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2 Recent Development in invivo Clinical Gene Therapy Platforms
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40
small number of people with an IRD after a onetime injection in each eye and
ongoing follow‐up assessments suggesting a long‐term benefit. Furthermore, to
address reimbursement concerns, it was reported that Spark committed to offer
rebates to health insurers if patients failed to meet specified vision thresholds
30–90days and 30months following Luxturna treatment[16, 17]. Five years on,
there have been no additional retinal gene therapies approved despite numerous
development programs since Luxturna was approved (see Table2.1). Some of the
trials have reported safety events while others have reported efficacy hurdles associated with what’s considered a high bar for approval by the FDA[20].
2.1.1.4 Zolgensma (onasemnogene abeparvovec), Marketed by Novartis
Zolgensma claims the title of the first FDA‐approved invivo gene therapy for a
genetic disease, which is administered systemically. It was also the first AAV vector administered systemically at 1.1E14 vg/kg, which was the highest dose of AAV
at that time. Zolgensma is now approved in more than 40 countries and more than
2000 patients have been treated with Zolgensma globally across clinical trials,
managed access programs, and in the commercial setting.
Zolgensma was developed to treat SMA which affects motor neurons. SMA is a
rare, genetic neuromuscular disease and a leading genetic cause of infant
death[21]. SMA is actually a group of inherited neuromuscular disorders characterized by loss of lower motor neurons in the spinal cord. The loss of lower motor
neurons leads to progressive muscle weakness, muscle wasting and low muscle
tone (hypotonia) which affects muscle functions responsible for breathing, swallowing and basic movement[22, 23].
SMA is caused by deletion or mutation of the SMN1 gene, which encodes a
protein known as SMN. This protein plays an important role in the functioning
and maintenance of motor neurons. The SMN2 gene is a paralog of SMN1 and
also encodes the SMN protein, which can compensate for the loss of the SMN1
gene. However, most SMN protein produced by the SMN2 gene is not functional,
which means that the SMN2 gene can only partially compensate for the loss of the
SMN1 gene. For this reason, an individual with SMA who has more copies of the
SMN2 gene will produce more functional SMN protein and may be better able to
compensate for the loss of the SMN1 gene, leading to less severe disease. Generally,
more copies of SMN2 are associated with milder SMA disease[23].
SMA1 onset typically occurs before 6 months of age and is characterized by
progressive weakness, including loss of respiratory and swallowing functions.
Infants with SMA1 do not achieve major development milestones and experience
progressive respiratory failure and frequent pulmonary infections[24]. Untreated
SMA, in infants with two copies of SMN2 usually results in premature death or
the need for permanent ventilation by 2 years of age. Loss of motor neurons cannot be reversed, so it is imperative to diagnose SMA and begin treatment,
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2.1 Introduction 43
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including proactive supportive care, as early as possible to halt irreversible motor
neuron loss and disease progression. This observation has led to the addition of
SMA to the Recommended Uniform Screening Panel (RUSP) for newborn screening programs[25].
Zolgensma (Onasemnogene abeparvovec) is a recombinant self‐complementary
AAV9 containing a human SMN transgene under the control of a chicken β‐actin
promoter and cytomegalovirus enhancer, which together ensure rapid and sustained transcription of SMN messenger RNA. The AAV9 capsid and promoter/
enhancer ensures body wide biodistribution, including into the brain and spinal
cord via the blood‐brain barrier. Zolgensma is marketed by Novartis Pharmaceuticals
and was designed to directly address the genetic cause of the disease by replacing
the function of the missing or non‐working SMN1 gene to halt disease progression
through sustained SMN protein expression with a single, onetime IV infusion.
Zolgensma is indicated for the treatment of pediatric patients less than 2 years of
age with all types of SMA (with bi‐allelic mutations in the SMN1 gene), Package
Insert– ZOLGENSMA (fda.gov).
The efficacy and safety of Zolgensma in patients with SMA type 1was assessed
in a 2‐year, open‐label, phase 1 study (START). Data demonstrated that a onetime
13
infusion of dose 6.7
14
vg/kg in 12 patients resulted in longer survival than observed in historical
× 10
1.1
vg/kg of body weight in 3 patients or a therapeutic dose
× 10
controls. Two of three patients in the low‐dose cohort and all patients in the
therapeutic‐dose cohort were alive without the need for permanent ventilation at
24months of age[3]. Patients in the therapeutic‐dose cohort also had significantly
improved motor function and motor milestone achievements compared with historical cohorts. Eleven of twelve patients sat unassisted for ≥5 seconds, and two
children pulled to a stand, stood, and walked independently. Regulatory approval
was based on the data from this study. A long‐term follow‐up study is in progress
but interim results were recently published in which a favorable safety profile was
observed for up to 6.2 years after dosing, with sustained and durable efficacy (all
patients were alive and were without the need for permanent ventilation[26]. This
long‐term follow‐up study will monitor patients for 15 years (Long‐Term Follow‐up
Study for Patients From AVXS‐101‐CL‐101– Full Text View– ClinicalTrials.gov).
Subsequently, Phase 3 (STR1VE) studies in different countries were initiated.
The STR1VE‐US study which enrolled 22 symptomatic SMA patients, provided
further evidence for the safety and efficacy of Zolgensma[27]. There were two
patient deaths reported during these Phase 3 studies. However, the deaths (due
to respiratory complications) were deemed unrelated to the intervention[28].
Analysis of postmortem tissue samples from these patients enabled an assessment of the vector biodistribution. This was the first study to demonstrate in
humans the widespread biodistribution of vector genomes and transgene expression throughout the CNS and peripheral organs after intravenous delivery of
2 Recent Development in invivo Clinical Gene Therapy Platforms
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44
AAV9‐mediated gene therapy to treat a neurodegenerative disease. Zolgensma
achieved an effective distribution, transduction and expression throughout the
CNS and restored SMN expression[28].
Novartis is also developing an intrathecally (IT) administered version of
Zolgensma called OAV‐101 IT which uses a lower dose of the AAV vector than
currently approved for IV administration. This has the potential to broaden access
to older patients with SMA. A Phase 1 study (called STRONG) with OAV‐101 IT
led to significant increases in HFMSE (Hammersmith Functional Motor Scale‐
Expanded) scores and a clinically meaningful response in older patients ≥2 years
and <5 years old with SMA Type 2. AveXis presents AVXS‐101 IT data demonstrating remarkable increases in HFMSE scores and a consistent clinically meaningful response in older patients with SMA Type 2 | Novartis. In October 2019, the
FDA partially suspended this trial because of findings in animals that showed
dorsal root ganglia (DRG) mononuclear cell inflammation, which was sometimes
accompanied by neuronal cell body degeneration or loss. The hold was lifted 2
years later after review of data from Novartis’ comprehensive nonclinical toxicology study in nonhuman primates (NHP) that addressed all issues identified,
including questions of DRG injury following IT administration. Following this
announcement, Novartis started a Phase 3 trial (called STEER) in patients with
SMA Type 2 aged between 2 and 18 years (see Table2.2), which will build upon
the Phase 1/2 STRONG study results.
With a $2.1million price tag, Zolgensma is often described as one of the most
expensive drugs in the world. However, Novartis has justified this based on its
dramatic effects in stopping SMA progression and helping babies reach milestones such as sitting up and chewing that they otherwise would not reach. The
high cost has been debated on multiple points, including exacerbating inequalities in access to medicines for patients living in different countries, together with
long‐term effectiveness of the gene therapy[30]. Zolgensma has been in the news
more recently when two children with SMA died after receiving Zolgensma. The
deaths resulted from acute liver failure, 5–6weeks posttreatment and about one to
10days after doctors began to taper corticosteroids. Systemic corticosteroids are
administered before and after the gene therapy infusion to dampen the immune
response to the AAV9 capsid, which would otherwise trigger liver enzyme elevations. Indeed, the label for Zolgensma includes a black box warning that the drug
“can increase liver enzyme levels and cause acute serious liver injury or acute
liver failure.” Nevertheless, Novartis acknowledged these are the first fatal cases
reported. Novartis Confirms Deaths of Two Patients Treated with Gene Therapy
Zolgensma (genengnews.com).
Table2.2 Clinical trials withAAV-mediated gene replacement therapy forbrain/CNS disease.
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Indication scDNA Capsid Sponsor Clinical Phase NCT
Spinal Muscular
Atrophy (SMA)
Giant Axonal
Neuropathy
Canavan disease ASPA AAV9
Ceroid
Lipofuscinoses
CLN
FTD with GRN
mutations
(FTD‐GRN)
Parkinson’s disease GBA1 AAV9 Prevail Phase ½ NCT04127578
Huntington’s
disease
AAV‐Olig001: novel AAV comprising a chimeric mixture of AAV1, 2, 6, 8, and 9[29].
SMN1 AAV9 Novartis Phase 3 (IV in
GAN AAV9 Taysha Gene
AAV ‐
Olig‐001
CLN3
AAV9
CLN6
AAV9
CLN7
AAV9
CLN5
AAV9
GRN AAV9 Prevail Phase ½ NCT04408625
HTT AAV5 UniQure Phase ½ NCT04120493/NCT05243017
Therapies
Aspa Myrtelle Phase ½ Phase ½ NCT04998396NCT04833907
Amicus
Amicus
University of Texas
Southwestern
Medical Center
Neurogene
pre‐symptomatic
SMA) Phase 3b (IV
in symptomatic
SMA) Phase 1 (IT)
Phase 3 (IT in type
2 SMA)
Phase 1 NCT02362438
Phase ½
Phase ½
Phase ½
NCT03505099
NCT0485187NCT03381729 NCT05089656
NCT03770572
NCT02725580
NCT04737460
NCT05228145
2 Recent Development in invivo Clinical Gene Therapy Platforms
Target tissue
)
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2.1.2 Introduction: rAAV-cDNA (gene) Therapy Candidates
inClinical Development
There are many rAAV‐based cDNA replacement therapies that have reached the
clinical development stage, which are not yet approved. These candidate AAV‐
mediated gene therapies have been developed to target a variety of diseases that
affect the eye, brain, heart, liver, and skeletal muscle. These target tissues have
many cells that need to receive the therapeutic gene for the therapy to be effective
and therefore need to receive appropriate doses of the gene therapy product
(measured in vector genomes, vg). Gene therapies that are administered to a local
area of a smaller organ such as the eye, require a smaller dose compared to gene
therapies for skeletal muscle diseases, which require systemic administration for
delivery to all muscles and therefore require much larger doses (Figure2.1).
In the next section, candidate gene therapies are grouped according to the tissue
type/system they target, which includes the eye, brain/central nervous system,
heart, liver, and skeletal muscle. It is noteworthy that although many AAV‐
mediated gene therapies target the liver, the target indications are associated with
Dose of gene therapy (vg
Eye (local target)
11
~1x10
vg
Figure2.1 Target organs for AAV-mediated gene therapies in clinical development.
Target tissue size and accessibility impacts dose. Source: Modified from Tretiakova 2019,
Scientific American[31].
Brain (local target)
12
vg
~1x10
Heart (systemic/local)
~1x1015/~1x10
Liver (systemic)
~1x10
12
14
vg
Muscle (systemic)
15
~1x10
vg
2.1 Introduction 47
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pathology in non‐liver tissues. In these cases, the liver is used as the organ that
produces the protein encoded by the transgene.
2.1.2.1 AAV-Gene Replacement Clinical Trials forthe Eye
The approval of Luxturna for LCA2 and RP patients with a biallelic RPE65mutation has resulted in a large number of additional gene replacement therapy
clinical trials for IRD patients. The diseases targeted are Achromatopsia, Choroideremia, Leber congenital amaurosis types 1 and 2 (LCA1, LCA2), Leber Hereditary Optic Neuropathy (LHON), RP, and X‐linked RP.
2.1.2.2 Clinical Trials forHeart Disease
There are several AAV‐mediated gene therapy trials targeting the heart. However,
the only trials in which a cDNA replacement approach is used are shown in
Table2.3. The other clinical trials use AAV to deliver transgenes which express
proteins that operate as bypass mechanisms. For example, delivery of SERCA2a
(sarco/endoplasmic reticulum Calcium‐ATPase) with an AAV1 vector was developed to treat heart failure. SERCA2a regulates cardiac contraction and relaxation
by its role in controlling the level of Ca2+ in the cytosol and SR in the cardiomyocyte[32]. It was observed in the failing heart in animal models and in humans that
there is a reduction in expression of SERCA2a at both the mRNA and protein
level[33]. This led to nonclinical studies assessing the effectiveness of increased
levels of SERCA2a in ameliorating the heart failure phenotype and then to the
human clinical trials (CUPID 1 and 2) with a single intracoronary infusion of
AAV1‐SERCA in HFrEF patients. Even though the CUPID trials failed to demonstrate an improvement in outcomes in HFrEF patients, another trial is underway
Table2.3 Clinical trials withAAV-mediated gene replacement therapy forheart disease.
Indication cDNA Capsid Sponsor
Danon
Disease
Friedreich’s
Ataxia
LAMP2B
(lysosome‐
associated
membrane
protein 2B)
FXN
(Frataxin)
AAV9 Rocket
AAVrh10
AAVrh10
Pharmaceuticals
Lexeo
Therapeutics
Weill Medical
College of Cornell
University
Clinical
Phase NCT
Phase 1 NCT03882437
Phase 1/2
Phase 1
NCT05445323
NCT05302271
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with the same vector and route of administration, but with a higher dose (CUPID
3), Modulation of SERCA2a of Intra‐myocytic Calcium Trafficking in Heart Failure
With Reduced Ejection Fraction– Full Text View– ClinicalTrials.gov.
2.1.2.3 Clinical Trials for Hematologic and Metabolic Disease (Targeting the Liver)
A large number of trials are ongoing in which liver is the target organ for AAV
delivery (Table 2.4). In certain instances, such as hemophilia A and B and Gaucher
disease, the liver is used to produce and secrete an enzyme that functions outside
of the liver. In other instances, PKU, Wilson’s disease, AAV delivery replaces a
defective metabolic enzyme which functions within the liver.
2.1.2.4 Clinical Trials forSkeletal Muscle
Treating skeletal muscle disease that presents as a muscular dystrophy/myopathy
(Table2.5).
2.1.3 Introduction: rAAV-as aVehicle forinvivo Gene Editing
One of the key limitations of canonical AAV delivery of a cDNA transgene is that
the transgene exists in an episomal form that may not persist over time, particularly
when delivered to very young patients with actively growing organs [37].
Additionally, many genetic diseases are caused by dominant mutations that cannot
be corrected simply by ectopically expressing a wild‐type cDNA transgene. To overcome these limitations, numerous gene editing approaches have been attempted,
with strong proof of principle in animal models, and in a few cases initiation of
clinical trials [38]. For the discussion in this section, gene editing refers to any
method designed to alter the chromosomal DNA invivo in a targeted fashion. These
include passive methods that rely solely on cell‐based DNA repair machinery, such
as homologous recombination methods, and methods actively catalyzed by site‐
directed nucleases, such as zinc finger nucleases (ZFN) and CRISPR‐Cas systems.
2.1.3.1 Non-nuclease Mediated Methods
One method by which chromosomal DNA can be altered to correct a gene or
insert a novel sequence is through homologous recombination, an approach that
is relatively inefficient and requires cells to be in a mitotic state[39]. AAV is used
as a DNA donor to carry a sequence with the desired chromosomal modification
flanked by homology arms, which target this sequence to a precise chromosomal
location. Recombination between the donor arms and the homologous endogenous sequence leads to replacement of the endogenous sequence with that templated by the AAV vector[40, 41]. While this process can take place in the absence
of exogenous nucleases, it can be enhanced by nucleases that create double‐strand
breaks at the site of homology, as homology‐directed repair (HDR) is one pathway
used by cells to repair double‐stranded breaks[42]. Homologous recombination
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