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Commentary | Open Access | Volume 3 | Issue 1 | 2022 | DOI No.:
10.46439/stemcell.3.013

THE SIGNIFICANCE OF TRIPLE-CAPSID-MUTANT AAV8 FOR TREATMENT OF SANFILIPPO
SYNDROME TYPE B

Frederick Ashby, Coy Heldermon*

University of Florida, College of Medicine, Gainesville, FL 32610-0278,USA

*Corresponding Author:
Coy Heldermon
University of Florida, College of
Medicine, Gainesville, FL 32610-0278,USA
E-mail:Coy.heldermon@medicine.ufl.edu

Received date: April 03, 2022; Accepted date: April 26, 2022

Citation: Ashby F, Heldermon C. The significance of triple-capsid-mutant AAV8
for treatment of Sanfilippo Syndrome Type B. Arch Stem Cell
Ther.2022;3(1):11-17.

Copyright: © 2022 Ashby F, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution,and reproduction in any medium,provided the
original author and source are credited.

 

ABSTRACT

Sanfilippo Syndrome Type-B remains an untreatable childhood neurodegenerative
disease with great burden for both patient and caregiver. Very few clinical
trials have been undertaken to treat the disease, and none of these have yet
yielded clinically obtainable products for patients. Caused by a simple enzyme
function deficiency, Sanfilippo Syndrome Type-B has been considered a great
prospect for gene-therapy interventions. Adeno-associated virus (AAV) remains a
major choice for therapeutic gene delivery due to its relatively
low-immunogenicity, versatility and tissue tropism. However, many clinical
trials with AAV continue to use wild-type capsids, which in many cases are not
able to reach stable transgene expression for long enough to be clinically
effective in most cases. Previous research in AAV gene-therapy has created a
litany of novel AAV capsids that can improve overall transduction efficiency far
above that of wildtype AAV capsids. One such example is the triple-capsid mutant
AAV8 (TCM8), which has been shown to exhibit transgene expression far superior
to other capsids in Sanfilippo mouse models, specifically. Originally designed
to bypass capsid ubiquitination intracellularly, mouse studies suggest this TCM8
vector outperforms both AAV5 and AAV9 when delivered to the central nervous
system. This implies it as an ideal contender for an effective gene-therapy
clinical trial candidate and has the potential to advance the progress of
Sanfilippo Syndrome treatment. Here we provide commentary on the TCM8 vector and
its context in the field of Sanfilippo Syndrome Type-B research.

 

KEYWORDS

Sanfilippo Syndrome, Mucopolysaccharidosis, Adeno-associated virus,
Gene-therapy, AAV8, Capsid mutants

 

SANFILIPPO SYNDROME TYPE-B

Sanfilippo Syndrome, or Mucopolysaccharidosis (MPS) III, was first described in
1963 as an inherited condition of intellectual disability associated with
significant mucopolysacchariduria, specifically of heparan sulfate [1]. The
pathological elevation in mucopolysaccharides placed it in the same disease
category as Hurler’s Syndrome (MPS I) and Hunter’s Syndrome (MPS II), however
typically with less somatic manifestations and more central nervous system (CNS)
dysfunction. MPS III is characterized on the cellular level by lysosomal
distention, and grossly by organomegaly, coarsened facies and central nervous
system degeneration [2]. Symptom onset typically happens in the first few years
of life and can initially present as regression of developmental milestones and
can be initially mistaken for isolated autism spectrum disorder (ASD). Recurrent
ear, nose and throat infections are common in this disease, along with diarrhea
and in some cases hearing loss [3]. After this initial phase, the next decade is
typically characterized by behavioral problems, sleep disturbances and
progressive cognitive and motor decline [4-8]. The final stage of the disease is
typically characterized by severe CNS dysfunction, with seizures and coma
[9,10]. MPS III Type A and B comprise over 80% of cases and have the most
aggressive symptoms within the Sanfilippo Syndrome category with death commonly
occurring within the first two decades of life. The most common cause of
mortality is pneumonia, followed by cardiorespiratory failure [11].

The accumulation of heparan sulfate (HS), a sulfonated repeating-disaccharide
glycosaminoglycan (GAG), in the context of MPS III occurs definitively from
biallelic mutations affecting an enzyme involved in the degradation pathway.
While each type is almost clinically indistinguishable, biochemically MPS III
mutations affecting the SGSH gene (17q25.3) are categorized as Type A; while
mutations affecting the NAGLU gene (17q21.2) are categorized as type B;
mutations affecting the HGSNAT gene (8p11.21-p11.1) are Type C; and mutations
affecting the GNS gene (12q14.3) are Type D[12] – with Type A and B commonly
being the most severe. Of note, there remains an ARSG gene (17q24.2) in the HS
degradation pathway, which if mutated would be referred to as Type E, however
this has yet only been described in animal models [13]. All four types of
confirmed human MPS III (A, B, C and D) have had causative mutations such as
missense, nonsense and splicing along with small and large indels [13,14],
illustrating the allelic heterogeneity of the disease. While promoter mutations
and other gene-regulation-level mutations are not frequently described in MPS,
promoter/3’-UTR mutations have been reported in MPS I [15]. Phenotypically, MPS
III has a very wide range of severity depending on the degree of lost
degradation function, due to either loss of respective enzyme expression, enzyme
function or possibly a combination in rare circumstances. Due to this very
simple pathophysiology, most MPS III therapies have the goal of increasing
activity levels of the affected enzyme to ameliorate disease course. Enzyme
Replacement Therapy (ERT) has been a reasonable proposal for treatment, along
with gene-therapy and stem cell therapy, yet there are still no approved
treatments for MPS IIIB.

 

AAV GENE THERAPY

 

Adeno-associated Virus (AAV), a replication deficient parvovirus, originally
discovered as a contaminant [17,18], remains a popular choice for gene-therapy,
in large part due to its relatively low immunogenicity, selective tissue tropism
and overall versatility [19-21]. Seroprevalence studies suggest that over 90% of
participants have been exposed to at least one serotype of AAV, with heavy
variation between serotypes and populations [22-24]. Despite high
seroprevalence, to date there have been no known diseases confirmed to be caused
by the virus. However, there remains a long-standing debate on the relationship
with AAV (wild or vector) and certain cancers [25,26]. The high prevalence of
neutralizing antibodies to AAV in the general population remains a significant
challenge to effective AAV treatments. Currently, there are three approved AAV
gene-therapies (Table 1): AAV1-LPLS447X driven by cytomegalovirus (CMV) promoter
for treatment of Lipoprotein Lipase Deficiency (LPLD) in 2012 [27]; AAV2-RPE65
driven by a CMV/Chicken- β-actin (CβA) hybrid promoter for treatment of
inherited retinal dystrophy (RD) caused by biallelic RPE65 dysfunction in 2017
[28-30]; and self-complementary AAV9-SMN1 driven by a CMV/ CβA hybrid promoter
for treatment of spinal muscular atrophy 1 (SMA1) in 2019 [31]. It is worth
noting that each of these products utilizes wild-type AAV capsids. Currently,
there are over a hundred active clinical trials involving AAV gene-therapy
(ClinicalTrials.gov) treating a litany of diseases.

Capsid Brand Name Generic Name Disease Trans-Gene Clinical Trial wtAAV1 Glybera®
Alipogene tiparvovec LPLD CMVp-LPL(S447X) NCT02904772* wtAAV2 Luxturna®
voretigene neparvovec- rzyl RD
(RPE65 subtype) CMVp/CβAp-RPE65 NCT00999609 wtAAV9 Zolgensma® onasemnogene
abeparvovec-xioi SMA1 CMVp/CβAp-scSMN1 NCT03381729

*Trial discontinued by company.

Table 1: Currently Approved AAV Gene-therapies.

 

CLINICAL TRIALS FOR MPS IIIB TREATMENT

 

The clinicaltrial.gov registry currently only has 16 trials registered for
Sanfilippo B (Table 2; Figure 1). Out of these 16 trials, 9 are observational
with no treatment focus. The remaining 7 were focused on novel treatments. Four
of these studies investigated two candidates for ERT: AX 250 (NCT03784287;
NCT02754076) and SBC-103 (NCT02324049; NCT02618512), by both intravenous (IV)
and intracerebroventricular (ICV) delivery methods. AX 250 is a chimeric fusion
of recombinant human α-N-acetylglucosaminidase and truncated human insulin-like
growth factor 2 (rhNAGLUIGF2), while SBC-103 is only a recombinant human
α-Nacetylglucosaminidase (rhNAGLU). At least in the context of the study
endpoints, such as developmental quotient (DQ), grey matter volume and
age-equivalence (AE), SBC-103 did not appear to give adequate disease correction
[32] when delivered IV (NCT02324049 or NCT02618512). However, it should be noted
that family members of trial participants have claimed a noticeable improvement
of non-endpoint metrics associated with both symptoms and quality of life, but
these results have yet to be published in peer review. Meanwhile, the ICV trial
of AX 250 is ongoing (NCT03784287). Two of the clinical trials for treatment of
MPS IIIB investigated AAV gene therapy as a method. The first utilized a
pseudotyped rAAV2/5- huNAGLU (wtAAV2 genome within a wtAAV5 capsid) administered
intracerebrally (NCT03300453) by a 16-point intraparenchymal injection method in
4 patients with MPS IIIB. The patients were 20-53 months old at the time of
treatment, with the youngest patient showing the best developmental outcomes
overall, suggesting an optimal window for treatment [33]. However, it should be
noted that a 5-year follow-up study found an escalating cell-mediated immune
response in the cerebrospinal fluid (CSF) of study participants [34],
underscoring the importance of recognizing the role of immunity in long-term
treatment response [35]. The second AAV trial in MPS IIIB utilized
rAAV9-CMVp-huNAGLU administered IV (NCT03315182). The study aimed to leverage
the AAV9 serotype’s superior ability to cross the blood-brain barrier [36,37],
which allows much less invasive administration. Continued development of this
gene therapy product was recently discontinued by the company but had no
reported significant adverse events. Additionally, the lentiviral-transduced
autologous hematopoietic stem cell transplant based study that was just starting
with Orchard Therapeutics was also discontinued by the company. This leaves MPS
IIIB with no active trials using a gene therapy approach to curative therapy,
reinforcing a need for development of approaches in this area.

 



 

Figure 1: Current Clinical Trials in MPS IIIB: Out of the 16 clinical trials
registered through the US National Libraries of Medicine (USNLM), 6 were
randomized controlled trails (RTC’s). Only two of these trials tested rAAV
treatments, and both utilized capsids from wtAAV serotypes. All data was
obtained through the clinicaltrials.gov website.

Study Name Study Type Study Identifier Intervention Study Sponsor Results
Natural History Study of Patients With Mucopolysaccharidosis Type IIIB (MPS
IIIB, Sanfilippo Syndrome Type B) Observational, Prospective, Cohort NCT01509768
N/A Shire Published in peer-review [57],
completed 2013 Natural History Studies of Mucopolysaccharidosis III
Observational, Prospective, Cohort NCT02037880 N/A Nationwide Children’s
Hospital None provided, completed 2015 Natural History Study to Characterise the
Course of Disease Progression in Participants With Mucopolysaccharidosis Type
IIIB Observational, Prospective, Case- series NCT02293408 N/A Alexion Pharm.
None provided, completed 2017 Neurobehavioral Phenotypes in MPS III
Observational, Prospective, Cohort NCT01873911 N/A University of Minnesota; NIH
U54NS065768 Published in peer-review [7,8],
completed 2014 A Retrospective Chart Review of Deceased Patients With
Mucopolysaccharidosis Type IIIB Observational, Retrospective, Case-series
NCT02293382 N/A Alexion Pharm. None provided, completed 2015 A Study of
Mucopolysaccharidosis Type IIIB (MPS IIIB) Observational, Prospective, Case-
series NCT02493998 N/A Allievex Corp. None provided, completed 2019 Biomarker
for Sanfilippo Type A-B-C-D Disease (BioSanfilippo) Observational, Prospective,
Cohort NCT02298686 N/A CENTOGENE GmbH
Rostock None provided, completed 2021 Evaluation of Blood Brain Barrier
Integrity and Structural Abnormalities in MPS IIIB Patients Using Multimodal
Magnetic Resonance Imaging Observational, Prospective, Case- series NCT02090179
N/A Alexion Pharm. None provided, completed 2016 A Treatment Study of
Mucopolysaccharidosis Type IIIB (MPS IIIB) Interventional, Randomized Controlled
Trial, Phase-1/2 NCT02754076 ERT,
AX 250, IV Allievex Corp. None provided, completed 2020 A Treatment Extension
Study of Mucopolysaccharidosis Type IIIB Interventional, Randomized Controlled
Trial, Phase-2 NCT03784287 ERT,
AX 250, ICV Allievex Corp. None provided, ongoing until 2025 Safety,
Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC- 103 in
Mucopolysaccharidosis III, Type B (MPS IIIB) Interventional, Randomized
Controlled Trial, Phase-1/2 NCT02324049 ERT,
SBC-103, ICV Alexion Pharm. Published on USNLM,
completed 2017 A Open Label Study in Previously Studied, SBC-103 Treatment Naïve
MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and
Pharmacodynamics / Efficacy of SBC- 103 Administered Intravenously
Interventional, Randomized Controlled Trial, Phase-1/2 NCT02618512 ERT,
SBC-103, IV Alexion Pharm. Published on USNLM, Published in peer-review [32],
completed
2018 Intracerebral Gene Therapy in Children With Sanfilippo Type B Syndrome
Interventional, Randomized Controlled Trial, Phase-1/2 NCT03300453 Gene-therapy,
rAAV2/5- hNAGLU UniQure Biopharma B.V. Published in peer-review [33],
completed 2019 Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB
(MPSIIIB) Interventional, Randomized Controlled Trial, Phase-1/2 NCT03315182
Gene-therapy, rAAV9.CMV. hNAGLU,
ABO-101 Abeona Therapeutics, Inc None provided, ongoing until 2022 A Long-term
Follow-up Study of Patients With MPS IIIB Treated With ABO-101 Observational,
Prospective, Cohort NCT04655911 Prior participation in ABO-101 Abeona
Therapeutics, Inc None provided, ongoing until 2026

ERT: Enzyme Replacement Therapy; IV: Intravenous; ICV: Intracerebroventricular

Table 2: Sanfilippo Type-B Clinical Trials Summary.

DEVELOPMENT OF THE TCM8 VECTOR

Efforts have been made for years to improve the effectiveness of AAV capsids in
the context of human gene-therapy. While relatively effective in some trials,
wild-type AAV capsids have not evolved to fill the niche they serve in
gene-therapy treatment, but rather have evolved to propagate and survive in
their natural host environment [38]. While AAV is weakly immunogenic, systemic
AAV genetherapy typically requires very large vector loads to achieve desired
effects, frequently exceeding 1013 vg/kg per patient. This can elicit complement
activation with thrombocytopenia, humoral immunity within the liver and other
organ injury, and in severe cases lifethreatening anaphylactic immune responses.
Improving the efficiency of AAV vector can lower the dose required to achieve
clinically significant outcomes, and thus reduce the risks to the patient while
reducing the production cost of treatment. Vector efficiency has previously been
improved preclinically by a combination of selective evolution of capsids
[39-41], site-directed mutagenesis [42,43], capsid shuffling and chimerism
[44-46], and even deep-learning simulation [47].

In order to identify better serotypes and methods for transduction of the brain,
AAV5, AAV8, AAV9 and AAVrh10 were compared in wild type (WT) and MPS IIIB mouse
models using a variety of injection methods, IV, thalamic, ventricular, ventral
tegmental area or 6 intraparenchymal sites, to deliver a green fluorescent
protein (GFP) reporter. In all mice, the broadest brain transduction was with
the 6 intraparenchymal site injections. In contrast, the broadest transduction
of WT brain marginally favored AAV9, however AAV8 clearly provided much broader
and more intense brain transduction in MPS IIIB mice, and the other serotypes
were similar between WT and MPS IIIB mice [48,49].

Building upon this disease specific enhanced brain tropism, the capsid
modification principle was applied to AAV8 capsids. The triple-capsid mutant
AAV8 (TCM8) proposed for treatment of Sanfilippo Syndrome type-B was originally
designed to address the issue of capsid ubiquitination leading to proteasomal
degradation of vectors post viral entry. Proteasomal degradation of capsids has
been extensively reported to be a major cause of lost vector efficiency [40-54],
so the next logical step in improving vector efficiency for many researchers has
been to identify ways to circumvent this process. The process of ubiquitination
is partially dependent on phosphorylation of amino acid residues on the target
protein, therefore site-directed mutagenesis of exterior-facing serine,
threonine or tyrosine residues to a sterically similar hydrophobic amino acid,
such as phenylalanine for cyclic groups or valine for aliphatic groups, was
shown to profoundly inhibit the ubiquitination process [42] without altering the
capsid proteins’ function. The subsequent AAV8 capsids created included a double
mutant (Y444 + 733F) and triple mutant (Y444 + 733F + T494V) that were designed
based on these principles using X-ray crystallography to reference the exterior
facing portions of the capsid. The triple-capsid mutant AAV8 had significantly
stronger transduction efficiency compared to the double-mutant or wtAAV8, as
measured by green-fluorescent protein (GFP) trans-gene expression in MPS IIIB
mice [55]. Therefore, it was proposed as an optimal candidate to explore as a
clinical therapy vector, specifically for MPS IIIB. Subsequently this AAV TCM8
vector was made with a codon-optimized NAGLU sequence insert and used for
neonatal treatment of MPS IIIB mice with either the 6 intra-parenchymal
injections or a single cisterna magna injection (Publication Currently Under
Review). The treated mice demonstrate broad and high-level brain NAGLU activity
and complete correction of functional and lifespan measures with either
injection method demonstrating the clinical potential of the AAV TCM8 vector for
correction of this disorder.

 

CONCLUSION

 

In summary, the results from the TCM8 studies in MPS IIIB overall suggest that
this modified capsid vector may be capable of treating MPS IIIB patients with
far greater efficiency than any treatments currently being investigated in
humans. This is particularly apparent by the results published by Gilkes et al.
2016 [49], which suggest wtAAV8 is superior to the two other capsid serotypes
currently under clinical trial (AAV5 & AAV9), at least in MPS IIIB mice. The
subsequent follow-up by Gilkes et al. in 2021[55] show a profoundly increased
transduction efficiency in TCM8 above wtAAV8, which would imply a commensurately
higher efficiency than wtAAV5 & wtAAV9. Our follow-up studies using a
therapeutic gene (Publication Currently Under Review) also show significant
results. All of this is to suggest TCM8 may make an ideal candidate for clinical
trial in MPS IIIB patients. One important limitation to the work done thus far
relates to the phylogenetic divergence between humans and mice, and past animal
studies in AAV have demonstrated the considerable effect this can have on AAV
tissue tropism. One such example is the tropism of wtAAV8 for mouse hepatocytes
without such a commensurate effect being observed in human hepatocytes [56],
underscoring the need for humanized-liver mouse models in hepatocyte targeting
rAAV studies and the consideration of humanized tissue models in-general. While
it important to note that rAAV expression in a mouse model may or may not
translate to humans well, currently the evidence suggests AAV TCM8 is a prime
candidate for rAAV treatment of MPS IIIB. With the absence of a non-human
primate MPS IIIB model, it is difficult to test TCM8 comparatively in primates
preclinically, especially if this preference for TCM8 in the CNS is disease
model dependent, as appears to be the case in the previous mouse studies.[49]

Given the lack of current treatments or gene therapy clinical trials in this
disease, the AAV TCM8-coNAGLU gene therapy vector is highly promising to advance
treatment progress for MPS IIIB patients.

 

ACKNOWLEDGEMENTS

 

The Heldermon lab would like to acknowledge Sanfilippo Children’s Research
Foundation, Sanfilippo Fundacja and Sanfilippo Initiative, Cure Sanfilippo,
Lacerta Therapeutics, and NIH/NINDS R01NS102624.

 



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