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13.3 Assessing the Biologic Relevance of AAV Integration Profile 335
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field stems from the fact that not all the cancer genes in one organism are found
in a different organism. Moreover, the accuracy of annotation between different
species genomes (cross annotation) depends on the computational strategy used
and impacts the study outcome.
13.3 Assessing the Biologic Relevance of AAV
Integration Profile
The Rian locus, primarily miR341, have shown to be rAAV vector integration site
that is responsible for HCC development in neonatal mice[1, 2, 10, 20, 30]. This
locus encodes for many regulatory noncoding RNAs that are expressed highly in
neonatal mice, compared with adult mice. AAV vector integration in Rian locus in
neonatal mice leads to dysregulation of the flanking genes and regulatory elements. In line with no HCC identified in adult mice, Rian integrations were not
found in adult mice in many studies[13, 15]. Large animals and human genomes
lack the Rian locus, especially an ortholog of mir341. A homolog of the delta‐like
homolog 1‐deiodinase type 3 (DLK1‐DIO3) region where the Rian locus is in
murine genome exists on human chromosomal 14. However, no evidence indicates that the genome integration has occurred in the DLK1‐DIO3 region in AAV
treated large animals and humans.
While most data from adult mice, nonrodents (dogs and NHP), and humans
have suggested that the integration of AAV vectors is a rare event, often in the
random sites across the genome with no hotspots or clusters, preferred regions of
integration in rodents, large animals and human have been identified to be chromosomal breakage sites, DNA palindromic regions, active genes, GC‐rich regions,
and CpG islands[13, 99], presumably due to highly active genes or regions where
chromosome is unwound by transcriptional machinery and DNA strand is easily
accessible for breakage and random integration to occur.
The biological consequence of AAV integration in a genome depends on the
sites of the integration and the genes affected. The integration event can be clinically silent and the cells with the integration may stay unchanged in terms of
biological functions if the integration does not change the protein expression,
structure, and/or functions. However, the integration may lead to a genotoxic
event if insertions and deletions subsequently change the expression of genes
related to cell cycle or cell proliferation, or interfere with the chromosome stability. It is worth to mention that multiple genetic mutations are needed to sustain
the clonal expansion and transform to a full malignancy, especially in the cellular
program that favors self‐renewal replication over proliferation in connection with
differentiation or senescence. The process may take years to develop, but no
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336
animal model is fully translatable and there are no other species that can be reasonably studied as long as humans.
It is known that hepatocytes can become polyploid during normal liver homeostasis, which could have been scored in the current assays as low‐level clonal
expansion. In addition, clonal expansion could happen in the normal appearing
hepatocytes during the aging process or in presence of chronic infection of
HBV. Aging is also considered as the strongest risk factor for neoplastic disease in
humans. The nature of clonal expansion, if detected in preclinical animal models
or patients under AAV treatment after long time follow‐up, needs to be carefully
examined to determine the relevance to AAV genome integration and to differentiate from aging. AAV integration and clonal expansion in the absence of tumor
formation have been observed in hemophilia dogs after long‐term follow‐up of
AAV treatment[27]. It is currently unknown if the clonal expansions detected in
the dogs were pre‐malignant and could result in malignancies if the dogs had
lived longer. However, hemophilic dogs treated with AAV GTx and followed for
more than 10 years did not identify hepatic neoplasia, suggesting the clonal
expansion observed in these dogs may have been age‐related[26, 32–34].
Assessing the risk of an integration profile is based not only on the location of
the integration within the genome, but more importantly the functional consequence of the integration events. If there are no apparent changes in cell behavior
(e.g. increased cell proliferation) or alteration of gene expression that may lead to
subsequent oncogenic transformation the integration event may be considered
non adverse. To proactively understand potential tumorigenesis risk caused by
AAV genome integration, liver tissues from AAV vector‐treated preclinical animals may be profiled for genome integration and clonal expansion. The genes
with concerning integration events may be further evaluated for expression
changes and downstream functional alteration. Human genetics and pharmacology database may be utilized to evaluate the long‐term adverse effects and carcinogenesis potential of the loci harboring vector integration[100, 101]. If clonal
expansion and tumors are identified after AAV treatment, the relevance of genome
integration to the tumor formation needs to be assessed at molecular level. Genetic
materials should be obtained from the cancer tissue biopsy and adjacent healthy
tissue and examined for the presence of AAV vector DNA and insertional events.
The molecular events, including vector copy numbers, genome integration profile, and the resulting gene expression changes in the tumor tissue may be compared with those in the adjacent normal tissue. If high copy numbers of AAV
vector DNA and insertional events are detected in the tumor, the cellular genes
near the IS may be examined further for the dysregulation that may lead to the
functional changes related to cell cycle regulation, cellular proliferation, genome
stability, and oncogenesis. These molecular and cellular signals together with evidence of clonal expansion and pathological changes will be evaluated to identify
13.4 Conclusion and Future Direction 337
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the associations among insertional events, clonal expansion, and tumor development. In some situations, the direct causality of integration events on tumor
development will not be discernable, but the weight of evidence (WOE) combining cellular and molecular, physiological, and pathological signals, as well as
patients predisposed genetic background, preexisting medical conditions related
to cancer risk and cotreatments will be holistically evaluated to identify the possible causes.
13.4 Conclusion and Future Direction
The data on AAV integration and functional consequence when viewed in totality
across species and the years of clinical experience with AAV therapeutics indicates the human risk of tumorigenesis following AAV gene therapy is likely to be
low. The literature reviewed in this chapter on long‐term follow‐up of AAV gene
therapy in nonrodents and humans indicates that AAV integration poses minimal
risk for hepatocellular tumor and consequently the hepatic tumors observed in
mice treated with AAV vectors are unlikely to translate to oncogenic risk in man.
The most compelling data set indicating that AAV gene therapy is unlikely to pose
human oncogenic risk is the experience gained from patients treated with
AVXS‐101/Zolgensma. Zolgensma is administered at a high dose of 2E14 vg/kg.
This vector uses the strong chicken‐beta‐actin promoter (CBA) and is administered to infants less than two years of age, both of which are attributes that mouse
studies[2] indicate have the highest risk of hepatocellular tumor development.
There is no indication in the publicly available literature that patients treated with
Zolgensma are prone to developing neoplasia, which is consistent with more than
two decades of human clinical trial experience and long‐term follow‐up with
AAV, indicating that there is no neoplastic risk in humans. One caveat to this
conclusion is that Zolgensma is a self‐complementary AAV vector and where
HCC has been observed in mice, the vector was a single‐stranded AAV vector.
Differences in integration profile and tumorigenesis in mice related to single vs.
self‐complementary AAV vectors is an area for further investigation.
An import aspect of understanding the biologic consequences of AAV integration is the methods used for assessing integration. These methods are evolving to
more comprehensively assess the integration of different components of the DNA
delivered by the vector. To date, the most frequently used methods have relied on
PCR‐based methods (e.g. LM‐PCR) that focus on identifying the integration site
nearby a small portion of the vector DNA (e.g. ITR). While PCR methods may be
more sensitive, new methods are evolving that are designed to capture the diversity of DNA that is delivered in the vector capsid using homologous probes to
capture the vector DNA followed by NGS to identify the associated genomic DNA.
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The expanding use of AAV GTx and the interest in the scientific and regulatory
community on insertional mutagenic risk suggest that additional work needs to
be done to understand the human relevance of the HCC findings in mice.
Additional studies in species other than mice need to be done to assess the relevance of HCC observed in mice. To date, there have been no long‐term studies in
rats assessing the neoplastic potential of AAV. An extensive review of the experience gained from decades of conducting two species (mice and rats) carcinogenic
studies to assess human carcinogenic risk of chemicals has found that when mice
are the only species to develop liver tumors the observation is not considered relevant for human safety assessment[102–104].
In order to develop a better understanding of potential human risk associated
with AAV genomic integration, there needs to be additional investigation into:
(1) understanding species differences in neoplastic outcome following AAV treatment, (2) a more comprehensive understanding of the forms of AAV‐delivered
DNA that integrates into the host cell genome, and (3) an assessment of altered
cell function associated with AAV integration. Ultimately, it will be data from
long‐term follow‐up of humans treated with AAV gene therapy that will provide
definitive data on the risk of AAV‐associated HCC observed in mice.
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