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PD biomarkers to assess treatment response. Mass spectrometry is a powerful
technology to detect the change of these molecules before and after treatment.
Histology and imaging techniques to quantify substrate inclusions in tissues have
been utilized as surrogate endpoints for efficacy in the clinic. For genome regulation platform, mRNA detection of downstream target RNA expression is an
important target engagement biomarker for preclinical studies. See Chapter10 for
a comprehensive review of different methods for measuring PD biomarkers.
3.3 Safety and Monitoring Biomarkers and Readouts
Like other therapeutic modalities such as biologics and small molecule drug, safety
assessment of in vivo GTx products is required at both preclinical and clinical
development stages. The nonclinical safety evaluation uses small and/or large animal species to establish proof‐of‐concept and safety profile of the biologically
active dose levels and route of administration[23]. The nonclinical safety profile,
together with preclinical pharmacology data will inform clinical dose selection and
safety monitoring. Clinical data collected over the last 20 years from more than
3000 patients treated with rAAV GTx indicating the therapeutic modality is generally well‐tolerated and efficacious[24]. As a wealth of preclinical and clinical data
becoming available in recent years, the field is experiencing emerging knowledge
and gaining mechanistic understanding of toxicities related to rAAV‐based GTx.
The treatment‐emergent safety findings with AAV GTx in patents have been
associated with hepatotoxicity and thrombotic microangiopathy (TMA), and
brain magnetic resonance imaging (MRI) findings of uncertain significance with
some treatment‐emergent serious adverse events (TESAEs) resulting in deaths of
study subjects. Other toxicities have primarily been reported in animal studies
following AAV vector administration, including DRG and peripheral nerve toxicities, primarily seen in nonhuman primates[25]. Another potential risk of AAV
vectors is oncogenicity due to integration and insertional mutagenesis. For invivo
genome editing therapies, engineered nuclease‐induced off‐target editing needs
to be assessed.
The contributing factors to these toxicities are quite complex and may involve
variables of vector design (capsid serotype and DNA construct), dose level, dose
regimen, ROA, product quality, and intrinsic patient, and disease‐specific characteristics. For example, rAAV serotypes and promoters have broad tissue tropism
and high expression which could affect safety profiles. Higher vector dose levels
have been shown to increase risk of toxicity with greater incidences and more
serious adverse events (SAEs)[26].
Empty AAV capsids in the drug product are considered an impurity as they do
not carry the genomic payload that exerts a therapeutic effect. There has been
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much debate on the effect of empty capsids on clinical outcome. Vector titers are
determined using PCR‐based methods of quantifying copy numbers of DNA
genome packaged inside the capsid. Empty capsids are thus not accounted for in
dose calculation yet add to increased total AAV exposure in patients. AAV8 empty
capsids are fully capable of triggering strong B and T cell immune responses in
humans which pose a safety concern[27]. It has been shown that AAV8 empty
capsids inhibited liver transduction in mice[28]. Conversely, it was proposed that
empty capsids may act as decoys for preexisting antibody to AAV to ameliorate
transduction inhibition [29]. Overall, low empty capsid content is desirable to
increase the safety margin by maximizing the DNA delivered per mass of capsid
protein. Finally, a patient’s preexisting immune status to wild‐type AAV, genetic
background and disease severity are additional host‐related factors that may acerbate drug toxicity. For instance, certain lysosomal or metabolic diseases have
increased autoimmunity risk[30, 31].
3.3.1 Assessment ofgenotoxicity
Evaluating a therapeutics’ effect on the integrity of the genetic material is an
important part of safety assessment. With regards to GTx, the main components
assessed to understand genotoxicity risk include: (i) AAV vector‐mediated insertional mutagenesis risk; (ii) risk of germline transmission of AAV vector, and
(iii) for gene therapies that utilize engineered nuclease to edit the genome, an
assessment of off‐target genome editing is necessary. Genome alteration events
need to be accurately detected and risks adequately assessed in preclinical and/or
clinical development phases of GTx.
3.3.1.1 AAV Integration/Insertional Mutagenesis Risk
AAV genomes mostly persist in host cell nucleus as episomal circular forms[32].
Wild‐type AAVs can integrate, in low frequency, into host genomic DNA, which is
mediated by the Rep protein[33]. Recombinant AAVs that lack the Rep/Cap genes
are even less efficient in integration. The integration sites of rAAV are largely
random though may favor open chromatin regions near actively transcribed
genes[34]. Vector design (serotype and promoter) and product quality (impurity)
may affect the integration outcomes but factors that influence the risk of oncogenicity remain to be further investigated.
To date, oncogenesis of hepatocellular carcinoma (HCC) associated with rAAV
insertional mutagenesis has only been reported in mice[35, 36]. HCC occurs as a
background tumor in most laboratory mouse strains and mice have enhanced sensitivity to HCC relative to humans, which argues the translatability to human. In
hemophilia A dogs treated with rAAV‐FVIII and monitored for up to 10 years,
2 out of 9 dogs showed evidence of clonal expansion of hepatocytes with
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integrated rAAV 4 years post vector administration [19]. Though integrations
were near oncogenes or growth control genes, no histological evidence of HCC or
other lesions was observed. No clinical oncogenesis has been attributed to AAV
integration in patients. Long‐term follow‐up monitoring and detection of rAAV
integration should be risk‐based. More detailed information on studies, methodologies, data analysis, and oncogenesis risk assessment associated with rAAV
integration can be found in Chapter13.
3.3.1.2 AAV Germline Transmission Risk
Nonclinical safety assessment of AAV germline transmission risk is generally supported by studies in the literature, a Sponsor’s AAV biodistribution studies in animals evaluating gonad tissue for vector copy number, and on a case‐by‐case basis
if additional developmental and reproductive toxicology studies are needed.
3.3.1.3 Off-Target Gene Editing
The field of using engineered nucleases to correct genetic disease is rapidly evolving and expanding. These genome editing components such as ZFN, TALEN, and
CRISPR can be designed to efficiently create double‐stranded breaks at the target
DNA sites to accomplish the intended genome modification by triggering cell’s
intrinsic DNA repair mechanisms. Due to imperfect specificity of the designer
nucleases, off‐target cleavage sites have been detected at unintended genomic
sites though in lower frequency. These off‐target effects cause short insertions and
deletions (indels) and/or large genomic rearrangements, which may lead to oncogenesis. Therefore, clinical applications of genome editing tools require thorough
understanding of off‐target activities and risks in both preclinical and clinical
studies.
Much progress has been made in defining a workflow that incorporates multiple approaches to detect and quantify off‐target sites. Various in silico tools based
on computer algorithms have been developed and used to predict and/or rank
off‐target sites by scanning the reference human genome. It is important to note
that genetic heterogeneity of individual genome variation also needs to be analyzed. In vitro cell‐based and biochemical methodologies such as GUIDE‐seq,
oligonucleotide capture, CIRCLE‐seq and SITE‐seq are available to perform unbiased, genome‐wide off‐target cleavage site identification. The computational and
experimental approaches can be combined to nominate potential off‐target editing sites[37]. After careful ranking of these sites based on frequency, location,
oncogenic risk, etc., top sites are further validated in cell type of interest and/or
invivo samples using more targeted techniques such as amplicon sequencing. In
addition, large genomic alterations of chromosomal deletions, inversions and
translocations also need to be evaluated. The standardized and conventional
karyotyping methodologies can provide valuable analysis on chromosomal
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abnormalities at the DNA structure level. In recent years, next‐generation
sequencing techniques have been developed to identify large gene modifications
with greater resolution, sensitivity, and specificity [38]. Comprehensive review
can be found in Chapter14.
3.3.2 Biomarkers forImmune-Mediated Toxicity
Host immune response against rAAV GTx represents a major hurdle for human
applications. Natural infections of wild‐type AAVs are generally benign and have
not been reported to cause any disease or illness[39], therefore, are classified as
nonpathogenic. GTx, however, is distinct in introducing non‐replicative recombinant virus in a single high‐titer bolus dose via an unnatural ROA. Compared with
biologics such as monoclonal antibody therapy, rAAVs illicit more complex
immune responses due to the multi‐component nature of the therapeutic modality. rAAV GTx introduces multiple foreign antigens to humans (aside from impurities carried over from the production and purification process): the protein capsid,
the DNA genome, and the transgene‐expressed product (protein or RNA). These
components are capable of inducing strong innate and adaptive (acquired) immune
responses that can affect safety and efficacy. rAAV treatment induces a high level
of anti‐AAV neutralizing antibodies in animals and humans, which presents a significant limitation for vector re‐administration. For this reason, it is more critical to
establish a minimum effective dose to benefit patients than other therapeutic
modalities. Before rAAV treatment, a significant proportion of human populations
have been naturally infected with wild‐type AAVs and acquired adaptive immunity, including humoral B cell‐dependent antibody response and T‐cell‐mediated
cellular response. The preexisting anti‐AAV neutralizing antibody (NAb) response
is more prevalent (as high as 74% prevalence for AAV2[40]) than capsid‐specific
CD8+ T‐cell response and the two do not necessarily correlate. Both humoral and
cellular immunities to wild‐type AAVs cross‐react with rAAV capsids, consequently, this may prevent efficient cell transduction and/or lead to elimination of
transduced cells [41], and possibly liver toxicity and TMA. Additionally,
TLR‐MyD88 sensing of high CpG content in vector DNA genome induces type
1interferon secretion and subsequent cellular response to capsids, which may lead
to hepatotoxicity and loss of transgene expression. Cellular and humoral responses
to transgene expressed product could further complicate the outcome or efficiency of GTx.
3.3.2.1 Hepatotoxicity
Dose‐dependent liver toxicity following systemic administration of rAAV has
been the most common adverse event in clinical trials[42]. This was first reported
in a patient receiving AAV2‐ssFIX at 2E12 vector genome per kilogram (vg/kg)
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dose in hemophilia B trial[41]. The clinical presentation was transient serum
transaminase (e.g. alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) elevations between 4 and 6 weeks post vector infusion. The peak
increase in liver enzymes coincided with decline and eventual loss of factor IX
activity. This effect was associated with the appearance of AAV2 capsid‐specific
CD8+ T‐cell response[43]. This cytotoxic cellular response can be detected by
ELISpot where incubation of PBMCs with capsid peptides stimulates IFN‐γ
secretion. The underline mechanism could be that rAAV antigen peptides activate
resting memory T cells originated from previous natural infection with wild‐type
AAV. There is also recent evidence that this capsid‐specific CD8+ T‐cell response
reflects primary immune responses following vector administration [44]. The
cytotoxic T‐cell response may destroy transduced hepatocytes and result in loss of
transgene expression, thereby limiting long‐term benefits of the therapy. This type
of adverse event can be managed by prophylactic or reactive intervention of glucocorticoid (prednisolone) or other immune‐modulating agents such as mycophenolate mofetil or tacrolimus. Hepatotoxicity is a known safety risk associated with
Zolgensma in the treatment of children with spinal muscular atrophy based on
data collected during clinical trials and in post‐marketing setting[45]. Elevated
aminotransferases as well as acute liver failure warning have been added to
Zolgensma label. No loss of SMN transgene expression has been reported possibly
owing to the target cells of spinal motor neurons are protected from the immune
response.
However, some clinical trial (NCT01687608) subjects who have received a
scAAV8 vector expressing the hyperactive hFIX‐R338L variant lost transgene
expression even with immune‐modulating agents[18]. The hepatotoxicity, capsid
immunity, and loss of transgene expression was possibly attributed to elevated
CpG content in the transgene (mostly introduced during codon optimization)
stimulated TLR innate immune response which in turn potentiated adaptive
response against the capsids. It has also been reported that some transaminase
elevations in hemophilia trials had no evidence of capsid‐specific cellular immune
response and no loss of transgene expression[46]. Lastly, death due to cholestatic
liver failure was reported in pediatric patients with X‐linked myotubular myopathy at AAV doses greater than 1E14
Though rAAV‐induced hepatotoxicity presents a complex clinical picture, ALT
and AST have been commonly used as a biomarker for reactive steroid treatment
intervention. These liver enzymes are not specific to liver injury because skeletal
and cardiac muscle injury often trigger ALT and AST elevation, making them
unsuitable for detecting the onset of rAAV‐induced liver injury in patients with
underlying muscle impairment such as Duchenne muscular dystrophy (DMD). In
addition, when the liver enzyme increase is detected, the irreversible elimination
of transduced liver cells might have already happened. Sensitive and specific
vg/kg[47].
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biomarkers that can predict or detect early‐onset liver injury are desirable. Serum
glutamate dehydrogenase (GLDH) has been established as one of the promising
biomarkers out of novel biomarker identification effort for drug‐induced liver
injury. It would be worth testing whether GLDH is an early and specific biomarker
to detect rAAV hepatotoxicity.
3.3.2.2 Thrombotic Microangiopathy
SAEs of hemolytic anemia, thrombocytopenia, and acute renal injury that are
consistent with TMA have been observed for several clinical trials involving high
doses of systemically delivered rAAVs. Two independent DMD trials (NCT03368742
and NCT03362502) of rAAV9 expressing a micro‐dystrophin with a muscle‐
specific promoter reported several cases of TMA within two weeks of vector
administration at doses greater than 5E13
vg/kg level. Evidence of complement
activation has been presented by the sponsors and SAEs were resolved with a C5
complement inhibitor, Ecrulizumab, and other treatments, including glucocorticoids. Zolgensma also revealed a potential role for complement in rAAV host
immune responses that induce TMA[48]. Novartis Safety Data as of 31July 2021
reported 9 cases of TMA among over 1400 patients with one death due to sepsis
after TMA recovery. The risk of TMA has been updated in Zolgensma product
information. Additional trials that have reported TMA include a liver‐targeted
rAAV capsid LK03 to treat Severe Methylmalonic Acidemia at 5E13
(NCT04581785) and a novel capsid 4D‐C102 to treat Fabry disease at 1E13
via IV infusion (NCT04519749).
Complement is a surveillance system of innate immunity that protects the host
from pathogens. Classical, alternative, and lectin pathways are three distinct but
overlapping proteolytic activation cascades that lead to complement activation.
All three pathways converge on C3 convertase, which leads to the formation of
membrane attack complex to cause cell lysis. The rapid antibody response against
the capsid detected in patients at time of TMA and high complement activation
suggest that anti‐AAV and rAAV antigen‐antibody complex activated classical
pathway through C1q binding to Fc portion of the antibody complex. Alternative
pathway may also be involved as preclinical studies showed that AAV capsids
physically interacted with many components of complement pathway and alternative pathway activation has been linked to thrombocytopenia in NHP[49].
There have been no known preventative measures for TMA. Early detection is
primarily based on clinical symptoms and frequent laboratory evaluations that
monitor platelet count, renal function, and hemolytic anemia during the first two
weeks. Alteration of serum complement components that are indicative of complement activation are useful biomarkers to confirm the involvement of complement in TMA. These include consumption of complement factors (C3, C4, Factor
B, Factor H, and Factor I) and increase of split products (Bb, C5b‐9) in serum.
Complement activation may prime myeloid cells for cytokines secretion and
vg/kg
vg/kg
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further amplification of downstream immunity. It would be helpful to test if proinflammatory cytokine increase is detectable at time of TMA. Additional adaptive
immunity monitoring may aid in the investigation of mechanisms behind AAV‐
induced TMA toxicity.
3.3.2.3 Muscle Toxicity
Serious adverse events involving muscle have been reported by four investigational
rAAV gene therapies for the treatment of DMD (NCT05096221, NCT03368742,
NCT04281485, and 2020‐002093‐27). These therapies use different AAV serotypes
(AAVrh7.4, AAV9, AAV8) to deliver various versions of a micro‐dystrophin
transgene driven by different muscle‐specific promoters (MHCK7, CK8, MSP, and
Spc5.12) through IV administration. Five participants across studies experienced
muscle‐related toxicity between 3 and 7weeks in dose range of 1E13‐2E14 vg/kg.
SAEs commonly exhibited extremity and bulbar muscle weakness. Three individual patients experienced severe respiratory muscle compromise and increased cardiac troponin‐I levels. SAEs were resolved following immunosuppressive and
other supportive treatments.
All patients affected by the SAEs share strikingly similar genotypes with
genomic deletions in the N‐terminal part of the dystrophin gene. The deleted
sequences are present in the transgene, rendering the patients being cross‐
reactive immunological material (CRIM)‐negative[50]. T‐cell‐mediated immune
response to transgene protein epitopes corresponding to the N‐terminal deleted
region was detected by positive ELISpot test in all participants with these skeletal
muscle and cardiac SAEs. Anti‐dystrophin antibodies from 1 patient also mapped
to N‐terminal deleted epitope[51]. Sponsors are starting to exclude patients with
these at‐risk genotypes from clinical trials. This is the first report that associated
anti‐transgene immune response to adverse events in humans, highlighting the
importance of measuring both humoral and cellular response to transgene in
DMD patients receiving rAAV GTx.
3.3.2.4 Immunogenicity Assessment forrAAV Gene Therapy
Immunogenicity to AAV‐based gene therapies is an important assessment to evaluate efficacy and safety of the drug. Observed adverse events during clinical
development have been implicated with host immune responses against AAV
gene therapies, resulting in comprehensive evaluation of immunogenicity during
nonclinical and clinical development. Consequently, health authorities do see
immunogenicity testing as a focus area in the nonclinical and clinical setting. A
comprehensive summary of regulatory considerations for rAAV GTx is summarized in Yang etal.[52].
Immunogenicity of AAV gene therapies is complex due to the nature of the therapy bearing three components: the capsid, the DNA content as well as the invivo
generated active drug, paired with risk factors associated with manufacturing,
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treatment‐related risks like dose and ROA[52] and the high prevalence of preexisting immunity in humans [40]. Besides the immunogenicity risks listed above,
patient‐related risk factors, including age and disease status, need to be considered
to complete the picture of all potential immunogenicity risks and are captured in a
single repository document, the immunogenicity risk assessment.
For more detailed information on AAVs immune responses in patients, mitigation strategies and bioanalytical assessments please refer to Chapter5. Immune
response to transgene‐expressed proteins, including genome editing reagents and
methods of detection can be found in Chapter12.
3.3.3 Safety Biomarkers forNonimmune Organ-Specific Toxicity
3.3.3.1 Dorsal Root Ganglia Toxicity
Dorsal root ganglia are bilateral structures that emerge from the dorsal root of the
spinal nerves. DRGs are located in the peripheral nervous system outside of the
blood‐brain barrier and yet surrounded by a thin layer of CSF and have direct
communication with the CSF compartment. DRG neurons relay somatosensory
information, including those for pain and temperature from the peripheral nerves
to the central nervous system of spinal cord and brain. In addition to primary
sensory neuron cell bodies, DRGs also contain satellite glial cells that form a layer
around neuronal cell bodies, small blood vessels constituted of endothelial cells
and smooth muscle cells, and immune cells of macrophages and lymphocytes.
Capillaries in DRG allow blood molecules to enter the DRG and interact with
neuronal and nonneuronal cells.
Both systemic IV administration and CSF delivery can result in efficient transduction of DRGs. DRG pathology findings of mononuclear cell infiltration and
inflammation, neuronal degeneration, and/or satellite glial cell proliferation have
been reported for 33NHP studies involving different capsid serotype, promoters,
and transgenes[8]. The DRG pathology peaked at approximately 1 month and
extended to 5months followed by decrease in severity after 6months post dose.
While viral purification methods and sex had no influence, ROA and dose levels
are significant contributors to the incidence and severity of the toxicity. CSF local
delivery (via intra‐cisterna magna or intrathecal injects) and greater than 1E13 vg/
animal had greater impact than IV administration and lower dose. Similar DRG
toxicity findings have been observed in piglet, mouse, and rat studies following
rAAV administration[49].
Several lines of evidence suggest that underlying mechanism of the toxicity is
cellular stress due to transgene mRNA and/or protein overexpression[14]. Initial
experiment of co‐administration of immunosuppressives did not mitigate DRG
toxicity. Whether the immune response to rAAV vector or transgene product may
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also play a role remains to be investigated. The clinical relevance of DRG safety
findings in preclinical animal studies is currently unclear.
Circulating neurofilament light chain (NFL) in serum/plasma has been identified as
a noninvasive safety biomarker for AAV‐induced DRG toxicity in NHP[53]. NFL is a
versatile fluid biomarker across diverse neurological diseases. Neurofilaments are
abundant scaffolding proteins to support neuronal cell structure. Neurofilament light
chain is one of the subunits and primarily expressed in axon of a neuron. Damage to
neurons due to injury, disease, or other toxicity release NFL into both CSF and blood
compartments. The Quanterix Simoa NFL assay has received Breakthrough Device
designation by the FDA as a prognostic aid in relapsing‐remitting multiple sclerosis.
Additional clinical validation of NFL as a prognostic biomarker has been reported for
Huntington’s[54], Alzheimer’s[55], and spinocerebellar ataxia[56, 57]. NFL is a differential diagnostic biomarker in Parkinson’s disease that can discriminate between
Parkinson and atypical parkinsonian disorders[58]. In addition, NFL is also being used
as a surrogate endpoint for efficacy in amyotrophic lateral sclerosis program[59].
3.3.3.2 Other Target Organ Toxicity Biomarkers
Toxicity biomarkers are biomarkers that are capable of detecting liver, kidney, bone
marrow, and other target organ injuries. The essential characteristics of these type
of biomarker(s) are excellent specificity to tissue damage of the indicated target
organ, high sensitivity to low dose toxicity, and early detection or prediction that
allows timely intervention and treatment decisions. Additional ideal features
include easy accessibility, noninvasive sample acquisition, and reasonably low
cost. Consortium efforts involving industry and health authorities for biomarker
qualification of organ toxicity have taken a translational approach. Nonclinical
safety biomarkers are identified by correlating with histopathology toxicity findings in animal species commonly used in safety assessment. For example, cardiac
troponins T (cTnT) and I (cTnI) are safety biomarkers to indicate cardiotoxicity in
animals and may be used to help estimate nontoxic human dose. The utility of
these biomarkers in clinical studies is validated by comparison to the current
standard biomarker performance and/or functional readouts. Nephrotoxicity and
cardiotoxicity biomarkers have been fully qualified for use in the clinic to monitor
drug‐induced injury to kidney and heart, respectively[60]. GTx drug developers
can incorporate these biomarker endpoints based on context of use into rAAV clinical trials to address patient safety and for decision‐making. New safety biomarkers
for liver, skeletal muscle, and vascular injury are in the process of being qualified
with the regulatory agencies as drug development tools to support clinical trials[60]. These biomarkers, though not yet qualified as drug development tools, can
be used as exploratory endpoints in GTx trials for information gathering, or for
decision‐making after discussion and gaining the agency’s acceptance.
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3.4 Predictive and Diagnostic Biomarkers forStudy
Enrollment and Patient Stratification
A predictive biomarker is used to identify individuals who are more likely than
similar individuals without the biomarker to experience a favorable or unfavorable effect from exposure to a medicinal product. The utility of predictive biomarkers is not limited to clinical trial settings, where they can be used to either select
patients for participation or to stratify patients into biomarker positive and negative groups, as they can also assist in informing patient care decision. Predictive
biomarkers are for example protein levels and DNA mutations. They are often
chosen initially based on the mechanism of action of the drug and understanding
pathophysiology. Usually, predictive biomarkers are evaluated in clinical trials
comparing the outcome of individuals with and without the biomarker. There are
cases where there is sufficient evidence to use a certain biomarker only in populations enriched for the putative predictive biomarker.
Prognostic biomarkers on the other hand are used to identify the likelihood of a
clinical event, disease recurrence, or progression in patients who have the disease
or medical condition of interest. They are often used as eligibility criteria in clinical trials to identify patients who are more likely to have clinical events or disease
progression. Thus, they are widely used as enrichment factors in drug development. Distinguishing predictive and diagnostic biomarkers can be difficult with
some being both, predictive and diagnostic.
In general, all the concepts listed above apply to the clinical development of
gene therapies and are very much driven by the program specifics. Especially the
patient selection based on the predictive biomarkers of protein expression and/or
gene mutation is of importance, given that to date AAV gene therapies are given
as a single treatment with a “point of no return” once administered to a patient,
reflected in the clinical development starting with an effective and safe dose to be
administered into the patients predicted from an extensive preclinical program.
3.4.1 Preexisting Anti-Capsid Antibody
The prevalence of preexisting anti‐AAV capsid antibodies in humans is generally
high and can reach up to 80% of the individuals, depending on a variety of factors
such as age, geographic location/ethnicity, and serotype[40]. To date, in most of
the clinical trials testing an AAV‐based gene therapeutic product, patients bearing
preexisting antibodies above a certain threshold (titer) are excluded, to ensure an
efficacious therapy and/or to avoid any possible adverse events. Such findings due
to preexisting anti‐capsid antibodies, namely efficacy loss and/or adverse events
have been reported in nonclinical and clinical trials[9, 41]. As our current understanding of the effect of preexisting anti‐capsid antibodies is still limited, the
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