Abstract
Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular
dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by
loss-of-function mutations. SMA is an autosomal recessive disorder
affecting motor neurons that is typically caused by homozygous
whole-gene deletions of SMN1 . DMD is an X-linked recessive muscle
disease most often due to exon deletions, but also duplications and
smaller sized variants within the DMD gene. Gene replacement
therapy offers the opportunity to correct the underlying genetic defect
by the introduction of a functional gene. We review the transformative
work from clinical trials to United States Food and Drug Administration
approval of onasemnogene abeparvovec-xioi in SMA and its application in
clinical practice and the early results of microdystrophin delivery in
DMD. We also review the introduction of antisense oligonucleotides to
alter pre-mRNA splicing to promote exon inclusion (as in nusinersen in
SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular
therapeutics. There are multiple promising novel genetically mediated
therapies on the horizon, which in aggregate point towards a hopeful
future for individuals with SMA and DMD.
Manuscript
Introduction
Gene therapy provides a new avenue to treat life-limiting neuromuscular
disorders. For single-gene conditions resulting from absent or reduced
gene expression, as in spinal muscular atrophy (SMA) and Duchenne
muscular dystrophy (DMD), the goal of gene replacement therapy is to
deliver an intact copy of the disrupted gene, known as a transgene, to
cells so they can express a functional protein to alleviate disease.
This has been performed ex vivo for hematological and
immunological disorders by removing hematopoietic stem and progenitor
cells from affected individuals and introducing a transgene into the
extracted cells typically using a viral vector in a tissue
culture.1 The goal is to integrate the transgene into
the host genome so that when the treated cells are reintroduced into the
patient, they transfer the transgene onto their daughter cells after
engraftment. In contrast, gene therapy for neuromuscular conditions
requires transduction of long-lived, non-replicating nerve and slower
replicating muscle cells, and so in vivo gene therapy strategies
are preferred. Here, a transgene is packaged within a viral vector and
delivered directly into an affected individual, where the viral
machinery allows the transgene to enter cells and replicate without need
to integrate into the host genome.1
There are several considerations for in vivo gene replacement
therapy in neuromuscular disease. One advantage of this method is the
lack of integration of the transgene, which has been shown in some cases
to result in unwanted mutations and an increased risk of
cancer.2 A major advance has been the development of
adeno-associated virus (AAV) vectors, which are not known to be
associated with human disease and only weakly activate the innate immune
system.3,4 There are many AAV serotypes that differ in
terms of tissue tropism and prevalence of pre-existing antibodies in the
general population, leading AAV9 to be a common vector in neuromuscular
gene therapy due to its ability to efficiently transduce the nervous
system and muscle, and lower prevalence of high titers of pre-existing
neutralizing AAV9 antibodies in the community.5,6 A
limitation to the use of an AAV vector though is its small carrying
capacity of 5 kilobases, which is much smaller than the DMDgene.7
Another step towards progress in neuromuscular therapeutics was the
introduction of antisense oligonucleotides (ASO). Distinct from gene
therapy, there is no introduction of foreign genetic material to
generate novel transgene expression, but instead this is an RNA-based
therapeutic strategy to alter expression of existing genes. ASOs are
short sequences of modified synthetic nucleotides that bind to specific
sites within pre-mRNA to alter splicing based on their design, and
thereby change exon number in the mature transcript to produce a more
functional protein. They may also be engineered to promote degradation
of the transcript in diseases that result from toxic gain-of-function
mutations, as in Huntington disease, but are not applicable in disease
with loss of protein function like SMA and DMD.8
In this review, we highlight the tremendous progress in genetically
mediated therapies for SMA and DMD, with a focus on ASOs and gene
replacement therapy. We explore some exciting novel therapeutics using
alternative strategies as well in order to show the bright future ahead
for neuromuscular medicine.
- Gene Therapy in Spinal Muscular Atrophy
- Understanding Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) results from degeneration of the anterior
horn cells of the spinal cord and motor nuclei in the lower brainstem,
and is associated with progressive, symmetric, proximal more than distal
muscle weakness and atrophy. The most common form is due to biallelic
loss-of-function variants in SMN1 (survival motor neuron 1 gene).
Occurring in about 8 in 100,000 live births, it has been the leading
inherited cause of infant death.9 SMN1 is
located on the long arm of chromosome 5, specifically the 5q13.2 region,
and thus SMN1- related SMA may also be referred to as 5q SMA.
About 94% of individuals with SMN1- related SMA carry homozygous
deletions of exon 7, though alleles with smaller deletions, nonsense
variants, frameshift variants, splice site mutations, and missense
variants have all been described.10 There is a group
of disorders known as non-5q spinal muscular atrophies that may mimic
the clinical appearance to SMN1- related disease, but are due to
many other genetic etiologies and often on close evaluation have
distinguishing features from typical SMA.11 Hereafter,
the use of SMA will exclusively refer to 5q spinal muscular atrophy.
Individual phenotypes of SMA are largely driven by copy number of a
modifying gene, SMN2 . This gene is nearly identical toSMN1 , with a unique C to T transition in exon 7 that results in
exclusion of exon 7 during post-transcriptional processing, leading to
the production of mostly nonfunctional SMN protein. However, 10-15% of
mRNAs from SMN2 retain exon 7 and produce some full-length SMN
protein.12,13 The phenotypic severity is inversely
related to the number of copies of SMN2 present, where
infantile-onset SMA is typically associated with 2 copies ofSMN2 , while adult-onset SMA is typically associated with 4 or
more copies of SMN2. 10,14,15
Prior to the onset of disease-modifying therapies, SMA was categorized
into types based upon age and severity of presentation. Children with
Type 0 SMA typically have 1 copy of SMN2 and have neonatal onset
of symptoms, historically dying well within the first 6 months of life
from respiratory complications. Type 1 SMA is the most common of the
subtypes and has been classified as disease onset after birth but prior
to 6 months of age, with inability to sit
unassisted.16 Children with Type 1 SMA have 2-3 copies
of SMN2 and have a life expectancy of about 2 years of age due to
respiratory failure prior to directed treatments.17,18Type 2 SMA is a more attenuated form, with symptom onset in later
infancy or toddlerhood, being able to sit but not able to walk. They
often have 3 copies of SMN2, and eventually lose the ability to sit
unsupported, but two-thirds live through their
mid-twenties.19 Type 3 refers to individuals who
achieve the ability to walk but then lose that skill, with 3-4 copies ofSMN2 , and associated with a normal lifespan. For Type 4 SMA, with
4 or more copies of SMN2 , symptoms begin after 30 years of age,
and individuals typically continue to ambulate and have a normal life
expectancy.19
Landscape of non-gene replacement therapy treatment options for Spinal
Muscular Atrophy
Prior to 2016, there were no approved disease-modifying therapies in the
United States for SMA. Historically, the mainstay of care focused on
management of complications of the disease and improving quality of
life. Supporting respiratory function, nutritional and gastrointestinal
status, bone health, mobility, neurodevelopment, and psychosocial
wellness were and remain cornerstones of comprehensive spinal muscular
atrophy care.20,21
The first medication approved by the U.S. Food and Drug Administration
(FDA) for the treatment of SMA was nusinersen, a 2-methoxyethyl modified
ASO designed to target the intronic splicing silencer N1 to suppress the
routine splicing out of exon 7 from SMN2 pre-mRNA (Table 1). By
displacing the hnRNP proteins at the site, nusinersen increases the
synthesis of transcripts containing exon 7 and ultimately full-length
SMN protein.22 In a multicenter phase 3 randomized,
double-blind, sham-controlled trial of nusinersen in infants with Type 1
SMA treated at a mean age of 7.9 weeks, the trial terminated early due
to a high percentage (41%) of treated infants showing improvement in
motor milestones on Section 2 of the Hammersmith Infant Neurological
Examination, compared to 0% in the control group. In the final
analysis, 51% of treated infants showed a motor milestone response and
an overall increased likelihood of survival over 13
months.23 This work was followed by a phase 3 trial of
Type 2 SMA children aged 2-9 years. After 15 months of treatment, there
was an increase in ~4 points on the Hammersmith
Functional Motor Scale-Expanded compared to a decrease in
~1 point in the control group, resulting in early
termination. Though, there was no significant difference between groups
in the proportion of children who were able to stand alone or walk with
assistance.24
For adults with Type 3 SMA treated between 18 and 59 years of age with
nusinersen, they were able to walk further by a modest amount over 10
months of treatment when compared to baseline on the 6-minute walk test
(mean 369.5 meters v. 377.75 at final visit).25Nusinersen was approved by the FDA for all types of SMA and is
administered intrathecally as the ASO cannot cross the blood-brain
barrier. It is a life-long treatment, requiring three lumbar punctures
per year in the maintenance phase after completion of four loading
doses. Monitoring for thrombocytopenia, coagulation abnormalities and
renal toxicity is recommended at baseline and prior to each dose. It is
overall a safe and well tolerated treatment, though sedation may be
necessary in young children or those with procedural anxiety, and
advanced surgical planning may be needed in those considering spinal
fusion for scoliosis.26
An emerging alternative to nusinersen is the orally bioavailable small
molecule, risdiplam. It is in a different class of therapeutics to ASOs
as risdiplam may be given enterally in liquid form daily instead of
requiring intrathecal administration.27 Risdiplam is a
centrally and peripherally distributed splicing modifier that binds to
exon 7 of SMN2 pre-mRNA, displacing hnRNP proteins and promoting
inclusion of exon 7 for production of full-length SMN
protein.27,28 Risdiplam has shown to be safe in
healthy volunteers despite concerns of off-target effects based on a
related splicing modifier RG7800 demonstrating retinal toxicity in
cynomolgus monkeys.29 Based on interim analyses of
FIREFISH (NCT02913482), 93% of SMA Type 1 infants aged 1-7 months had
at least a 4 point improvement in motor functioning from baseline on the
total score of the Children’s Hospital of Philadelphia Infant Test of
Neuromuscular Disorders (CHOP-INTEND) after 16 months of
treatment.30 In addition, improvement in motor
functioning has been suggested for treated individuals with Type 2 and
Type 3 SMA ranging in age from 2 to 25 years old in a multicenter,
double-blind, placebo-controlled study (SUNFISH,
NCT02908685).31 As of June 2020, risdiplam remains
under priority review with the FDA.
Gene Replacement Therapy for children with Spinal Muscular Atrophy
In May 2019, onasemnogene abeparvovec-xioi became the first in
vivo systemically delivered gene therapy approved by the FDA (Table 1).
The treatment involves a one-time intravenous (IV) administration ofSMN complementary DNA, from which full-length SMN protein may be
produced. The transgene is under the control of a cytomegalovirus
enhancer/chicken-beta-actin hybrid promoter within a self-complementary
adeno-associated viral serotype 9 (scAAV9) to drive high levels of gene
expression.32 This serotype of AAV is ideal due to its
ability to cross the blood-brain barrier and its robust transduction of
brain and spinal cord neurons, including alpha motor neurons known to
underlie the pathogenesis of SMA.33 The engineering of
a self-complementary template allows the coding region of the
recombinant virus to form an intramolecular double-stranded DNA,
allowing for efficient replication and transcription rather than waiting
for host cell-mediated synthesis of the second
strand.34 One-time administration is possible based
upon the longevity and non-replicating nature of motor neurons.
In an SMA mouse model with a typical lifespan of 13 days, gene
replacement using 5x10e11 genomes demonstrated excellent motor outcomes
and survival was extended from a median age of 15.5 days in a group
treated with scAAV9 without SMN to more than 250 days in the treated
cohort with scAAV9-SMN when administered intravascularly on postnatal
day 1.32,35 There was partial improvement in survival
when mice were treated at postnatal day 5, and little effect at
postnatal day 10, which may be related to physiologic postnatal
astrocyte genesis and associated trapping of AAV9 in
mice.36
In the landmark phase 1/2a, open-label, dose escalation trial of
onasemnogene abeparvovec of 15 Type 1 SMA children with two copies ofSMN2 treated between 0.9 and 7.9 months of age, there was marked
improvement in motor milestones and all had event-free survival
(ventilatory support < 16 hours per day) compared to 8% of
natural history controls at 20 months of age. Of the 12 individuals in
the high-dose cohort (2x10e14 vector genomes/kilogram of body weight),
11 were able to sit unassisted for at least 5 seconds, 9 for at least 30
seconds, 9 could roll over, and 2 were able to crawl and walk
independently.37
After the first patient was noted to have significantly elevated serum
aminotransferase levels, alanine aminotransferase (ALT) 31X ULN and
aspartate aminotransferase (AST) 14X ULN but without clinical
manifestations, subsequent patients were immunosuppressed with
prednisolone 1 mg/kg for 30 days starting 1 day prior to gene transfer.
Prednisolone attenuated this response, with only three individuals in
the high-dose cohort showing elevations in AST and ALT. Two had
elevations of less than 10X ULN, and one individual had elevations that
required additional prednisolone as a result of ALT at 35X ULN and AST
at 37X ULN.37 All aminotransferase elevations were
transient and asymptomatic.
Follow-up for an additional two years post-gene transfer revealed two
additional patients achieved independent sitting for at least 30 seconds
and two others achieved standing with support.38 In
addition, the majority (11/12) of children tolerated at least partial
oral feeding safely and spoke by the end of long-term follow-up. Dosing
earlier than three months of age may be associated with greater
improvement in motor outcomes, and to this point, the oldest patient in
the trial at 7.9 months (also with low baseline motor functioning)
demonstrated only modest improvement in functioning.38
Phase 3 trials are underway in the United States, Europe, and East Asia,
as well as trials exploring pre-symptomatic treatment and intrathecal
onasemnogene abeparvovec-xioi administration for individuals with moreSMN2 copies (NCT03505099, NCT03306277, NCT03461289, NCT03837184,
NCT03381729), with encouraging interim results.39 As
of June 2020, the open-label phase 1/2a trial of intrathecal
onasemnogene abeparvovec remains on a partial hold by the FDA after
review of non-human primate data demonstrating inflammation of the
dorsal root ganglia, which has not been seen in any humans who had
already received intrathecal gene transfer.40
The clinical practice of gene therapy for Spinal Muscular Atrophy
Newborn screening for SMA has revolutionized care, allowing early
identification of SMA and thus maximizing response to gene
transfer.41–43 While SMA was included in the
recommended U.S. universal screening program for newborn screening in
2018, implementation is slow and is currently active in only a minority
of states.44 While initial clinical trials of gene
replacement therapy targeting young infants with SMA with 2 copies ofSMN2 , FDA approval for onasemnogene abeparvovec-xioi was granted
for all children with SMA less than 2 years of age without end-stage
disease.5
Once an eligible individual is identified via newborn screen or in
clinic, confirmatory SMA genetic testing with SMN2 copy number
should be completed (Figure 1). Once the genetic diagnosis is confirmed,
a safety evaluation with AAV9 titers and baseline “SMA gene transfer
laboratories” (ALT, AST, bilirubin, prothrombin time, platelet counts,
as well as consideration of human immunodeficiency virus (HIV),
hepatitis B and C serologies) are essential prior to onasemnogene
abeparvovec administration.45 Elevated AAV9 titers may
increase risk of immunogenicity and limit efficacy of treatment, and so
individuals with anti-AAV9 antibody titers greater than 1:50 have been
excluded from intervention.45 The prescribing
information also recommends monitoring troponin I levels at baseline and
after treatment to monitor for cardiac effects, although no clinical
cardiac toxicity has been noted.37
Onasemnogene abeparvovec is given via IV infusion over 60 minutes at a
dose of 1.1 x 10e14 vg/kg.37,45 Prednisolone 1
mg/kg/day begins one day prior to gene transfer, and is recommended for
at least 30 days prior to weaning, with adjustment in dosing depending
on ongoing monitoring; in some instances, the prednisolone dose may need
to be increased to further suppress the AAV9 immune
response.37 Weekly laboratory monitoring should
continue until AST and ALT are normalizing (<2X ULN) and then
may be spaced out. The most common side effects include vomiting and
elevated aminotransferases. Onasemnogene abeparvovec-xioi carries a
black box warning of acute liver injury after an individual with Type 1
SMA with premorbid elevated aminotransferases developed acute liver
injury with jaundice, AST 80X ULN and ALT 45X ULN, and massive
inflammation of liver biopsy 7 weeks after treatment administration
under the managed access program.45 The child returned
to baseline status after use of corticosteroids and had already
completed the recommended 30 days of 1 mg/kg of prednisolone and a
2-week taper. There is also description of transient decreases in
platelet counts and elevations in cardiac troponin-I levels of unclear
clinical significance.45 Overall, onasemnogene
abeparvovec is a safe and highly effective treatment when care is given
to treat children with no underlying liver dysfunction, and prednisolone
is adjusted based upon close monitoring throughout the immediate
post-treatment period.
Although the viral vector for onasemnogene abeparvovec-xioi does not
cause human disease, guardians and childcare providers of infants who
undergo gene transfer are counseled on use of protective gloves when
coming into direct contact with patient bodily fluids and waste, as well
as good hand hygiene for 4-6 weeks after administration to minimize
exposures as a result of viral shedding. If exposed, caregivers may
develop AAV9 immunity precluding them from future potential AAV9
therapies. Breastfeeding was restricted in the phase 1 trial before,
during, and 30 days after gene transfer out of the theoretical risk of
passive maternal transfer of anti-AAV9 antibodies, however the risks and
benefits should be weighed on an individual basis with the treating
physician.5,37,45 Vaccinations may be adjusted at the
discretion of the treating physician and may be given at least one week
prior to gene transfer. Inactivated vaccinations may be given at any
time post gene transfer, but live attenuated vaccines should not be
given until 4 weeks after completing the prednisolone
course.5,37,46,47
- Gene Therapy in Duchenne Muscular Dystrophy
- Understanding Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is on the severe end of the spectrum
of X-linked dystrophinopathies, which are life-limiting muscle diseases
associated with mutations in the dystrophin-encoding gene, DMD .
DMD is characterized by loss of ambulation prior to age 13 while the
milder form, Becker muscular dystrophy, has a wide phenotypic spectrum
with loss of ambulation after 16 years or not at all. Dystrophin is
located on the cytoplasmic side of the muscle fiber plasma membrane,
providing structural integrity to the cell when bound to the associated
transmembrane glycoprotein complex. Absence of dystrophin causes muscle
membrane instability, leading to degeneration with impaired
regeneration, fibrosis and fatty infiltration in
muscle.48
DMD is identified in about 1 in 5000 to 6000 live male
births.49,50 Although males are mostly affected as
this is an X-linked recessive disorder, symptomatic female carriers have
been described with variable age of onset and severity of
symptoms.51 Early symptoms of DMD include delayed
gross motor milestones, calf enlargement, a waddling gait, toe-walking,
and a Gower’s maneuver. Symptoms are first noticed ~2-3
years of age, though significant delays in diagnosis
occur.52 Diagnosis is confirmed with DMDdeletion and duplication analysis and sequencing, though in very rare
instances muscle mRNA analysis may be needed.53
Approximately 60-70% of dystrophinopathies result from deletions of one
or more exons within the DMD gene.54,55 Less
common mutations include intragenic duplications, single nucleotide
variants, splice site changes, and deletions and insertions of a few
nucleotides. Clinicians typically use the reading frame rule to assist
in phenotype predictions. Deletions that result in a shift in the mRNA
translational reading frame (out-of-frame deletions) lead to very
minimal or absent dystrophin production and a more severe DMD phenotype.
Deletions that preserve the translational reading frame (in-frame
deletions) lead to incomplete dystrophin production with some residual
function and are predicted to lead to a milder BMD phenotype. About 90%
of individuals with DMD due to intragenic deletions are out-of-frame,
though this is not as consistently seen in BMD with in-frame
deletions.56–58
DMD results in multisystem dysfunction as a result of the underlying
muscle disease, as well as adverse effects from long-term enteral
corticosteroids used as a part of current standard of care.
DMD-associated cardiomyopathy and conduction defects will be explored in
more detail in other articles in this special edition, as well as the
respiratory complications from progressive loss of strength of
respiratory and bulbar muscles. Gastrointestinal function is also
affected, with constipation, reflux and delayed gastric emptying that in
part may be related to altered function of dystrophin in smooth muscle
in the gastrointestinal tract. Short stature, obesity and low bone
mineral density are common and may be complicated by corticosteroid use.
Orthopedic sequelae include contractures and scoliosis.
Neurodevelopmental disorders like intellectual disability, learning
disabilities, autism spectrum disorder and attention-deficit
hyperactivity disorder, are seen at higher rates compared to the general
population. 59,60 Further, patients and their
caregivers are at increased risk of depression and anxiety.
Multidisciplinary muscular dystrophy care is vital to address the many
needs of these individuals and ensure the best possible
outcomes.61–63 Although advances like scoliosis
surgery and non-invasive ventilation have increased the median survival
of individuals with DMD to ~30 years, the importance of
disease-directed therapies remains.64
Landscape of non-gene therapy treatment options for Duchenne Muscular
Dystrophy
Glucocorticoids have been the long-standing crux of neuromuscular care
for DMD, first showing benefit in 1974.65 Their
specific mechanism of action in DMD and effects in BMD remain unknown.
Prednisone and deflazacort, a corticosteroid prodrug, improve motor
functioning, delay onset of cardiomyopathy, reduce the need for
scoliosis surgery, and may prolong survival (Table
1).66,67 Daily corticosteroid use is not without side
effects and alternative dosing regimens have been suggested, including
weekend dosing, which may be equally beneficial for motor outcomes and
have less effects on weight gain or reduction in linear
growth.68 Treatment has evolved from initiation at the
start of motor decline, to more recently around 4-5 years of age prior
to decline in motor skills, though there may be benefit to starting at
an even younger age with a weekend dosing regimen.69Medication typically continues indefinitely while monitoring for side
effects, which may prompt dose reductions. Weight gain, hirsutism and
cushingoid appearance are the most common side effects, though short
stature, delayed puberty, fractures, reflux, hypertension, cataracts,
acne, striae, and behavioral dysregulation all may occur. Physicians,
patients and families must also be aware of the possible need for
stress-dose steroids around the time of illness or scheduled surgeries
in order to prevent adrenal crises.
Despite decades of research on the genetics and spectrum of mutations of
DMD, novel treatments addressing the underlying pathophysiology have
only recently emerged. Exon skipping interventions were the first viable
precision therapies for DMD. Exon skipping relies on the use of
antisense oligonucleotides (ASO) to bind at a specific location of the
DMD pre-mRNA, altering splicing to exclude the exon in the mature
mRNA.8 When applied in DMD to deletions that disrupt
the reading frame, masking one exon may restore the reading frame and
result in some expression of shortened but functional dystrophin.
Eteplirsen is a first-generation morpholino ASO, otherwise known as a
phosphorodiamidate morpholino oligomer (PMO), that has modifications to
the ribose sugar to avoid degradation from nucleases and improve target
affinity. It promotes exon 51 exclusion and restores the reading frame
in individuals with amenable mutations (e.g., deletions of exons 48-50
or exon 52). Despite the large number of variants, ~13%
of all individuals with DMD bear exon 51 skipping-amenable mutations.
The second and third most applicable sites for single exon skipping are
at exon 45 and 53, making up 8.1% and 7.7% of all DMD mutations
respectively.70 Eteplirsen is administered by IV
infusion weekly, typically via an implanted central venous catheter.
Clinical trials of the PMO have demonstrated a small but significant
amount of dystrophin expression, attenuation of respiratory decline
based on forced vital capacity, and improved ambulation in the majority
of treated individuals when compared to historical
controls.71–75 The FDA approved eteplirsen in
September 2016 based on limited data using the surrogate marker of
dystrophin expression, no adverse events and the expectation of future
clinical benefit (Table 1).76
The second ASO to be approved by the FDA for DMD was the exon
53-skipping PMO, golodirsen (Table 1). With once weekly IV infusions
over 48 weeks, 25 individuals with DMD showed increased dystrophin
expression compared to baseline.77 The FDA noted
concerns of renal toxicity seen in animal models treated with a 10X
higher dose than what has been used in humans, as well as risk of
indwelling catheter infections in their initial rejection, requesting
renal function monitoring and demonstration of meaningful change in
functional outcomes in the larger scale phase 3 ESSENCE trial
(NCT02500381) that is currently underway.78
Ataluren is a distinct small molecule therapy administered enterally
that induces ribosomal readthrough of premature stop codons as a result
of DMD nonsense mutations, which comprise about 10% of all DMD
cases (Table 1).54,79 While the primary endpoint of
improvement in ambulation was not met in the phase 3 trial, additional
analyses and review of registry data suggest a
benefit.80–82 Ataluren has conditional authorization
in Europe by the EMA, but is not approved by the
FDA.83,84 There are a number of other small molecule
therapies, exon-skipping technologies, and steroidal therapies currently
under investigation or under FDA review that are beyond the scope of
this review.85–87
Gene transfer for children with Duchenne Muscular Dystrophy
Gene replacement therapy in DMD holds great promise among emerging
therapies by directly providing a functional copy of the DMDgene, addressing the underlying genetic defect regardless of the
underlying mutation. With the discovery of AAV vectors, efficient
transgene transduction in muscle was achieved without the challenges
seen with in vivo use of adenovirus or lentivirus
vectors.3 However, due to the large size of the
dystrophin gene and small carrying capacity of AAV vectors, researchers
have designed synthetic microdystrophins, removing many of the
spectrin-like repeats and the C-terminal domain to produce a transgene
that may fit within an AAV vector and produce a functional, internally
truncated protein akin to “in-frame” BMD-like
mutations.3 The first in-human trial of AAV-mediated
gene transfer in DMD was performed in 6 patients via intramuscular
delivery. Safety was established, but transfer resulted in no
significant levels of microdystrophin expression.88 In
addition, evidence of immunogenicity was noted with detectable T-cell
responses to the AAV vector and the microdystrophin transgene. This
informed subsequent trials by highlighting challenges with pre-existing
neutralizing antibodies against the vector, poor vector uptake due to
AAV2.5 serotype, and lack of tissue specificity of the CMV early
enhancer plus promoter, which may have boosted the immune
response.3,88,89 There are three active IV
microdystrophin trials in the United States with important differences
in AAV serotype, promoter, transgene, and inclusion criteria
(NCT03769116,, NCT03362502, NCT03368742).3
Results from an open-label phase 1/2a trial of systemic microdystrophin
in four children with DMD using an AAVrh74 vector and MHCK7 promoter
revealed high levels of microdystrophin expression 12 weeks after gene
transfer and functional improvements in motor outcome measures sustained
over a 1-year period.90 All participants showed a
reduction in creatine kinase levels at 1 year of age (though levels
fluctuated in between), and all scores improved by at least 2 points on
the North Star Ambulatory Assessment compared to baseline. The treatment
was safe, with self-limited vomiting and transient liver enzyme
elevations as the most common adverse effects. A dose of 2.0 x 10e14
vg/kg was used in boys aged 4-6 years and AAVrh74-binding antibodies
were permitted up to 1:400.37,90 All children were on
a weekend steroid regimen prior to enrollment, and so an additional 1
mg/kg daily dose of prednisone (or equivalent) was given each weekday
for 30 days and weaned over 2-4 weeks. In this small sample, there were
only modest elevations of liver enzymes, with gamma-glutamyltransferase
peaking at four times ULN. It is not clear if this milder hepatic
response than as was seen with onasemnogene abeparvovec in SMA may be
due to sample size, engineering or specifics of the vector or transgene,
or pre-existing use of steroids as standard-of-care in DMD. A
double-blind, placebo-controlled trial is underway (NCT03769116).
Surrogate gene therapy represents another mutation-independent
therapeutic avenue by delivery of genes via AAV vectors that can
substitute for dystrophin. Utrophin bears much of the structural and
functional elements of dystrophin, and its upregulation via AAV-mediated
gene transfer has been successful at restoring muscle function in animal
models.91 Similarly, B4GALNT2 (GALGT2) upregulation
via AAV-mediated delivery results in increased expression of
dystrophin-associated proteins, correction of muscle histopathology, and
improvement in cardiac function in preclinical
studies.92–94 Their clinical benefit in children with
DMD remains unknown.
Conclusions
Precision medicine for neuromuscular disorders has transformed in the
past decade with commercially available gene replacement therapy for SMA
and ASOs for both SMA and DMD. Additional small molecule and gene
therapies are currently in development for these and other neuromuscular
conditions, like risdiplam for SMA and gene replacement therapy for DMD
and X-linked myotubular myopathy.27,86,95–97 Further,
gene editing using CRISPR/Cas9 systems has been successful in large
animal models in DMD and are progressing in their development toward
human applications.98 Yet, as exciting as these
treatments are, clinicians must remain committed to continued
multidisciplinary care of the complications of the underlying
neuromuscular disease as we are learning about the long-term safety and
longevity of these therapies. Efforts to expand gene therapy for SMA for
those of older ages (NCT03381729) are ongoing, along with research on
how to safely and effectively treat those with pre-existing AAV
antibodies.99,100 It is unknown if the combination of
gene replacement with other genetically-mediated therapies will provide
added benefit. This requires further evaluation as families and health
care systems are facing the high costs of these
interventions.101,102 By fostering collaboration
between researchers, clinicians, patient advocacy groups, government,
and industry, the field will continue to move forward in this new era of
neuromuscular medicine.
References
1. High KA, Roncarolo MG. Gene therapy. New England Journal of Medicine.
2019;381(5):455–464. doi:10.1056/NEJMra1706910
2. Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M,
Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, De Ridder D, et al.
Insertional mutagenesis combined with acquired somatic mutations causes
leukemogenesis following gene therapy of SCID-X1 patients. Journal of
Clinical Investigation. 2008;118(9):3143–3150. doi:10.1172/JCI35798
3. Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne
Muscular Dystrophy. Molecular Therapy. 2018;26(10):2337–2356.
https://doi.org/10.1016/j.ymthe.2018.07.011.
doi:10.1016/j.ymthe.2018.07.011
4. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune Responses to
Viral Gene Therapy Vectors. Molecular Therapy. 2020;28(3):709–722.
https://doi.org/10.1016/j.ymthe.2020.01.001.
doi:10.1016/j.ymthe.2020.01.001
5. Al-Zaidy SA, Mendell JR. From Clinical Trials to Clinical Practice:
Practical Considerations for Gene Replacement Therapy in SMA Type 1.
Pediatric Neurology. 2019;100:3–11.
https://doi.org/10.1016/j.pediatrneurol.2019.06.007.
doi:10.1016/j.pediatrneurol.2019.06.007
6. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF,
Masurier C. Prevalence of serum IgG and neutralizing factors against
adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy
population: Implications for gene therapy using AAV vectors. Human Gene
Therapy. 2010;21(6):704–712. doi:10.1089/hum.2009.182
7. Dong JY, Fan PD, Frizzell RA. Quantitative analysis of the packaging
capacity of recombinant adeno-associated virus. Human Gene Therapy.
1996;7(17):2101–2112. doi:10.1089/hum.1996.7.17-2101
8. Scoles DR, Minikel E V, Pulst SM. Antisense oligonucleotides A
primer. Neurol Genet. 2019;5:323. doi:10.1212/NXG.0000000000000323
9. Mostacciuolo ML, Danieli GA, Trevisan C, Müller E, Angelini C.
Epidemiology of spinal muscular atrophies in a sample of the Italian
population. Neuroepidemiology. 1992 [accessed 2020 May
10];11(1):34–38. https://www.karger.com/Article/FullText/110905.
doi:10.1159/000110905
10. Wirth B. An update of the mutation spectrum of the survival motor
neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).
Human Mutation. 2000;15(3):228–237.
doi:10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
11. Darras BT. Non-5q spinal muscular atrophies: The alphanumeric soup
thickens. Neurology. 2011 [accessed 2020 May 10];77(4):312–314.
http://www.ncbi.nlm.nih.gov/sites/. doi:10.1212/WNL.0b013e3182267bd8
12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in
the SMN gene regulates splicing and is responsible for spinal muscular
atrophy. Proceedings of the National Academy of Sciences of the United
States of America. 1999;96(11):6307–6311. doi:10.1073/pnas.96.11.6307
13. Butchbach MER. Copy number variations in the survival motor neuron
genes: Implications for spinal muscular atrophy and other
neurodegenerative diseases. Frontiers in Molecular Biosciences.
2016;3(MAR):1–10. doi:10.3389/fmolb.2016.00007
14. Calucho M, Bernal S, Alías L, March F, Venceslá A, Rodríguez-Álvarez
FJ, Aller E, Fernández RM, Borrego S, Millán JM, et al. Correlation
between SMA type and SMN2 copy number revisited: An analysis of 625
unrelated Spanish patients and a compilation of 2834 reported cases.
Neuromuscular Disorders. 2018 [accessed 2020 Jun 2];28(3):208–215.
https://doi.org/10.1016/j.nmd.2018.01.003. doi:10.1016/j.nmd.2018.01.003
15. Wirth B, Brichta L, Schrank B, Lochmüller H, Blick S, Baasner A,
Heller R. Mildly affected patients with spinal muscular atrophy are
partially protected by an increased SMN2 copy number. Human Genetics.
2006;119(4):422–428. doi:10.1007/s00439-006-0156-7
16. Russman BS. Spinal muscular atrophy: Clinical classification and
disease heterogeneity. Journal of Child Neurology. 2007;22(8):946–951.
doi:10.1177/0883073807305673
17. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule
DM, Kang PB, Reghan Foley A, Yang ML, Martens WB, et al. Observational
study of spinal muscular atrophy type I and implications for clinical
trials. Neurology. 2014;83(9):810–817. doi:10.1212/WNL.0000000000000741
18. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB,
Swoboda KJ, Reyna SP, Sakonju A, Darras BT, et al. Natural history of
infantile-onset spinal muscular atrophy. Annals of Neurology.
2017;82(6):883–891. doi:10.1002/ana.25101
19. Zerres K, Schöneborn SR. Natural History in Proximal Spinal Muscular
Atrophy: Clinical Analysis of 445 Patients and Suggestions for a
Modification of Existing Classifications. Archives of Neurology.
1995;52(5):518–523. doi:10.1001/archneur.1995.00540290108025
20. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone
E, Vitale M, Snyder B, Quijano-Roy S, et al. Diagnosis and management of
spinal muscular atrophy: Part 1: Recommendations for diagnosis,
rehabilitation, orthopedic and nutritional care. Neuromuscular
Disorders. 2018;28(2):103–115. doi:10.1016/j.nmd.2017.11.005
21. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ,
Kirschner J, Iannaccone ST, Crawford TO, Woods S, et al. Diagnosis and
management of spinal muscular atrophy: Part 2: Pulmonary and acute care;
medications, supplements and immunizations; other organ systems; and
ethics. Neuromuscular Disorders. 2018;28(3):197–207.
doi:10.1016/j.nmd.2017.11.004
22. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De
Vivo DC, Norris DA, Bennett CF, Bishop KM. Results from a phase 1 study
of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy.
Neurology. 2016;86(10):890–897. doi:10.1212/WNL.0000000000002445
23. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J,
Chiriboga CA, Saito K, Servais L, Tizzano E, et al. Nusinersen versus
sham control in infantile-onset spinal muscular atrophy. New England
Journal of Medicine. 2017;377(18):1723–1732. doi:10.1056/NEJMoa1702752
24. Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM,
Iannaccone ST, Kirschner J, Kuntz NL, Saito K, et al. Nusinersen versus
sham control in later-onset spinal muscular atrophy. New England Journal
of Medicine. 2018 [accessed 2020 May 12];378(7):625–635.
http://www.nejm.org/doi/10.1056/NEJMoa1710504. doi:10.1056/NEJMoa1710504
25. Walter MC, Wenninger S, Thiele S, Stauber J, Hiebeler M, Greckl E,
Stahl K, Pechmann A, Lochmüller H, Kirschner J, et al. Safety and
treatment effects of nusinersen in longstanding adult 5q-SMA type 3 – A
prospective observational study. Journal of Neuromuscular Diseases.
2019;6(4):453–465. doi:10.3233/JND-190416
26. Labianca L, Weinstein SL. Scoliosis and spinal muscular atrophy in
the new world of medical therapy: Providing lumbar access for
intrathecal treatment in patients previously treated or undergoing
spinal instrumentation and fusion. Journal of Pediatric Orthopaedics
Part B. 2019;28(4):393–396. doi:10.1097/BPB.0000000000000632
27. Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, Denk N,
Feng Z, Green L, Guerard M, et al. Discovery of Risdiplam, a Selective
Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the
Treatment of Spinal Muscular Atrophy (SMA). Journal of Medicinal
Chemistry. 2018;61(15):6501–6517. doi:10.1021/acs.jmedchem.8b00741
28. Sivaramakrishnan M, McCarthy KD, Campagne S, Huber S, Meier S,
Augustin A, Heckel T, Meistermann H, Hug MN, Birrer P, et al. Binding to
SMN2 pre-mRNA-protein complex elicits specificity for small molecule
splicing modifiers. Nature Communications. 2017 [accessed 2020 May
12];8(1). www.nature.com/naturecommunications.
doi:10.1038/s41467-017-01559-4
29. Sturm S, Günther A, Jaber B, Jordan P, Al Kotbi N, Parkar N, Cleary
Y, Frances N, Bergauer T, Heinig K, et al. A typ 1 healthy male
volunteer single escalating dose study of the pharmacokinetics and
pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing
modifier. British Journal of Clinical Pharmacology. 2019;85(1):181–193.
doi:10.1111/bcp.13786
30. Baranello G, Servais L, Day J, Deconinck N, Mercuri E, Klein A,
Darras B, Masson R, Kletzl H, Cleary Y, et al. P.353FIREFISH Part 1:
16-month safety and exploratory outcomes of risdiplam (RG7916) treatment
in infants with type 1 spinal muscular atrophy. Neuromuscular Disorders.
2019 [accessed 2020 Jun 30];29:S184.
http://www.nmd-journal.com/article/S0960896619309034/fulltext.
doi:10.1016/j.nmd.2019.06.515
31. Mercuri E, Baranello G, Kirschner J, Servais L, Goemans N, Pera M,
Tichy M, Yeung W, Kletzl H, Gerber M, et al. O.41Sunfish part 1:
18-month safety and exploratory outcomes of risdiplam (RG7916) treatment
in patients with type 2 or 3 spinal muscular atrophy. Neuromuscular
Disorders. 2019;29:S208. doi:10.1016/j.nmd.2019.06.595
32. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT,
Morales PR, Rich MM, Burghes AHM, et al. Rescue of the spinal muscular
atrophy phenotype in a mouse model by early postnatal delivery of SMN.
Nature Biotechnology. 2010;28(3):271–274. doi:10.1038/nbt.1610
33. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK.
Intravascular AAV9 preferentially targets neonatal neurons and adult
astrocytes. Nature Biotechnology. 2009;27(1):59–65.
doi:10.1038/nbt.1515
34. McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant
adeno-associated virus (scAAV) vectors promote efficient transduction
independently of DNA synthesis. Gene therapy. 2001 [accessed 2020 May
14];8(16):1248–54. http://www.ncbi.nlm.nih.gov/pubmed/11509958.
doi:10.1038/sj.gt.3301514
35. Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, Azzouz M.
Systemic delivery of scAAV9 expressing SMN prolongs survival in a model
of spinal muscular atrophy. Science Translational Medicine. 2010
[accessed 2020 May 14];2(35). www.ScienceTranslationalMedicine.org.
doi:10.1126/scitranslmed.3000830
36. Saunders NR, Joakim Ek C, Dziegielewska KM. The neonatal blood-brain
barrier is functionally effective, and immaturity does not explain
differential targeting of AAV9. Nature Biotechnology. 2009;27(9):804.
doi:10.1038/nbt0909-804
37. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior
TW, Lowes L, Alfano L, Berry K, Church K, et al. Single-dose
gene-replacement therapy for spinal muscular atrophy. New England
Journal of Medicine. 2017;377(18):1713–1722. doi:10.1056/NEJMoa1706198
38. Al-Zaidy S, Pickard AS, Kotha K, Alfano LN, Lowes L, Paul G, Church
K, Lehman K, Sproule DM, Dabbous O, et al. Health outcomes in spinal
muscular atrophy type 1 following AVXS-101 gene replacement therapy.
Pediatric Pulmonology. 2019;54(2):179–185. doi:10.1002/ppul.24203
39. One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene Therapy
for Spinal Muscular Atrophy: Phase 1 Study (STRONG) | MDA
Clinical & Scientific Conference 2020. [accessed 2020 May 14].
https://mdaconference.org/node/941
40. Cause of Inflammation That Led to AVXS-101 Trial Hold “Unknown,”
Novartis Says. [accessed 2020 May 14].
https://smanewstoday.com/2019/11/11/cause-of-inflammation-that-led-to-avxs-101-trial-hold-unknown-novartis-says/
41. Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day
J, Finkel R, Howell RR, Klinger K, Kuntz N, et al. Treatment Algorithm
for Infants Diagnosed with Spinal Muscular Atrophy through Newborn
Screening. Journal of neuromuscular diseases. 2018;5(2):145–158.
doi:10.3233/JND-180304
42. Glascock J, Sampson J, Connolly AM, Darras BT, Day JW, Finkel R,
Howell RR, Klinger KW, Kuntz N, Prior T, et al. Revised Recommendations
for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via
Newborn Screening Who Have 4 Copies of SMN2. Journal of Neuromuscular
Diseases. 2020;7(2):97–100. doi:10.3233/JND-190468
43. Lowes LP, Alfano LN, Arnold WD, Shell R, Prior TW, McColly M, Lehman
KJ, Church K, Sproule DM, Nagendran S, et al. Impact of Age and Motor
Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving
Single-Dose Gene Replacement Therapy. Pediatric Neurology.
2019;98:39–45. https://doi.org/10.1016/j.pediatrneurol.2019.05.005.
doi:10.1016/j.pediatrneurol.2019.05.005
44. Kellar-Guenther Y, McKasson S, Hale K, Singh S, Sontag MK, Ojodu J.
Implementing Statewide Newborn Screening for New Disorders: U.S. Program
Experiences. International Journal of Neonatal Screening. 2020
[accessed 2020 May 15];6(2):35.
https://www.mdpi.com/2409-515X/6/2/35. doi:10.3390/ijns6020035
45. FDA. Highlights of Prescribing Information - Zolgensma.
www.fda.gov/medwatch.
46. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M,
Bousvaros A, Dhanireddy S, Sung L, Keyserling H, et al. 2013 IDSA
clinical practice guideline for vaccination of the immunocompromised
host. Clinical Infectious Diseases. 2014 [accessed 2020 May
16];58(3).
https://academic.oup.com/cid/article-abstract/58/3/e44/336537.
doi:10.1093/cid/cit684
47. Immunization and Other Considerations in Immunocompromised Children
| Red Book® 2018 | Red Book Online | AAP
Point-of-Care-Solutions. [accessed 2020 Jun 2].
https://redbook.solutions.aap.org/chapter.aspx?sectionId=189639978&bookId=2205&resultClick=1
48. Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin
protects the sarcolemma from stresses developed during muscle
contraction. Proceedings of the National Academy of Sciences of the
United States of America. 1993;90(8):3710–3714.
doi:10.1073/pnas.90.8.3710
49. Mendell JR, Shilling C, Leslie ND, Flanigan KM, Al-Dahhak R,
Gastier-Foster J, Kneile K, Dunn DM, Duval B, Aoyagi A, et al.
Evidence-based path to newborn screening for duchenne muscular
dystrophy. Annals of Neurology. 2012;71(3):304–313.
doi:10.1002/ana.23528
50. Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn
bloodspot screening for Duchenne Muscular Dystrophy: 21 years experience
in Wales (UK). European Journal of Human Genetics.
2013;21(10):1049–1053. doi:10.1038/ejhg.2012.301
51. Soltanzadeh P, Friez MJ, Dunn D, von Niederhausern A, Gurvich OL,
Swoboda KJ, Sampson JB, Pestronk A, Connolly AM, Florence JM, et al.
Clinical and genetic characterization of manifesting carriers of DMD
mutations. Neuromuscular Disorders. 2010;20(8):499–504.
doi:10.1016/j.nmd.2010.05.010
52. Ciafaloni E, Fox DJ, Pandya S, Westfield CP, Puzhankara S, Romitti
PA, Mathews KD, Miller TM, Matthews DJ, Miller LA, et al. Delayed
Diagnosis in Duchenne Muscular Dystrophy: Data from the Muscular
Dystrophy Surveillance, Tracking, and Research Network (MD STARnet).
Journal of Pediatrics. 2009;155(3):380–385.
doi:10.1016/j.jpeds.2009.02.007
53. Gurvich OL, Tuohy TM, Howard MT, Finkel RS, Medne L, Anderson CB,
Weiss RB, Wilton SD, Flanigan KM. DMD pseudoexon mutations: Splicing
efficiency, phenotype, and potential therapy. Annals of Neurology.
2008;63(1):81–89. doi:10.1002/ana.21290
54. Bladen CL, Salgado D, Monges S, Foncuberta ME, Kekou K, Kosma K,
Dawkins H, Lamont L, Roy AJ, Chamova T, et al. The TREAT-NMD DMD global
database: Analysis of more than 7,000 duchenne muscular dystrophy
mutations. Human Mutation. 2015;36(4):395–402. doi:10.1002/humu.22758
55. Takeshima Y, Yagi M, Okizuka Y, Awano H, Zhang Z, Yamauchi Y, Nishio
H, Matsuo M. Mutation spectrum of the dystrophin gene in 442
Duchenne/Becker muscular dystrophy cases from one Japanese referral
center. Journal of Human Genetics. 2010;55(6):379–388.
doi:10.1038/jhg.2010.49
56. Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T,
Meng G, Müller CR, Lindlöf M, Kaariainen H, et al. The molecular basis
for duchenne versus becker muscular dystrophy: Correlation of severity
with type of deletion. American Journal of Human Genetics.
1989;45(4):498–506. doi:10.1016/1
57. Flanigan KM, Dunn DM, Von Niederhausern A, Soltanzadeh P, Gappmaier
E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, et al. Mutational
spectrum of DMD mutations in dystrophinopathy patients: Application of
modern diagnostic techniques to a large cohort. Human Mutation.
2009;30(12):1657–1666. doi:10.1002/humu.21114
58. Aartsma-Rus A, Van Deutekom JCT, Fokkema IF, Van Ommen GJB, Den
Dunnen JT. Entries in the Leiden Duchenne muscular dystrophy mutation
database: An overview of mutation types and paradoxical cases that
confirm the reading-frame rule. Muscle and Nerve. 2006;34(2):135–144.
doi:10.1002/mus.20586
59. Ricotti V, Mandy WPL, Scoto M, Pane M, Deconinck N, Messina S,
Mercuri E, Skuse DH, Muntoni F. Neurodevelopmental, emotional, and
behavioural problems in Duchenne muscular dystrophy in relation to
underlying dystrophin gene mutations. Developmental Medicine and Child
Neurology. 2016;58(1):77–84. doi:10.1111/dmcn.12922
60. Thangarajh M, Hendriksen J, McDermott MP, Martens W, Hart KA, Griggs
RC. Relationships between DMD mutations and neurodevelopment in
dystrophinopathy. Neurology. 2019;93(17):E1597–E1604.
doi:10.1212/WNL.0000000000008363
61. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D,
Case LE, Clemens PR, Hadjiyannakis S, Pandya S, et al. Diagnosis and
management of Duchenne muscular dystrophy, part 1: diagnosis, and
neuromuscular, rehabilitation, endocrine, and gastrointestinal and
nutritional management. The Lancet Neurology. 2018;17(3):251–267.
http://dx.doi.org/10.1016/S1474-4422(18)30024-3.
doi:10.1016/S1474-4422(18)30024-3
62. Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A,
Case LE, Cripe L, Hadjiyannakis S, Olson AK, et al. Diagnosis and
management of Duchenne muscular dystrophy, part 2: respiratory, cardiac,
bone health, and orthopaedic management. The Lancet Neurology.
2018;17(4):347–361. http://dx.doi.org/10.1016/S1474-4422(18)30025-5.
doi:10.1016/S1474-4422(18)30025-5
63. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK,
Cripe L, Herron AR, Kennedy A, Kinnett K, et al. Diagnosis and
management of Duchenne muscular dystrophy, part 3: primary care,
emergency management, psychosocial care, and transitions of care across
the lifespan. The Lancet Neurology. 2018;17(5):445–455.
http://dx.doi.org/10.1016/S1474-4422(18)30026-7.
doi:10.1016/S1474-4422(18)30026-7
64. Eagle M, Bourke J, Bullock R, Gibson M, Mehta J, Giddings D, Straub
V, Bushby K. Managing Duchenne muscular dystrophy - The additive effect
of spinal surgery and home nocturnal ventilation in improving survival.
Neuromuscular Disorders. 2007;17(6):470–475.
doi:10.1016/j.nmd.2007.03.002
65. Drachman DB, Toyka K V., Myer E. Prednisone in Duchenne Muscular
Dystrophy. The Lancet. 1974;304(7894):1409–1412.
doi:10.1016/S0140-6736(74)90071-3
66. Gloss D, Moxley RT, Ashwal S, Oskoui M. Practice guideline update
summary: Corticosteroid treatment of Duchenne muscular dystrophy -
Report of the Guideline Development Subcommittee of the American Academy
of Neurology. Neurology. 2016;86(5):465–472.
doi:10.1212/WNL.0000000000002337
67. Matthews E, Brassington R, Kuntzer T, Jichi F, Manzur AY.
Corticosteroids for the treatment of Duchenne muscular dystrophy.
Cochrane Database of Systematic Reviews. 2016;2016(5).
doi:10.1002/14651858.CD003725.pub4
68. Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, Viswanathan
V, Kornberg AJ, Bertorini TE, Nevo Y, Lotze T, et al. Randomized,
blinded trial of weekend vs daily prednisone in Duchenne muscular
dystrophy. Neurology. 2011;77(5):444–452.
doi:10.1212/WNL.0b013e318227b164
69. Connolly AM, Zaidman CM, Golumbek PT, Cradock MM, Flanigan KM, Kuntz
NL, Finkel RS, McDonald CM, Iannaccone ST, Anand P, et al. Twice-weekly
glucocorticosteroids in infants and young boys with Duchenne muscular
dystrophy. Muscle and Nerve. 2019;59(6):650–657. doi:10.1002/mus.26441
70. Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J,
van Ommen G-J, den Dunnen JT. Theoretic applicability of
antisense-mediated exon skipping for Duchenne muscular dystrophy
mutations. Human Mutation. 2009 [accessed 2020 May
23];30(3):293–299. http://doi.wiley.com/10.1002/humu.20918.
doi:10.1002/humu.20918
71. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP,
Alfano L, Gomez AM, Lewis S, Kota J, et al. Eteplirsen for the treatment
of Duchenne muscular dystrophy. Annals of Neurology.
2013;74(5):637–647. doi:10.1002/ana.23982
72. Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L,
David Young G, Milici AJ, Voss J, Dealwis U, et al. Eteplirsen treatment
for Duchenne muscular dystrophy. Neurology. 2018;90(24):e2135–e2145.
doi:10.1212/WNL.0000000000005680
73. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony
K, Abbs S, Garralda ME, Bourke J, Wells DJ, et al. Exon skipping and
dystrophin restoration in patients with Duchenne muscular dystrophy
after systemic phosphorodiamidate morpholino oligomer treatment: An
open-label, phase 2, dose-escalation study. The Lancet.
2011;378(9791):595–605.
http://dx.doi.org/10.1016/S0140-6736(11)60756-3.
doi:10.1016/S0140-6736(11)60756-3
74. Khan N, Eliopoulos H, Han L, Kinane TB, Lowes LP, Mendell JR,
Gordish-Dressman H, Henricson EK, McDonald CM. Eteplirsen treatment
attenuates respiratory decline in ambulatory and non-ambulatory patients
with duchenne muscular dystrophy. Journal of Neuromuscular Diseases.
2019;6(2):213–225. doi:10.3233/JND-180351
75. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye
EM, Mercuri E. Longitudinal effect of eteplirsen versus historical
control on ambulation in Duchenne muscular dystrophy. Annals of
Neurology. 2016;79(2):257–271. doi:10.1002/ana.24555
76. Ledford H. US government approves controversial drug for muscular
dystrophy. Nature. 2020. doi:10.1038/nature.2016.20645
77. Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan
J, Charleston JS, Sardone V, Domingos J, Dickson G, et al. Increased
dystrophin production with golodirsen in patients with Duchenne muscular
dystrophy. Neurology. 2020 Mar 5:10.1212/WNL.0000000000009233.
doi:10.1212/wnl.0000000000009233
78. Aartsma-Rus A, Corey DR. The 10th Oligonucleotide Therapy Approved:
Golodirsen for Duchenne Muscular Dystrophy. Nucleic Acid Therapeutics.
2020;30(2):67–70. doi:10.1089/nat.2020.0845
79. Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S,
Leonard EM, Almstead NG, Ju W, Peltz SW, et al. Safety, tolerability,
and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation
suppressor, following single- and multiple-dose administration to
healthy male and female adult volunteers. Journal of Clinical
Pharmacology. 2007;47(4):430–444. doi:10.1177/0091270006297140
80. McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM,
Goemans N, Heydemann P, Kaminska A, Kirschner J, Muntoni F, et al.
Ataluren in patients with nonsense mutation Duchenne muscular dystrophy
(ACT DMD): a multicentre, randomised, double-blind, placebo-controlled,
phase 3 trial. The Lancet. 2017;390(10101):1489–1498.
doi:10.1016/S0140-6736(17)31611-2
81. Mercuri E, Muntoni F, Osorio AN, Tulinius M, Buccella F, Morgenroth
LP, Gordish-Dressman H, Jiang J, Trifillis P, Zhu J, et al. Safety and
effectiveness of ataluren: comparison of results from the STRIDE
Registry and CINRG DMD Natural History Study. Journal of Comparative
Effectiveness Research. 2020 [accessed 2020 May 23];9(5):341–360.
https://www.futuremedicine.com/doi/10.2217/cer-2019-0171.
doi:10.2217/cer-2019-0171
82. Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly
AM, Day JW, Flanigan KM, Goemans N, et al. Ataluren treatment of
patients with nonsense mutation dystrophinopathy. Muscle and Nerve. 2014
[accessed 2020 May 23];50(4):477–487.
http://doi.wiley.com/10.1002/mus.24332. doi:10.1002/mus.24332
83. EMA. Translarna: EPAR - Product Information. 2020.
https://www.ema.europa.eu/en/documents/product-information/translarna-epar-product-information_en.pdf
84. FDA. FDA Briefing Document: Peripheral and Central Nervous System
Drugs Advisory Committee Meeting (NDA 200896 Ataluren). 2017 [accessed
2020 May 23]. https://www.fda.gov/media/112565/download
85. Hoffman EP, Schwartz BD, Mengle-Gaw LJ, Smith EC, Castro D, Mah JK,
Mcdonald CM, Kuntz NL, Finkel RS, Guglieri M, et al. Vamorolone trial in
Duchenne muscular dystrophy shows dose-related improvement of muscle
function. Neurology. 2019;93(13):E1312–E1323.
doi:10.1212/WNL.0000000000008168
86. Waldrop MA, Flanigan KM. Update in Duchenne and Becker muscular
dystrophy. Current Opinion in Neurology. 2019;32(5):722–727.
doi:10.1097/WCO.0000000000000739
87. Salmaninejad A, Jafari Abarghan Y, Bozorg Qomi S, Bayat H, Yousefi
M, Azhdari S, Talebi S, Mojarrad M. Common therapeutic advances for
Duchenne muscular dystrophy (DMD). International Journal of
Neuroscience. 2020. doi:10.1080/00207454.2020.1740218
88. Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis
S, Bowles D, Gray S, Li C, Galloway G, et al. Dystrophin immunity in
Duchenne’s muscular dystrophy. New England Journal of Medicine.
2010;363(15):1429–1437. doi:10.1056/NEJMoa1000228
89. Chamberlain JR, Chamberlain JS. Progress toward Gene Therapy for
Duchenne Muscular Dystrophy. Molecular Therapy. 2017;25(5):1125–1131.
http://dx.doi.org/10.1016/j.ymthe.2017.02.019.
doi:10.1016/j.ymthe.2017.02.019
90. Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF,
Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, et al. Assessment of
Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With
Duchenne Muscular Dystrophy. JAMA Neurology. 2020 Jun 15.
https://jamanetwork.com/journals/jamaneurology/fullarticle/2767086.
doi:10.1001/jamaneurol.2020.1484
91. Song Y, Morales L, Malik AS, Mead AF, Greer CD, Mitchell MA, Petrov
MT, Su LT, Choi ME, Rosenblum ST, et al. Non-immunogenic utrophin gene
therapy for the treatment of muscular dystrophy animal models. Nature
Medicine. 2019;25(10):1505–1511.
http://dx.doi.org/10.1038/s41591-019-0594-0.
doi:10.1038/s41591-019-0594-0
92. Chicoine LG, Rodino-Klapac LR, Shao G, Xu R, Bremer WG, Camboni M,
Golden B, Montgomery CL, Shontz K, Heller KN, et al. Vascular delivery
of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque
stimulates the expression of dystrophin and laminin α2 surrogates.
Molecular Therapy. 2014;22(4):713–724. doi:10.1038/mt.2013.246
93. Xu R, Jia Y, Zygmunt DA, Martin PT. rAAVrh74.MCK.GALGT2 Protects
against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.
Molecular Therapy. 2019;27(3):636–649. doi:10.1016/j.ymthe.2019.01.005
94. Xu R, Camboni M, Martin PT. Postnatal overexpression of the CT
GalNAc transferase inhibits muscular dystrophy in mdx mice without
altering muscle growth or neuromuscular development: Evidence for a
utrophin-independent mechanism. Neuromuscular Disorders.
2007;17(3):209–220. doi:10.1016/j.nmd.2006.12.004
95. Childers MK, Joubert R, Poulard K, Moal C, Grange RW, Doering JA,
Lawlor MW, Rider BE, Jamet T, Danièle N, et al. Gene therapy prolongs
survival and restores function in murine and canine models of myotubular
myopathy. Science Translational Medicine. 2014;6(220):220ra10.
doi:10.1126/scitranslmed.3007523
96. Kaiser J. Boys with a rare muscle disease are breathing on their
own, thanks to gene therapy. Science. 2019 May 2.
doi:10.1126/science.aax9005
97. Waldrop MA, Kolb SJ. Current Treatment Options in Neurology—SMA
Therapeutics. Current Treatment Options in Neurology. 2019;21(6).
doi:10.1007/s11940-019-0568-z
98. Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A,
Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, et al.
Gene editing restores dystrophin expression in a canine model of
Duchenne muscular dystrophy. Science. 2018;362(6410):86–91.
doi:10.1126/science.aau1549
99. Chicoine LG, Montgomery CL, Bremer WG, Shontz KM, Griffin DA, Heller
KN, Lewis S, Malik V, Grose WE, Shilling CJ, et al. Plasmapheresis
eliminates the negative impact of AAV antibodies on microdystrophin gene
expression following vascular delivery. Molecular Therapy.
2014;22(2):338–347. doi:10.1038/mt.2013.244
100. Orlowski A, Katz MG, Gubara SM, Fargnoli AS, Fish KM, Weber T.
Successful Transduction with AAV Vectors after Selective Depletion of
Anti-AAV Antibodies by Immunoadsorption. Molecular Therapy - Methods and
Clinical Development. 2020;16:192–203. doi:10.1016/j.omtm.2020.01.004
101. Stevens D, Claborn MK, Gildon BL, Kessler TL, Walker C.
Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy.
Annals of Pharmacotherapy. 2020. doi:10.1177/1060028020914274
102. Malone DC, Dean R, Arjunji R, Jensen I, Cyr P, Miller B, Maru B,
Sproule DM, Feltner DE, Dabbous O. Cost-effectiveness analysis of using
onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1
patients. Journal of Market Access & Health Policy. 2019;7(1):1601484.
doi:10.1080/20016689.2019.1601484
Table 1. Approved medications for spinal muscular atrophy and Duchenne
muscular dystrophy in the United States.
Legend: * - Approved for use in Europe for children with SMA less than
21 kilograms (approximately under 5 years of age) and up to threeSMN2 copies. # - Initial approval for
deflazacort for use in children with DMD five years of age and older was
revised to include children who are two years of age and older on June
7, 2019.
Figure 1. Clinical decision-making algorithm for the use of gene
replacement therapy in spinal muscular atrophy.
Legend: § - Evaluation for SMN2 copy number
should be conducted during genetic confirmation to inform prognosis and
aid in conversations about medical decision-making even though
treatments in the United States are not currently limited by SMN2copy number. † - Approved for use in Europe for
children with SMA less than 21 kilograms (approximately under 5 years of
age) and up to three SMN2 copies. ‡ - One
option includes the splicing modifier risdiplam, given as a daily
enteral medication, which is currently available under an expanded
access program (NCT04256265).