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2.1 Introduction 51
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Table2.5 Clinical trials withAAV-mediated gene replacement therapy forskeletal
muscle disease.
Clinical
Indication cDNA Capsid Sponsor
Phase NCT
Duchenne
muscular
dystrophy
(DMD)
Limb Girdle
Muscular
Dystrophy 2E
(LGMD2E)
Limb Girdle
Muscular
Dystrophy 2I
(LGMD2I)
X‐Linked
Myotubular
Myopathy
(XL‐MTM)
Mini/
micro‐
dystrophin
β‐sarcoglycan AAVrh74 Sarepta
FKRP
(Fukutin‐
related protein)
MTM1
(Myotubularin)
AAV9
AAVrh74
AAV9
AAV9
AAV9 Atamyo
AAV8 Audentes/
Pfizer Sarepta
Therapeutics
Solid
Biosciences
Genethon
Therapeutics
Therapeutics
Astellas
Phase 3
Phase 3
Phase
1/2
Phase
1/2/3
Phase ½ NCT03652259
Phase ½ NCT05224505
Phase ½ NCT03199469
NCT03362502
NCT03375164
NCT03368742
EU Clinical
Trials Register.
Clinical trial
2020‐002093‐27
can be used to repair a gene at the endogenous location in the genome or to insert
the desired therapeutic gene at a safe harbor locus, such as albumin.
One application of passive homologous recombination is the GeneRide technology developed by LogicBio, which is currently in clinical trials for pediatric
patients with severe methylmalonic acidemia (MMA)[43]. MMA is an inborn
error of metabolism that is caused by mutations in the methylmalonyl‐CoA
mutase gene (MMUT). MMA is characterized by life‐threatening metabolic crises
and multiorgan disease which can ultimately be lethal[44]. While addition of a
wild‐type MMUT cDNA could overcome the recessive defect, the need to treat
very young patients with actively growing livers would likely lead to dilution of
the episomal transgene overtime as has been seen with attempts to treat a neonatal mouse model[37, 44]. Furthermore, preclinical studies have shown treatment
of very young mice with an AAV construct with an active liver‐specific promoter
can lead to hepatocellular carcinoma[45].
To overcome these limitations, investigators used a promoterless integrating
cassette delivered by AAV. Specifically, the cassette contains homology arms for
the albumin locus, a P2A ribosomal skipping sequence and a codon‐optimized
MMUT sequence. The construct was packaged into either AAV8 or AAVDJ
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serotypes and used at various doses to treat mice within 1day of birth. Homologous
recombination directs integration of the construct into the albumin locus adjacent to the albumin stop codon. Following integration, a transcript is made under
control of the albumin promotor, which is then translated into 2 proteins, an
albumin‐2A fusion protein and a functional MMUT protein[43].
As mentioned above, homologous recombination is a relatively infrequent
event but in this case, the treatment outcome was helped by both the young age of
the mice and a selective advantage of growth for corrected hepatocytes. Treated
MMUT knockout mice followed over time show a significant increase in corrected
protein product between 2months posttreatment and 13–15months posttreatment. This increase occurred against the background of significant loss of AAV
genome copy number over this time. The level of integrated genomes (>10%)
increased over time in MMUT‐treated mice, while it remained below 1% in treated
wild‐type mice, consistent with a selective advantage in mutant mice. The albumin 2A fusion formed a secreted biomarker of integration that also showed a
dose‐dependent increase over time. Examination of liver by reflectance in situ
hybridization (RISH) also showed an increase in clusters of MMUT‐positive cells
over time. Finally, this editing outcome led to an increase survival and decrease in
the MMA metabolite in treated mice[43].
These results provide the rationale for a clinical trial NCT04581785, which is
currently in Phase 1 enrolling patients 6 months to 12 years of age. Following
delivery of the albumin‐2A‐MMUT construct encapsulated with LK03 serotype
rAAV, circulating albumin‐2A fusion protein was observed in the initial treated
patients, a biomarker of successful editing[46]. The positive data allowed extension into younger children where evidence of thrombotic microangiopathy (TMA)
was seen resulting in a clinical hold which has since been lifted following inclusion of additional mitigations in protocol.
Homology Medicines is also using a form of non‐nuclease mediated homologous recombination in their HMI‐103 product for treatment of Phenylketonuria
(PKU). Rather than integration into the albumin locus, the AAV construct is
designed to be integrated into the native locus of the causal PAH gene through
homologous recombination, replacing the mutant PAH sequence with a functional allele. However, rather than being driven by the endogenous promoter, the
gene expression is driven by a liver‐specific promoter, which is contained in the
AAV cassette. This design allows functional expression of the PAH gene from vector copies that remain episomal, which are likely to be significant given the relatively low frequency of homologous recombination. A novel capsid, HSC15 is
used to deliver the cassette. A Phase 1 trial NCT05222178was initiated in 2022.
2.1.3.2 Nuclease-mediated Homology Directed Repair
Early clinical studies using active nucleases to target transgenes to the albumin
locus have been performed by Sangamo to potentially provide treatments for
2.1 Introduction 53
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MPS1, MPS2, and hemophilia B[47]. This approach is similar to the GeneRide
approach in that the therapeutic gene is targeted for integration into the albumin
locus. The key difference is that an active nuclease is used to enhance the frequency of homologous recombination (by homology‐directed repair) [48].
Through protein engineering, zinc finger domains can be designed to specifically
bind to 3nucleotide sequences, thus fusing 6 engineered zinc fingers can provide
specificity for 18nucleotides. The zinc finger is then fused to a FOK1 endonuclease. Binding of the zinc finger‐Fok1 fusion results in DNA nicking, however delivery of a pair of zinc finger‐FOK1nuclease fusions, one binding to a top strand and
one binding to an immediately adjacent bottom strand results in a highly specific
double‐stranded DNA break targeting the albumin locus in this case. An AAV
construct with arms homologous to albumin flanking a cDNA encoding the therapeutic gene product is delivered and will integrate at the site of the break with a
high frequency. Successful integration leads to production of a fusion mRNA
expressing the albumin and the therapeutic transgene driven by the strong albumin promoter in the liver.
The feasibility of this approach was tested in preclinical disease models with
encouraging results. AAV8 vectors expressing the human FIX cassette with the
albumin homology arms and separate vectors expressing the ZFN pair specific for
the albumin gene, were delivered to mice, and high levels (60% of normal) of
human FIX were secreted to the plasma. This high level occurred despite the fact
that the level of albumin‐FIX mRNA fusion was only 0.5%. The design was ultimately optimized to express each ZFN on a separate vector which led to a three
vector product with 2 ZFNs and a DNA donor. This configuration of three components was introduced into the clinic for treatment of severe hemophilia B
(NCT02695160). A similar study was performed in a mouse model of Hurlers
Syndrome (MPS1) in which the IDUA gene, which is defective in MPS1, is
designed to be inserted into the albumin locus by ZFN‐mediated HDR. Delivery of
11
each component at 1.2–1.5
vg/mouse led to sustained transgene expression,
× 10
reduction of the pathogenic glycosyl amino glycans and amelioration of neuropathology [49]. Similar promising results were seen when the corrective
iduronate‐2‐sulfatase (I2S) gene was delivered along with albumin targeting zinc
finger nucleases to an MPS II mouse model[50].
Despite the promising preclinical data, clinical trials using ZFN targeting in
MPS 1, MPS II, and HemB were unsuccessful[47]. The studies were conducted in
parallel, allowing dose escalation information from one study to inform dose
selection for the other studies. The studies enrolled 9MPS II patients at doses of
12
vg/kg (N= 2), 1 × 1013 vg/kg (N= 2), 5 × 1013 vg/kg (N= 5), 3MPS I
5 × 10
patients at doses of 1 × 10
patient at a dose of 5 × 10
13
vg/kg (N =1), 5 × 1013 vg/kg (N =2) and 1 HemB
13
vg/kg. In contrast to the mouse studies in which the
AAV8 serotype was used, in these studies, the AAV6 serotype was used. The treatment was well tolerated with no serious treatment‐related adverse events. While
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some evidence of editing, as determined by the presence of albumin‐transgene
fusion was seen, the expression of transgene was variable and generally transient.
13
2MPSII and 1MPS I patient treated with the 1
dose showed the albumin‐
× 10
transgene fusion mRNA. There was also evidence of I2S expression in one patient
treated with the highest dose in the MPS II study; however, this was transient and
reduction may have coincided with transaminitis. None of the patients who had
previously been treated with enzyme replacement therapy were able to stop therapy without a rise in pathogenic glycosylaminogycans. Similarly, the HemB
patient was not able to cease FIX replacement. The reasons for lack of translation
between the preclinical and clinical studies is unclear. The need to deliver three
vectors to a cell for successful transgene insertion and expression may pose a barrier to successful dose translation between species.
2.1.4 Nuclease-mediated Gene Disruption following AAV Delivery
While there is extensive pre-clinical experience using AAV to deliver programable
nucleases such as CRISPR‐Cas9 to disrupt gene function for research studies[38],
the clinical experience is limited. The most advanced clinical trial is being conducted for treatment of Lebers Congenital Amaurosis (LCA), a retinal degenerative disease, caused by a mutation in the CEP290 gene which leads to aberrant
splicing of the mRNA and aberrant protein production. The therapeutic is known
as EDIT‐101 and consists of a single vector in which the Staphylococcus aureus
Cas9 (SaCas9) nuclease gene is driven by a photoreceptor‐specific promoter,
GRK1 and two guide RNAs (gRNA) utilize expression U6 promoters to drive
expression[51]. The guides bind to intronic sequences which flank the causative
IVS26mutation and direct Cas9 cleavage to these sites. This construct is encapsidated with an AAV5 capsid. The EDIT‐101 vector was used to treat multiple
explanted retinal samples from a patient and the gene‐edited outcome was determined by a sequencing method known as Uditas. Several editing outcomes were
observed including productive edits such as excision of the region containing the
cryptic splicing site and inversion of the region surrounding that site, which will
result in the cryptic splice no longer being recognized. Unproductive edits
included small insertions or deletions (indels) at the guide target site which do not
impact the aberrant splicing event. Interestingly, another common nonproductive
splicing event was insertion of AAV sequences at the guide target site. This occurs
at a frequency of about 5–10% of total edits and has been seen in other systems
indicative of a tendency of AAV to integrate at double‐strand breaks in
DNA. Overall, in the explants, the editing rate was 41.7 + 15.9% with the productive rate (excision and inversion) being about one‐third of this at 16.6%. While the
editing frequency at the target site correlates with efficacy, a second key concern
is off‐target editing creating mutations elsewhere in the genome. The researchers
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used a variety of techniques including in silico prediction, digenome seq on purified genomic DNA and GuideSeq to identify potential off‐targets and then used
directed sequencing to assess the frequency of off‐target events. Directed sequencing revealed that the off‐target events occurred at a frequency below the limits of
detection.
Given the exquisite specificity of CRISPR_Cas9 for sequences with full homology to guide RNA spacer regions, studies in preclinical species can be difficult. To
overcome this, a transgenic mouse model in which CEP290 IVS26was knocked
into the mouse genome was used. Levels of productive editing following sub‐
retinal injection were measured with a minimal target of 10% productive editing
11
(based on natural history). Based on this a therapeutic range of 3
× 10
to 3 × 1012
vg was established. While mice can be engineered to express the human sequence,
the anatomy of the eye is different than in humans and thus nonhuman primate
studies were required to validate dosing route. The NHP studies verified that the
GRK‐1 promoter restricted expression to photoreceptor cells (expression of nuclease within the target tissue is an important safety requirement) and also predicted
that therapeutic levels of productive editing could be obtained with doses between
11
and 3 × 1012 vg/mL.
7 × 10
This robust preclinical package has led to a Phase 1/2 clinical trial known as the
Brilliance Trial (NCT03872479). This is a dose escalation study of EDIT‐101in
which the product is injected sub‐retinally initially in cohorts of adult patients
and once safety is established in juvenile patients. The adult portion of the dose
escalation has been completed with no dose‐limiting toxicities or serious adverse
events.
A clinical trial was recently initiated to use AAV‐mediated delivery of SaCas9
and guides specific for sequences in the HIV genome for the treatment of HIV
(NCT03872479). While anti‐retroviral therapy (ART) is effective at controlling
viremia, it does not impact integrated proviruses and thus removal of therapy
results in renewed viremia. Gene editing holds the potential to remove the underlying proviral sequences. Preclinical data to support this approach comes from
NHP infected with SIV[52]. Following infection animals were put on ART and
viral load was measured. Approximately 5months after infection an AAV9 vector
expressing saCas9 and guides targeting the SIV long terminal repeat or the SIV
13
gag gene was administered iv at 10
gc/kg and necropsies were performed at
3weeks posttreatment. The AAV9 vector was widely distributed with evidence of
vector in spleen, lymph node, and in CD4 T cells. Evidence of editing, as determined by deletions between the guide‐targeted sequences in the 5′ or 3′ LTR and
gag was seen in multiple tissues. Comparison of lymph node posttreatment with
a biopsy sample pretreatment showed editing at variable levels, including 95%
editing in one sample. ART was not discontinued posttreatment so the impact of
this treatment on viremia is not clear.
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2.1.5 Challenges and Opportunities withAAV asa Delivery
Vehicle forNuclease-Mediated Gene Editing
It is important to acknowledge the challenges unique to AAV‐mediated delivery
of targeted nucleases. The first challenge is that components required for invivo
gene editing often exceed the capacity of packaging for AAV. A minimal configuration includes a nuclease, with control sequences such as a promoter and poly‐
adenylation sequence and a guide RNA often expressed from a separate Pol III
promoter. For the canonical SpCas9, the nuclease coding gene alone is 4.2
ing minimal room for control regions and separate guide cassettes. This has led to
a search for smaller nucleases through both genomic discovery and protein engineering and numerous small nucleases which are compatible with AAV have
been identified[53, 54]. However, new precision editing modalities, such as base
editing and prime editing, which require nuclease‐effector protein fusions, will
require further identification of smaller nucleases to be reliably packaged by
AAV[55].
The persistence of AAV, which is one of the key advantages for replacement
therapies, is a potential issue for AAV delivery of gene editing nucleases for two
reasons. First, the nucleases are of nonhuman origin and thus persistent expression may generate an immune response. A second concern is the potential accumulation of rare off‐target events over time. As mentioned above, the safety of
guides used in clinical trials is highly vetted but the ability to detect off‐targets is
limited to the number of cells analyzed and the length of exposure to treatment.
The consequences of persistence in a large number of cells are unknown.
Finally, AAV integration at the sites of double‐stranded breaks has been
described in multiple preclinical studies. In the case of EDIT‐101 [51], this
accounted for approximately 10% of all edits but was seen as a positive outcome as
the integrated AAV could disrupt the aberrant splicing event underlying the
pathology of LCA.
kb leav-
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