
Participant Characteristics
A total of 14 participants received one of four
doses of scAAV9/JeT-GAN: 3.5×1013 vg (2 partici-
pants), 1.2×1014 vg (4 participants), 1.8×1014 vg (5
participants), or 3.5×1014 vg (3 participants) (Fig.
S2). The mean age of the participants at dose
administration was 9.1 years (range, 6.3 to 14.5).
These are the only patients we have treated with
this agent. Baseline characteristics and immu-
nomodulation regimens for each dose group are
presented in Table 1 and Table S1, respectively.
The mean slope of the curve for the MFM-32
total percent score in the entire cohort before
treatment was −7.17 percentage points per year.
Primary Safety End Point
Through a median safety observation period of
68.7 months (range, 8.6 to 90.5), a total of 682
adverse events were recorded (Table 2). Two par-
ticipants who received the lowest dose died from
events deemed by the principal investigator to be
at least possibly related to the underlying dis-
ease. One of the two participants had undergone
spinal fusion surgery and died in the postopera-
tive period after an episode of emesis-induced
aspiration followed by anoxemia, which result-
ed in cardiac arrest and multiorgan failure 8
months after dose administration. The other par-
ticipant had recurrent pleural effusion in the
setting of respiratory insufficiency, with respira-
tory failure occurring 60 months after dose ad-
ministration.
nejm.org March 21/28, 2024 1095
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic and Clinical Characteristics of the Participants at Baseline.*

Total Cohort
Characteristic scAAV9/JeT-GAN Dose Group (N = 14)

3.5×1013 vg 1.2×1014 vg 1.8×1014 vg 3.5×1014 vg

(N = 2) (N = 4) (N = 5) (N = 3)
Age at dose administration — yr 12.2±3.3 9.3±2.5 8.5±1.8 7.7±0.6 9.1±2.3
Female sex 1 (50) 2 (50) 4 (80) 2 (67) 9 (64)
Race or ethnic group†
American Indian or Alaska Native 0 0 0 0 0
Asian 0 0 0 0 0
Black 0 0 0 0 0
Native Hawaiian or other Pacific 0 0 0 0 0
Islander
White 2 (100) 4 (100) 4 (80) 3 (100) 13 (93)
Unknown or not reported 0 0 0 0 0
Other or multiple 0 0 1 (20) 0 1 (7)
Hispanic or Latino ethnic group†
Yes 0 0 2 (40) 2 (67) 4 (29)
No 2 (100) 4 (100) 3 (60) 1 (33) 10 (71)
CRIM positive‡ 2 (100) 3 (75) 3 (60) 2 (67) 10 (71)
CRIM negative 0 1 (25) 2 (40) 1 (33) 4 (29)
AAV9 seropositive§ 1 (50) 1 (25) 2 (40) 2 (67) 6 (43)
Motor function¶
MFM-32 total percent score 42.7±4.4 52.9±13.7 71.2±7.5 71.2±7.1 61.9±14.3
mFARS score 64.0±4.2 58.9±11.1 40.1±11.2 35.3±3.9 47.3±14.1
Neuropathy Impairment Score 146.4±17.5 115.1±17.3 83.1±13.2 96.1±19.4 104.1±26.5
Ambulatory status
Ambulant 0 0 2 (40) 1 (33) 3 (21)
Ambulant with assistance only 0 3 (75) 3 (60) 2 (67) 8 (57)
Nonambulant 2 (100) 1 (25) 0 0 3 (21)
Pulmonary function
Forced vital capacity — % of 68.5±4.9 91.8±14.1 78.8±17.9 105.3±4.9 86.7±17.7
predicted value
Pulmonary support‖
None 2 (100) 3 (75) 4 (80) 3 (100) 12 (86)
Nocturnal BiPAP 0 1 (25) 1 (20) 0 2 (14)
Neurophysiological study — CMAP or
SNAP amplitude
Median CMAP, abductor pollicis 1.7±0.6 2.1±0.5 4.0±1.9 2.7±2.2 2.9±1.7
brevis
Peroneal CMAP, tibialis anterior 0.1±0.0 0.9±0.6 2.2±1.8 1.7±0.9 0.1±0.1
Median SNAP 0.0±0.0 1.8±3.5 0.7±1.6 0.9±1.6 1.0±2.1
Ulnar SNAP 0.0±0.0 0.5±1.0 0.0±0.0 1.3±1.8 0.4±1.0
Sural SNAP 0.0±0.0 0.0±0.0 0.0±0.0 1.7±2.9 0.4±1.3
Visual function: reduced visual acuity** 1 (50) 2 (50) 0 0 3 (21)

1096 n engl j med 390;12 nejm.org March 21/28, 2024

The New England Journal of Medicine

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy

Table 1. (Continued.)

* Plus–minus values are means ±SD. The investigational biologic product scAAV9/JeT-GAN is a self-complementary adeno-associated viral
serotype 9 vector that carries a codon-optimized human GAN transgene with expression controlled by the minimal synthetic recombinant
JeT promoter consisting of five elements. APB denotes abductor pollicis brevis, and BiPAP bilevel positive airway pressure, CMAP compound
motor-action potential, and SNAP sensory-nerve action potential.
† Race and ethnic group were reported by the participant or a parent of the participant.
‡ Cross-reactive immunologic material (CRIM) positivity refers to participants who were predicted to produce some residual gigaxonin protein
on the basis of their GAN genotype.
§ AAV9 seropositivity was defined as a serum neutralizing antibody titer of 1:5 or greater.
¶ Results of the 32-item Motor Function Measure (MFM-32) scale are reported as the total percent score, which is calculated as the per-
centage (0 to 100%) of achieved points in all subdomains divided by the maximum obtainable score of 96 points, with higher scores
indicating better motor function. Scores on the modified Friedreich Ataxia Rating Scale (mFARS) range from 0 to 93, with higher scores
indicating worse function). Neuropathy Impairment Scores range from 0 to 244, with higher scores indicating more impairment.
‖ Patients who required daytime ventilatory assistance or invasive ventilatory assistance were not included in this study.
** Visual acuity was considered to be reduced at study entry if the best-corrected visual acuity in either eye corresponded to a log10 of the
minimal angle of resolution of worse than 0.5.

A total of 48 serious adverse events were re-
corded during the safety observation period. The
most common of these events were scoliosis (in
9 participants), urinary tract infection (in 6), and
upper respiratory tract infection (in 5) (Table
S2). One serious adverse event, fever with eme-
sis, occurred 2 weeks after dose administration
in a participant who was predicted to have re-
sidual gigaxonin expression (CRIM positive) on
the basis of the GAN genotype; this participant
received an scAAV9/JeT-GAN dose of 3.5×1014 vg.
In the same participant, elevations in levels of
C-reactive protein (grade 3) and B-type natri-
uretic peptide (grade 1) were also possibly re-
lated to scAAV9/JeT-GAN. These events resolved
within 48 hours, and the participant was dis-
charged after intravenous fluid treatment for
emesis-related dehydration. One participant who
received an scAAV9/JeT-GAN dose of 1.8×1014 vg
had a grade 3 exacerbation of benign familial
neutropenia 3 days after dose administration;
the exacerbation resolved 8 days later. Serious
adverse events leading to hospitalization that
were possibly related to glucocorticoids in the
immunosuppressive regimen included grade 1
pneumonia, which resolved 9 days later; grade 3
skin infection, which was débrided and treated
with antibiotics, resolving 30 days later (nail bit-
ing was a contributing factor), and grade 3 bone
infection, which resolved 47 days later (foot
bracing was a contributing factor).
Of the 682 adverse events that occurred dur-
ing the safety observation period, 129 were
deemed to be at least possibly related to scAAV9/
JeT-GAN, including cerebrospinal fluid (CSF)
pleocytosis (14 events in 13 participants), an elevat-
ed CSF IgG index (14 events in 13 participants),
leukocytosis (12 events in 8 participants), throm-
bocytosis (11 events in 7 participants), and head-
ache (7 events in 7 participants) (Table S3). Two
participants in the 3.5×1014 vg–dose group had
mild elevations in hepatic transaminase levels
that were possibly related to scAAV9/JeT-GAN; a
single instance of an elevated aspartate amino-
transferase level (50 U per liter) was recorded in
1 participant, and 3 instances of an elevated ala-
nine aminotransferase level (range, 32 to 37 U per
liter) were recorded in 2 participants. Mild eleva-
tions in the alkaline phosphatase level (range,
140 to 194 U per liter) were recorded in 5 par-
ticipants who received a dose between 1.2×1014
vg and 3.5×1014 vg; these elevations were not at-
tributed to scAAV9/JeT-GAN.
Clinical End Points
The mean change in the slope of the curve of the
MFM-32 total percent score was −0.54 percent-
age points per year in the 3.5×1013 vg–dose
group, 3.23 percentage points per year in the
1.2×1014 vg–dose group, 5.32 percentage points
per year in the 1.8×1014 vg–dose group, and 3.43
percentage points per year in the 3.5×1014 vg–dose
group (signifying a numerical change in a posi-
tive direction for the last three dose groups)
(Table 3 and Fig. S3). Only the 1.8×1014 vg–dose
group met the prespecified efficacy threshold at
1 year, with a posterior probability of any change
in the slope, as compared with the pretreatment
slope across dose groups, of 99% (95% credible
interval, 99 to 99). The results for the other three
dose groups were below the threshold. The re-
sults for the change in the slope of the curve of
the mFARS score and the Neuropathy Impair-
ment Score, as compared with the pretreatment

n engl j med 390;12 nejm.org March 21/28, 2024 1097

The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Table 2. Adverse Events That Occurred during the Safety Observation Period.*

1098
Total Cohort
Event scAAV9/JeT-GAN Dose Group (N = 14)
3.5×1013 vg 1.2×1014 vg 1.8×1014 vg 3.5×1014 vg
(N = 2) (N = 4) (N = 5) (N = 3)
no. of no. of no. of no. of no. of
no. of participants no. of participants no. of participants no. of participants no. of participants
events (%) events (%) events (%) events (%) events (%)
Any adverse event 78 2 (100) 237 4 (100) 235 5 (100) 132 3 (100) 682 14 (100)
Any serious adverse event 16 2 (100) 18 4 (100) 10 5 (100) 4 3 (100) 48 14 (100)
Any adverse event of special interest† 20 2 (100) 48 4 (100) 62 5 (100) 39 3 (100) 169 14 (100)
Adverse event at least possibly 13 2 (100) 34 4 (100) 53 5 (100) 29 3 (100) 129 14 (100)
related to scAAV9/JeT-GAN‡
Adverse event at least possibly 11 2 (100) 39 4 (100) 70 5 (100) 24 3 (100) 144 14 (100)
related to prednisone
The

Adverse event at least possibly 44 2 (100) 136 4 (100) 133 5 (100) 48 3 (100) 361 14 (100)
related to disease
Common adverse events§
Abnormal vital capacity 5 2 (100) 11 4 (100) 12 5 (100) 2 3 (66) 30 13 (93)
CSF white-cell pleocytosis† 2 2 (100) 4 4 (100) 5 4 (80) 3 3 (100) 14 13 (93)

n engl j med 390;12

Upper respiratory tract infection 4 2 (100) 8 4 (100) 7 4 (80) 4 2 (66) 23 12 (86)
Acidosis 2 2 (100) 7 3 (75) 5 4 (80) 2 2 (66) 16 11 (79)
Hyperglycemia 4 2 (100) 8 4 (100) 7 4 (80) 1 1 (33) 20 11 (79)
Headache 1 1 (50) 3 2 (50) 9 5 (100) 4 2 (66) 17 10 (71)

nejm.org
Elevated CRP level† 2 1 (50) 3 3 (75) 3 3 (60) 2 2 (66) 10 9 (64)
n e w e ng l a n d j o u r na l

Thrombocytosis 0 0 6 4 (100) 5 2 (40) 7 3 (100) 18 9 (64)

The New England Journal of Medicine

of

Leukocytosis 2 1 (50) 4 2 (50) 5 3 (60) 4 2 (66) 15 8 (57)

Intracranial hypertension† 1 1 (50) 1 1 (25) 5 4 (80) 2 2 (66) 9 8 (57)
Elevated CSF IgG index† 2 2 (100) 4 4 (100) 4 4 (80) 4 3 (100) 14 13 (93)

March 21/28, 2024

Cough 0 0 4 3 (75) 5 3 (60) 1 1 (33) 10 7 (50)
m e dic i n e

Scoliosis 2 2 (100) 5 4 (100) 3 2 (40) 2 2 (66) 10 7 (50)

Urinary tract infection 5 1 (50) 14 4 (100) 2 1 (20) 5 2 (66) 26 7 (50)

* The median safety observation period was 34.3 months (range, 8.6 to 60.1) in the 3.5×1013 vg–dose group, 87.6 months (range, 80.2 to 90.5) in the 1.2×1014 vg–dose group, 70.5
months (range, 63.7 to 83.5) in the 1.8×1014 vg–dose group, 42.9 months (range, 37.1 to 46.6) in the 3.5×1014 vg–dose group, and 68.7 months (range, 8.6 to 90.5) in the total cohort.

No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
CRP denotes C-reactive protein, and CSF cerebrospinal fluid.

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
† Adverse events of special interest included laboratory, radiographic, or clinical signs or symptoms of neuroinflammation, peripheral or systemic inflammation (including but not
limited to thrombocytopenia, thrombotic microangiopathy, myocarditis, transaminitis, and acute kidney injury), increased intracranial pressure, or new sensory disturbance suggestive
of dorsal-root ganglion inflammation.
‡ Relatedness to scAAV9/JeT-GAN was determined by the principal investigator and reviewed by the independent data safety monitoring board.
§ Common adverse events were those that occurred in more than 50% of the study participants.
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy

slope, were varied; the posterior probability of scAAV9/JeT-GAN in Gan-knockout mice13; how-
any change in the slope was at least 95% in the ever, vector genomes and biodistribution to the
1.2×1014 vg–dose group, but the probabilities in dorsal-root ganglia and peripheral tissues was
the other three dose groups were below this lower than expected (Fig. 2A and 2B). Inflam-
threshold (Table 3). The slopes for these end matory infiltrates were absent in the limited
points are presented in Table S5, and long-term dorsal-root ganglia samples available or in the
follow-up data are presented descriptively (Figs. cervical spinal cord samples (Fig. 2C and 2E,
S4 through S7). Data were not adjusted for respectively). Giant axons, which are typical of
multiple comparisons, precluding any definitive this disorder, were present in the fasciculus
conclusions. gracilis of the cervical spinal cord samples
Median SNAP amplitudes increased, stopped (Fig. 2E).
declining, or became recordable after being ab-
sent in 5 participants (Fig. 1A) but remained Immunologic Response
absent in 8 participants; a detectable median Clinically asymptomatic, lymphocyte-predominant
SNAP amplitude that was observed in 1 partici- CSF pleocytosis was identified in 13 participants
pant in the natural history study was subsequent- on routine scheduled CSF examinations by 3 to
ly undetectable at baseline and after gene trans- 6 months after dose administration (Fig. S1).
fer. Between 6 and 24 months after gene transfer, These increases were self-limited and abated by
ulnar SNAP amplitudes increased, stopped de- 1 year after dose administration (Fig. S13C).
clining, or became recordable after being absent Serum and CSF neutralizing antibody titers to
in 6 participants (Fig. 1B) but remained absent in AAV9 increased after scAAV9/JeT-GAN adminis-
8 participants. The sural sensory response was tration, persisted to 1 year after dose adminis-
attainable in only 2 participants at baseline but tration (Fig. S13A and S13B), and remained ele-
was not recordable during follow-up (Fig. S8). vated in serum samples through 6 years after
Motor nerve responses, as recorded in the distal dose administration (Table S4). A total of 12
upper and lower extremities, showed a decline in participants had increased T-cell interferon-γ
CMAP amplitude both before and after gene responses to AAV9 capsid peptide pools within
transfer (Figs. S9, S10, and S11). 24 months after scAAV9/JeT-GAN administra-
A total of 11 pairs of nerve-biopsy specimens, tion (Fig. S14). T-cell interferon-γ responses to
obtained from the superficial radial sensory peptide pools of gigaxonin (encoded by the
nerve, were suitable for evaluation of regenerat- transgene) after gene transfer were negative. The
ing cluster quantification. At 1 year after dose participants who received rapamycin, with or
administration, among 8 participants, the re- without additional tacrolimus, had a diminished
generating cluster density in the superficial radial
AAV9 capsid interferon-γ response as compared
sensory nerve was 3 to 48 times as high as that with the participants without T-cell immuno-
at baseline (Fig. S12). modulation (Fig. S14). The level of serum neu-
tralizing antibodies was elevated earlier and
Biodistribution, Transgene Expression, and vector clearance occurred faster among the par-
Postmortem Analysis ticipants who were seropositive for AAV9 neu-
In the postmortem specimens obtained from tralizing antibodies at baseline than among the
one participant who received the lowest dose and seronegative participants (Fig. S15).
died from disease progression, nervous system
biodistribution was limited, with the greatest Discussion
distribution closest to the injection site (range,
0.05 to 0.45 copies of human codon-optimized In a phase 1 study involving children with giant
GAN [hGANopt] per host diploid genome in the axonal neuropathy, intrathecal administration of
spinal cord and <0.01 hGANopt per host diploid an AAV vector with a gigaxonin-encoding trans-
genome in most brain regions) (Fig. 2A). Trans- gene up to a single maximum dose of 3.5×1014
gene messenger RNA (mRNA) expression was vg was associated with adverse events but showed
detectable but often near the lower limit of de- a possible clinical benefit in motor function at
tection of the assay (Table S6). This finding was 1 year after gene transfer, as indicated by a change
consistent with that in a preclinical study of in the slope for a motor function measure (a

n engl j med 390;12 nejm.org March 21/28, 2024 1099

The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Clinical Efficacy End Points at 1 Year after Gene Transfer.*

End Point scAAV9/JeT-GAN Dose Group

3.5×1013 vg 1.2×1014 vg 1.8×1014 vg 3.5×1014 vg

(N = 2) (N = 4) (N = 5) (N = 3)
MFM-32 total percent score
Mean change in slope from baseline to 1 yr after −0.54 3.23 5.32 3.43
dose administration (95% credible interval) (−7.48 to 6.28) (−1.27 to 7.65) (1.07 to 9.57) (−1.89 to 8.82)
— percentage points per year
Posterior probability of any slowing of the slope, 44 (43 to 44) 93 (92 to 93) 99 (99 to 99)† 90 (89 to 90)
as compared with the pretreatment slope
(95% credible interval) — %
mFARS score
Mean change in slope from baseline to 1 yr after −8.69 −8.89 −3.50 −12.74
dose administration (95% credible interval) (−20.05 to 2.76) (−16.10 to −1.77) (−10.55 to 3.50) (−21.66 to −3.72)
— points per year
Posterior probability of any slowing of the slope, 93 (93 to 94) 99 (99 to 99)† 84 (83 to 85) 100 (100 to 100)†
as compared with the pretreatment slope
(95% credible interval) — %
Neuropathy Impairment Score
Mean change in slope from baseline to 1 yr after −2.02 −13.73 −4.46 10.59
dose administration (95% credible interval) (−20.04 to 16.20) (−24.46 to 3.11) (−15.59 to 6.51) (−3.04 to 24.28)
— points per year
Posterior probability of any slowing of the slope, 59 (58 to 60) 99 (99 to 100)† 79 (78 to 80) 6 (6 to 7)
as compared with the pretreatment slope
(95% credible interval) — %

* Bayesian efficacy analyses, stratified according to dose group, were conducted 1 year after dose administration. The term slope refers to the
rate of change in the curve of a motor function measure. The pretreatment slope represents the rate of change in the natural history of the
disease, which was determined in the entire cohort during the observational study (ClinicalTrials.gov number, NCT01568658). The mean
pretreatment slopes across the dose groups were −7.17 percentage points per year (95% credible interval, −8.36 to −5.97) for the MFM-32,
6.09 points per year (95% credible interval, 3.23 to 8.93) for the mFARS, and 1.85 points per year (95% credible interval, 2.49 to 6.25) for
the Neuropathy Impairment Score. The prespecified threshold for a positive result was a posterior probability of at least 95%. The widths of
credible intervals for the change in slope from baseline to 1 year after dose administration, as compared with the pretreatment slope, were
not adjusted for multiple comparisons, and no definite conclusions can be drawn from the results.
† This finding met the prespecified threshold for efficacy, with a posterior probability of at least 95%.

secondary end point). In a prespecified Bayesian
analysis with a probability threshold for an ef-
fect of at least 95%, the criterion was met in one
of four dose groups; however, these results were
not adjusted for multiplicity. The results for
other measures of clinical performance were
varied in a comparison with baseline scores.
Disease manifestations (e.g., visual impairment)
are not captured by the motor function measure.
To our knowledge, the Neuropathy Impairment
Score, a secondary end point in the study, has
not been formally validated in children, which
may be a contributory factor to the varied re-
sponses observed.18
The dose (total vector genomes) of scAAV9/
JeT-GAN that was administered intrathecally in
this study resulted in lower exposure than in
some other studies of systemic neuromuscular
gene therapy in which weight-based doses were
administered.19,20 Despite receiving a lower total
dose through intrathecal administration, all the
participants had persistently elevated serum and
CSF AAV9 neutralizing antibody levels after dose
administration. This finding suggests that im-
munosuppression did not prevent an adaptive
humoral anticapsid response; therefore, in pa-
tients who have undergone gene transfer, sys-
temic and probably intrathecal readministration
is most likely precluded in current or future
studies.
The CSF pleocytosis observed in these partici-
pants may have been responsive to glucocorti-
coids, but the condition did not appear to alter
anti-AAV9 capsid humoral or T-cell–mediated im-
mune responses. There were no clear antitrans-
gene T-cell immune responses in the participants

1100 n engl j med 390;12 nejm.org March 21/28, 2024

The New England Journal of Medicine

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy

Figure 1. Electrophysiological Changes after Gene 1.2×1014 vg 1.8×1014 vg 3.5×1014 vg

Transfer.
Panel A shows the antidromic median sensory-nerve A Median SNAP Amplitude from Digit II in 6 Participants
action potential (SNAP) amplitude from digit II in six par- 20
ticipants before and after gene transfer (marked as time
0 on the x axis). Emergence of a previously absent SNAP
amplitude response was observed in two participants (at
12 months and 18 months after gene transfer), and an
increase in a low but detectable median SNAP amplitude 15
was observed in two participants. Stable ongoing detec-

Median SNAP Amplitude (µV)

tion of a median SNAP amplitude to at least 6 years after
gene transfer was observed in one participant. One par-
ticipant had a detectable median SNAP amplitude in the
natural history study that was subsequently undetectable
10
at baseline and after gene transfer. The remaining eight
participants in the study had a persistently absent median
SNAP amplitude. The abbreviation vg denotes total vec-
tor genomes. Panel B shows the antidromic ulnar SNAP
amplitude from digit V in 6 participants. Emergence
of a previously absent SNAP amplitude response or an 5
increase in the ulnar SNAP amplitude by 6 to 24 months
after gene transfer was observed in five participants.
One participant had a persistent and stable ulnar SNAP
amplitude to 6 years after gene transfer. The remaining
eight participants had a persistently absent ulnar SNAP 0
amplitude. Additional motor responses in the upper and −4 −2 0 2 4 6
lower extremities and sensory responses in the lower Years before and after Gene Transfer
extremity are shown in Figures S8 through S11 in the
Supplementary Appendix. A median SNAP amplitude B Ulnar SNAP Amplitude from Digit V in 6 Participants
(Panel A) and an ulnar SNAP amplitude (Panel B) of 50
greater than 15 μV were derived at the electromyography
laboratory of the National Institutes of Health as the
normal value on the basis of data from adults; normal
values in children older than 5 years of age have been
found to be generally similar to those in adults.17 40
Ulnar SNAP Amplitude (µV)

predicted to be negative for CRIM (transgene- 30

naive) who received concomitant tacrolimus and
rapamycin, even though these participants were
at higher risk for such a response.21 These partici-
pants also had a lower interferon-γ T-cell immune 20

response to capsid than those who did not receive

T-cell immunomodulation. The participants who
received the highest dose of scAAV9/JeT-GAN
10
(3.5×1014 vg) and at least transient rapamycin
therapy had a higher AAV9 copy number in the
blood, as well as a longer period with a higher
copy number, than those in the lower-dose groups, 0
−4 −2 0 2 4 6
potentially leading to a longer systemic persis-
tence of the virus. Years before and after Gene Transfer

The scAAV9/JeT-GAN vector DNA and GAN

transgene expression were broadly distributed
throughout the nervous system in a postmortem
evaluation of a single seropositive participant who
received the lowest dose. Gene transfer levels
were consistent with expectations at this dose,
and low transgene mRNA expression was like-
wise consistent with the intentional use of the
weak JeT promoter.13 As expected, because of the
proximity of the spinal cord to the intrathecal
site of administration of the agent, distribution

n engl j med 390;12 nejm.org March 21/28, 2024 1101

The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Biodistribution in Nervous System B Biodistribution in Peripheral Tissue

Cerebral Cortex Mid Phrenic

Optic Nerve Right Radial Nerve
Thalamus
Intercostal 1
Basal Ganglia
Cerebellum Intercostal 2

Lateral Mid Brain Anterior

Diaphragm
C6 SC
Skeletal Muscle
C6 DRG
Iliopsoas
C6 DR
C7 SC Heart

C8 DRG Lung
Cervical Nerve
Pancreas
Thoracic SC
Liver
T1 DRG
Sympathetic Chain Spleen
L1 DRG Small Intestine
L4 DRG
Large Intestine
L4 DR Mid
Kidney
L4 VR Mid
L4 VR Prox Bladder
L5 SC Ovary
Sacral SC Upper
Thyroid
Sacral SC Mid or Lower
Sacral VR Uterus

Sacral DR Skin

0 0.1 0.2 0.3 0.4 0.5 10−4 10−3 10−2 10−1 100 101
Copies of hGANopt Copies of hGANopt
per Human Genome per Human Genome

C DRG Sample from a Participant D DRG Sample from a Control E Cervical Spinal Cord Sample from a
Participant

* *
*

* * N
* *
* N
*
* *

1102 n engl j med 390;12 nejm.org March 21/28, 2024

The New England Journal of Medicine

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy
Figure 2 (facing page). Postmortem Nerve Pathology
and Biodistribution 8 Months after Intrathecal Gene
Transfer.
Panels A and B show scAAV9/JeT-GAN biodistribution
in postmortem nervous-system and peripheral-tissue
specimens, respectively, in a participant with giant axo-
nal neuropathy 8 months after receiving the lowest intra-
thecal dose of scAAV9-JeT-GAN (3.5×1013 vg). This par-
ticipant had undergone spinal fusion surgery and died
in the postoperative period after an episode of emesis-
induced aspiration followed by anoxemia, which resulted
in cardiac arrest and multiorgan failure. Quantitative
polymerase-chain-reaction analysis of human codon-
optimized gigaxonin (hGANopt) was used to assess vector
DNA biodistribution. C denotes cervical, DR dorsal root,
DRG dorsal-root ganglia, L lumbar, Mid anatomical mid-
dle section along length of given tissue, Prox proximal,
SC spinal cord, T thoracic, and VR ventral root. Panels C
and D show photomicrographs of DRG samples (1-μm
sections stained with toluidine blue; original magnifica-
tion, 40×) from a participant with giant axonal neuropa-
thy and an age-matched control without the disorder,
respectively. Postmortem fixation artifact (evidenced by
satellite-cell vacuolation [asterisks]) was present in both
samples, but there was no evidence of neuronal loss or
inflammation. N denotes neuron (one of several). Panel E
shows a photomicrograph of postmortem cervical spinal
cord sample (resin-embedded tissue section stained
with hematoxylin and eosin; original magnification, 40×)
from a study participant with typical giant axonal neuropa-
thy. Numerous giant axons (arrows) were present in the
fasciculus gracilis. There was no evidence of inflamma-
tory infiltrates.
in the spinal cord was higher than in most brain
regions, and it is possible that higher doses than
those used in the study may be necessary to treat
the brain. The presence of vector DNA in the
spinal cord was consistent with findings in pre-
clinical studies and showed target engagement.
Expected giant axonal neuropathy–related find-
ings were observed in the peripheral nervous
system and ascending sensory tracts. In these
regions, there was no histologic evidence of lym-
phocytic infiltration or neuroinf lammation to
suggest scAAV9/JeT-GAN-induced toxic effects.
There is no assay to quantify GAN protein ex-
pression owing to the difficulty in generating a
specific antibody that recognizes gigaxonin.
Loss of SNAP amplitude responses in the me-
dian and ulnar nerves occurs early in the disorder
and, in our anecdotal experience, does not re-
emerge. Thus, restoration of sensory responses in
n engl j med 390;12 nejm.org
The New England Journal of Medicine
Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
the upper extremity in 6 of 14 participants by 6
to 24 months after dose administration and per-
sistent or increased SNAP amplitudes through 6
years after dose administration was unexpected.
There was, however, no electrophysiological re-
covery in the motor nerves. Regenerating nerve
cluster density among the participants was var-
ied at baseline (7 to 473 regenerative clusters per
square millimeter of subperineurial area); how-
ever, this value had generally increased at 1 year
after dose administration, a finding that reca-
pitulates observations in intrathecally treated
Gan-knockout mice.13
In this phase 1 study of intrathecal gene
transfer with scAAV9/JeT-GAN in persons with
giant axonal neuropathy, there were some indi-
cations of therapeutic benefit in motor function
scores and electrophysiological measures. Further
studies are warranted to determine the safety and
efficacy of this approach in patients with giant
axonal neuropathy.
The content of this article is solely the responsibility of the
authors and does not necessarily represent the official views
of the National Institutes of Health or the American Society of
Gene and Cell Therapy.
Supported by the National Institute of Neurological Disorders
and Stroke (NINDS), Division of Intramural Research, National
Institutes of Health (NIH); Hannah’s Hope Fund; Taysha Gene
Therapies; and Bamboo Therapeutics–Pfizer. Dr. Gray is supported
by a grant (R01 NS087175) from NINDS; Dr. Bharucha-Goebel, by
a grant (5T32AR056993) from the National Institute of Arthritis
and Musculoskeletal and Skin Diseases, NIH, a Child Neurology
Society Philip R. Dodge Young Investigator Award, and an Ameri-
can Society of Gene and Cell Therapy Career Development Award;
Dr. Sumner, by a grant (R35NS122306) from NINDS; and Dr. Kang,
by a grant (Z-A1000989) from the National Institute of Allergy
and Infectious Diseases, Division of Intramural Research, NIH.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the study participants and their families for partici-
pating in the natural history study and clinical study; the staff at
the Hannah’s Hope Fund, the NIH Clinical Center, the NINDS
Clinical Trials Unit, the NINDS Office of Technology Trans-
fer, Taysha Gene Therapies, the Immunology Core of the Gene
Therapy Program at the University of Pennsylvania, the Johns
Hopkins Neuromuscular Pathology Laboratory, the University
of North Carolina at Chapel Hill Vector Core–Pfizer, and the
Children’s Inn at NIH; Drs. Kenneth Fischbeck (NINDS), Beverly
Davidson (University of Pennsylvania), Barry Byrne (University
of Florida), Thomas Crawford (Johns Hopkins University), and
Kevin Flanigan (Nationwide Children’s Hospital) for serving as
data and safety monitoring board members; Drs. Mary-Kay Flo-
eter and Justin Kwan for serving as independent medical moni-
tors; and Dr. Jeffrey P. Palmer (Rare Disease Research Unit,
Pfizer) for encouraging the use of a Bayesian framework in the
analysis of the study data.
March 21/28, 2024 1103
 Intr athecal Gene Ther apy for Giant Axonal Neuropathy

Appendix
The authors’ full names and academic degrees are as follows: Diana X. Bharucha‑Goebel, M.D., Joshua J. Todd, Ph.D., Dimah Saade,
M.D., Gina Norato, Sc.M., Minal Jain, D.Sc., P.T., Tanya Lehky, M.D., Rachel M. Bailey, Ph.D., Jessica A. Chichester, Ph.D., Roberto
Calcedo, Ph.D., Diane Armao, M.D., A. Reghan Foley, M.D., Payam Mohassel, M.D., Eshetu Tesfaye, Ph.D., Bradley P. Carlin, Ph.D.,
Beth Seremula, M.S., Melissa Waite, M.S.P.T., Wadih M. Zein, M.D., Laryssa A. Huryn, M.D., Thomas O. Crawford, M.D., Charlotte J.
Sumner, M.D., Ahmet Hoke, M.D., Ph.D., John D. Heiss, M.D., Lawrence Charnas, M.D., Ph.D., Jody E. Hooper, M.D., Thomas W.
Bouldin, M.D., Elizabeth M. Kang, M.D., Denis Rybin, Ph.D., Steven J. Gray, Ph.D., and Carsten G. Bönnemann, M.D.
The authors’ affiliations are as follows: the Neuromuscular and Neurogenetic Disorders of Childhood Section (D.X.B.-G., J.J.T., D.S.,
A.R.F., P.M., C.G.B), National Institute of Neurological Disorders and Stroke (G.N., T.L., J.D.H.), the Rehabilitation Medicine Depart-
ment, Clinical Center (M.J., M.W.), National Eye Institute (W.M.Z., L.A.H.), and the National Institute of Allergy and Infectious Dis-
eases, Division of Intramural Research (E.M.K.), National Institutes of Health, Bethesda, and the Departments of Neurology (C.J.S.,
A.H., T.O.C.), Neuroscience (C.J.S., A.H.), and Pediatrics (T.O.C.), Johns Hopkins University School of Medicine, Baltimore — all in
Maryland; Children’s National Hospital, Washington, DC (D.X.B.-G.); the University of Iowa, Iowa City (D.S.); the Department of Pe-
diatrics and Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (R.M.B, S.J.G.),
and Taysha Gene Therapies (E.T.) — both in Dallas; the Gene Therapy Program, University of Pennsylvania Perelman School of Medicine,
Philadelphia (J.A.C.), Cencora PharmaLex, Conshohocken (B.P.C.), and Atorus Research, Newtown Square (B.S.) — all in Pennsylvania;
Affinia Therapeutics, Waltham (R.C.), and the Rare Disease Research Unit, Pfizer, Cambridge (L.C., D.R.) — both in Massachusetts; the
Departments of Pathology and Laboratory Medicine (D.A., T.W.B.) and Radiology (D.A.), University of North Carolina at Chapel Hill
School of Medicine, Chapel Hill; and the Department of Pathology, Stanford University School of Medicine, Stanford, CA (J.E.H.).

References
1. Opal P. GAN-related neurodegenera-
tion. In: Adam MP, ed. GeneReviews.
Seattle:​University of Washington, 2021
(https://www​.­ncbi​.­nlm​.­nih​.­gov/​­books/​
­NBK1136/​­).
2. Bomont P, Cavalier L, Blondeau F, et
al. The gene encoding gigaxonin, a new
member of the cytoskeletal BTB/kelch re-
peat family, is mutated in giant axonal
neuropathy. Nat Genet 2000;​26:​370-4.
3. Cleveland DW, Yamanaka K, Bomont
P. Gigaxonin controls vimentin organiza-
tion through a tubulin chaperone-inde-
pendent pathway. Hum Mol Genet 2009;​
18:​1384-94.
4. Allen E, Ding J, Wang W, et al. Gigax-
onin-controlled degradation of MAP1B
light chain is critical to neuronal survival.
Nature 2005;​438:​224-8.
5. Bharucha-Goebel DX, Norato G, Saade
D, et al. Giant axonal neuropathy: cross-
sectional analysis of a large natural his-
tory cohort. Brain 2021;​144:​3239-50.
6. Asbury AK, Gale MK, Cox SC, Bar-
inger JR, Berg BO. Giant axonal neuropa-
thy — a unique case with segmental neu-
rofilamentous masses. Acta Neuropathol
1972;​20:​237-47.
7. Bérard C, Payan C, Hodgkinson I,
Fermanian J, MFM Collaborative Study
Group. A motor function measure for neu-
romuscular diseases: construction and
validation study. Neuromuscul Disord
2005;​15:​463-70.
8. Trundell D, Le Scouiller S, Gorni K,
Seabrook T, Vuillerot C. Validity and reli-
ability of the 32-Item Motor Function
Measure in 2- to 5-year-olds with neuro-
muscular disorders and 2- to 25-year-olds
with spinal muscular atrophy. Neurol Ther
2020;​9:​575-84.
9. Johnson-Kerner BL, Roth L, Greene
JP, Wichterle H, Sproule DM. Giant axonal
neuropathy: an updated perspective on its
pathology and pathogenesis. Muscle Nerve
2014;​50:​467-76.
10. Federici T, Taub JS, Baum GR, et al.
Robust spinal motor neuron transduction
following intrathecal delivery of AAV9 in
pigs. Gene Ther 2012;​19:​852-9.
11. Gray SJ, Nagabhushan Kalburgi S,
McCown TJ, Jude Samulski R. Global CNS
gene delivery and evasion of anti-AAV-
neutralizing antibodies by intrathecal
AAV administration in non-human pri-
mates. Gene Ther 2013;​20:​450-9.
12. Snyder BR, Gray SJ, Quach ET, et al.
Comparison of adeno-associated viral
vector serotypes for spinal cord and mo-
tor neuron gene delivery. Hum Gene Ther
2011;​22:​1129-35.
13. Bailey RM, Armao D, Nagabhushan
Kalburgi S, Gray SJ. Development of intra-
thecal AAV9 gene therapy for giant axonal
neuropathy. Mol Ther Methods Clin Dev
2018;​9:​160-71.
14. Gray SJ, Matagne V, Bachaboina L, Ya-
dav S, Ojeda SR, Samulski RJ. Preclinical
differences of intravascular AAV9 delivery
to neurons and glia: a comparative study
of adult mice and nonhuman primates.
Mol Ther 2011;​19:​1058-69.
15. Mussche S, Devreese B, Nagabhushan
Kalburgi S, et al. Restoration of cytoskel-
eton homeostasis after gigaxonin gene
transfer for giant axonal neuropathy. Hum
Gene Ther 2013;​24:​209-19.
16. Wu R, Lv H, Wang H, Wang Z, Yuan Y.
The pathological features of common he-
reditary mitochondrial dynamics neurop-
athy. Front Neurosci 2021;​15:​705277.
17. Kang PB. Normal values tables. In:
McMillan HJ, Kang PB, eds. Pediatric
electromyography: concepts and clinical
applications, 1st ed. Cham, Switzerland:​
Springer, 2017:​373-374.
18. Haberlová J, Seeman P. Utility of
Charcot-Marie-Tooth Neuropathy Score in
children with type 1A disease. Pediatr
Neurol 2010;​43:​407-10.
19. Chand DH, Zaidman C, Arya K, et al.
Thrombotic microangiopathy following
onasemnogene abeparvovec for spinal
muscular atrophy: a case series. J Pediatr
2021;​231:​265-8.
20. Chand D, Mohr F, McMillan H, et al.
Hepatotoxicity following administration
of onasemnogene abeparvovec (AVXS-101)
for the treatment of spinal muscular atro-
phy. J Hepatol 2021;​74:​560-6.
21. Bönnemann CG, Belluscio BA, Braun
S, Morris C, Singh T, Muntoni F. Dystro-
phin immunity after gene therapy for
Duchenne’s muscular dystrophy. N Engl J
Med 2023;​388:​2294-6.
Copyright © 2024 Massachusetts Medical Society.

1104 n engl j med 390;12 nejm.org March 21/28, 2024

The New England Journal of Medicine

Downloaded from nejm.org by CARLOS E. HERNANDEZ BORROTO on March 29, 2024. For personal use only.
No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.