Mucopolysaccharidosis type IIIB: a current review and exploration of the AAV therapy landscape

Abstract

Mucopolysaccharidoses type IIIB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase. This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction. Current treatment options are expensive, limited, and presently there are no approved cures for mucopolysaccharidoses type IIIB. Adeno-associated virus gene therapy has significantly advanced the field forward, allowing researchers to successfully design, enhance, and improve potential cures. Our group recently published an effective treatment using a codon-optimized triple mutant adeno-associated virus 8 vector that restores N-acetyl-alpha-glucosaminidase levels, auditory function, and lifespan in the murine model for mucopolysaccharidoses type IIIB to that seen in healthy mice. Here, we review the current state of the field in relation to the capsid landscape, adeno-associated virus gene therapy and its successes and challenges in the clinic, and how novel adeno-associated virus capsid designs have evolved research in the mucopolysaccharidoses type IIIB field.

Introduction

Mucopolysaccharidoses type IIIB (MPS IIIB) or Sanfilippo syndrome is a rare autosomal recessive disorder caused by mutations in N-acetyl-alpha-glucosaminidase (Naglu). The estimated incidence rate for MPS IIIB is 1 in 200,000 newborns, reported by the USA National Organization for Rare Disorders (https://rarediseases.org/rare-diseases/mucopolysaccharidosis-type-iii). There is currently no known cure for MPS IIIB, and early intervention is necessary to prevent irreversible neuronal damage and neuroinflammation caused by the progressive buildup of heparan sulfate (HS) (Heldermon et al., 2013; Grover et al., 2020; Kong et al., 2020). Despite promising preclinical therapies and approval for numerous clinical trials for MPS disorders in the past decade, finding a lifelong cure that is effective, affordable, and safe is riddled with challenges (ClinicalTrials.gov). In this review, we describe the clinical manifestation of MPS IIIB, current and potential treatment options, the advantages, successes, and challenges associated with adeno-associated virus (AAV) gene therapy approaches, and how novel AAV capsid engineering advancements have changed the landscape of MPS IIIB therapy.

Search Strategy and Selection Criteria

This review focused on studies found on the PubMed database using the following keywords: MPS IIIB, Heparan Sulfate, Glycosaminoglycans, Natural History MPS IIIB, AAV, NAb and TAb, AAV Gene therapy, Pre-natal testing, Newborn Screening, neutralizing antibodies, and MPS. The ClinicalTrial.gov database was used in addition and the following keywords were used: MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, and MPS. All cited manuscripts were published between 1999 and 2023. There were no limitations placed on the search criteria for either database.

Etiology of Mucopolysaccharidoses Type IIIB

MPS is a group of rare genetic lysosomal disorders that is caused by the inability to breakdown glycosaminoglycans (GAGs) (Nagpal et al., 2022). There are currently seven known types and 13 subtypes (Kaczor-Kamińska et al., 2022). MPS type III has four subtypes, each related to different enzymatic deficiencies that work together to break down GAGs: A, B, C, and D. MPS IIIA and MPS IIIB have the highest incidence rates (Spahiu et al., 2021; Table 1). MPS IIIB is an autosomal recessive disorder that renders NAGLU dysfunctional, causing an aggregation of GAGs in lysosomes (Kaczor-Kamińska et al., 2022). More specifically, NAGLU breaks down the linear polysaccharide HS in this degradation pathway (Kubaski et al., 2020; Figure 1). HS is a complex GAG researched for its role in repair biology and extensive functions including, inflammation, tissue remodeling, and cellular development and growth (Hayes and Melrose, 2023). HS accumulation has been linked to several central nervous system manifestations (Costi et al., 2022). It has been shown that HS modulates the aggregation of amyloid-β peptides, helping to regulate neuroinflammation related to Alzheimer’s disease (Ozsan McMillan et al., 2023). The malfunctioning of HS results in a progressive impairment and degradation of the central nervous system (CNS), causing a proliferative effect on the rest of the body’s systems. GAGs in addition to the structural function they provide are also involved in signal transduction and pathway activation (Hayes and Melrose, 2023). Under normal conditions GAGs are essential components of the extracellular matrix and regulate neural stem cell homeostasis, neuronal growth, and brain development (Rowlands et al., 2015; Latchoumane et al., 2021). Irregularity in the function of GAGs leads to a disruption in cellular homeostasis, priming an inflammatory response (Costi et al., 2022). Due to the diverse nature of GAGs, there is a potential for a wide range of disease related symptoms to occur, predominantly neurological symptoms in the case of MPS IIIB. The resulting neurological symptoms of MPS IIIB highlight the need for a CNS directed therapeutic approach.

Table 1.

Current AAV clinical trials for MPS III

Gene	Enzyme	Incidence	Number of clinical trials	Treatments using AAV	Vectors used
SGSH	Heparan N-sulfatase	1 in 100,000	12	3	scAAV9.U1a.hSGSH (NCT02716246), AAVrh10-h.SGSH (NCT03612869)
NAGLU	Alpha-N-acetylglucosaminidase	1 in 200,000	7	2	rAAV2/5-Hnaglu (NCT03300453), rAAV9.CMV.Hnaglu (NCT03315182)
HGSNAT	Heparan-alpha-glucosaminide N-acetyltransferase	1 in 1.5 million	0	0	N/A
GNS	N-acetylglucosamine 6-sulfatase	1 in 1 million	0	0	N/A

AAV: Adeno-associated virus; MPS III: mucopolysaccharidosis type IIIB; N/A: not applicable.

Figure 1.

MPS IIIB etiology explained.

Describing how the disease develops from gene to protein to enzyme to lysosomal storage accumulation and finally cell death, compared to a normal healthy cell. Created with BioRender.com. AAV: Adeno-associated virus; MPS III: mucopolysaccharidosis type IIIB.

Mucopolysaccharidoses Type IIIB Diagnosis and Disease Manifestation

The best way to improve MPS IIIB patient outcomes is to treat early to prevent irreversible neurological dysfunction and organ damage. Blood and urine tests can be used as a diagnostic tool to detect elevated levels of GAGs in order to aid in an accurate diagnosis of MPS IIIB, however signs and symptoms of delayed development are first required to order these tests (Kubaski et al., 2020). MPS IIIB diagnosis is difficult due to the diverse and complex symptoms involved in disease progression and presentation. An obvious solution to facilitate early diagnosis and treatment is to implement newborn screening (NBS) for MPS IIIB. NBS has rapidly developed and expanded in the last decade. Specifically, several lysosomal storage diseases are now included in or are in the process of becoming included in NBS panels across the globe, including but not limited to MPS IVA (Morquio syndrome), MPS I, Pompe disease, Gaucher disease, and Fabry disease (Chien et al., 2020). The need for NBS is due to the progressive nature of lysosomal storage diseases, narrow effective treatment windows, and technological advancements in screening tools (Chien et al., 2020). Fortunately, the ability to screen for and incorporate MPS IIIB into NBS panels is becoming more likely as mass spectrometry multiplex assays can now detect MPS IIIB markers (Khaledi and Gelb, 2020).

Until MPS IIIB biomarkers are included in NBS, diagnosis will be dependent on current limited screening tests and symptom manifestation. Clinical manifestations that arise from MPS IIIB are complex and affect multiple organ systems, including the cardiovascular and respiratory systems (Nagpal et al., 2022). The clinical course for MPS IIIB has been divided into three distinct phases (Gilkes and Heldermon, 2014; Figure 2). Phase I starts with a short period of relative normalcy prior to symptom onset, with developmental delay typically noticed between ages two and six (Gilkes and Heldermon, 2014). Symptoms in this phase can include hearing loss, speech and language developmental delays, and motor deficits. Okur et al. (2022) suggest that there is significant atrophy in the brains of MPS IIIB patients stemming from a reduction of the cortical gray matter that is noticeable within the first decade of life. Due to these numerous and diverse symptoms, diagnosis can often be delayed due to the lack of knowledge and/or awareness of MPS IIIB (Delaney et al., 2014).

Figure 2.

Phases of MPS IIIB diagram.

MPS IIIB clinical development phases I-III and the concurrent signs/symptoms within each of the three distinct clinical development phases over the course of the patient’s life. Created with BioRender.com. MPS III: Mucopolysaccharidosis type IIIB.

Phase II onset begins between the ages of eight to early teens, although the age range of this phase can shift depending on disease severity. It is characterized by the regression of or failure to reach developmental milestones, pronounced periods of hyperactivity and aggressive behavior, appearance or worsening of coarse facial features, and the progression of organomegaly (Gilkes and Heldermon, 2014; Kubaski et al., 2020). However, it is important to note that hepatomegaly appears to cause no clinical dysfunction (Andrade et al., 2015; Okur et al., 2022). This phase is often the most difficult for care givers due to the rapid changes in behavior and difficulty in managing symptoms.

Phase III, or the final stage of MPS IIIB, is marked by severe dementia, loss of motor function, seizure activity, patients are largely bed-ridden and require constant care, and ultimately death occurs prior to the end of the second decade of life (Gilkes and Heldermon, 2014). Death is due to the severe neurological degeneration resulting from the buildup of HS but is often proximately caused by respiratory tract infections, such as pneumonia, resulting from diminished airway protection (Lavery et al., 2017).

Mucopolysaccharidoses Type IIIB Treatments

Several treatment approaches for MPS III have been pursued, including stem-cell therapy, enzyme replacement therapy (ERT), and gene therapy (Taylor et al., 2019; Kong et al., 2020). As with other lysosomal storage diseases, treatment challenges include the ability to target neurological dysfunction, increasing the longevity for treatment effectiveness, and manufacturing a product that is affordable for patients. In this section, we briefly describe the successes and challenges of current treatments for MPS IIIB, and how targeted engineering of drugs has advanced the field.

Hematopoietic stem cell transplants (HSCT) have successfully aided in the treatment of several lysosomal storage diseases but has been disappointing for treatment of MPS III (Kong et al., 2020). HSCT involves the removal of unhealthy cells followed by the introduction of healthy stem cells either from the patient themselves (autologous) or from a suitable donor (allogeneic). This procedure is typically done through the use of an IV and in a hospital setting, although HSCT can now be performed in an outpatient setting (Bazinet and Popradi, 2019). HSCT has been used for MPS IIIB patients in the past. Universally, HSCT was unable to reverse neurological dysfunction or prevent additional neurocognitive decline when administered later in life, suggesting that early intervention is critical for improved patient outcomes (Taylor et al., 2019). Preclinically, HSCT has been delivered with a lentivirus in an MPS IIIB mouse model. Both lentiviral gene therapy and HSC transplant approaches have been demonstrated to improve survival in the mouse model when given intravenously and intracranial delivery of lentiviral constructs provides some disease correction. Results from ex vivo lentiviral transduction of HSCs with subsequent transplant provided improvement in cranial and liver heparan sulfate storage, mitigated immune activation, and extended survival (although these corrections did not reach levels observed in healthy mice) (Holley et al., 2017). This approach was pursued further by Orchard Therapeutics in 2019 using HSCT for MPS IIIA with at least one child dosed (NCT04201405).

Another option for treating MPS IIIB is enzyme replacement therapy or ERT. ERT involves an infusion to replace or supplement enzymes into a patient who suffers from a condition that causes a deficiency or lack of an enzyme. ERT is typically administered through an IV containing the enzyme in solution although it can be administered intracranially. In theory, ERT is an effective treatment candidate for MPS IIIB. Unfortunately, ERT has a limited capacity to cross the blood-brain barrier and target neurological dysfunction, the core of MPS IIIB disease symptomology. In addition, the drug half-life of ERT is typically short and unsustainable over longer periods of time, requiring infusions every two weeks (Taylor et al., 2019). A phase 1/2 open label clinical study for MPS III showed that intravenous ERT delivery of NAGLU reduced visceral HS storage, but neurocognitive improvements were limited and the reduction of HS levels in cerebral spinal fluid (CSF) was both transient and negligible (Whitley et al., 2019). To overcome this shortcoming, a new drug called BMN 250 was developed. BMN 250 is a NAGLU-IGF2 fusion protein that utilizes the insulin-like-growth-factor 2 (IGF2) to target NAGLU to lysosomes through interactions with surface mannose-6-phosphate receptors. Unlike most ERT treatments, BMN 250 was delivered directly into the central nervous system via an intracerebroventricular cannular injection, causing a reduction in HS levels in both the brain and viscera of MPS III patients (Kong et al., 2020). Although ERT is promising when directly targeting neurological function, the financial burden of frequent treatments for similar ERT can exceed half a million dollars annually. The high cost not only limits patient access to the treatment in countries with non-universal healthcare systems but has even caused limited approval of ERT in countries with universal national healthcare systems (Taylor et al., 2019). Enzyme enhancement therapies including chaperone therapy rely on small molecules to prevent the misfolding of proteins, increasing stability and preventing aggregation (Seker Yilmaz et al., 2021). Chaperone therapy has been used in MPS IIIC patient fibroblasts with promising results that encourage further research into the topic (Matos et al., 2014).

In contrast with HSCT and ERT, adeno-associated virus (AAV) gene therapy has the potential to overcome many MPS IIIB treatment challenges and is considered to be among the most successful therapies for lysosomal storage diseases pre-clinically (Rapti and Grimm, 2021). AAV has been widely used due to its specificity, relative safety and low pathogenicity, and its ability to induce lifelong gene (and subsequently protein) expression following a single administration (Albert et al., 2017; Maurya et al., 2022). The use of gene therapy in clinical trials has increased by more than 200% in the last 30 years (ClinicalTrials.gov). Currently, over 200 trials are in progress and/or completed in 2023 (ClinicalTrials.gov). In 2017, the United States Food and Drug Administration (FDA) approved the first ever AAV gene therapy and subsequently approved two more in 2019 (He et al., 2021). Following those approvals, in late 2022 the FDA approved Hemgenix for hemophilia B, the first gene therapy treatment approved to treat hemophilia B (Jordan, 2023). Several more AAV based gene therapy products are approved by the European Medicines Agency and are under review by the FDA, such as Roctavian for hemophilia A and Upstaza for aromatic L-amino acid decarboxylase deficiency. While there are no currently approved AAV therapies for MPS IIIB (FDA.gov), there have been several clinical trials for MPS IIIB (NCT03315182, NCT02754076, NCT02493998, and NCT03227042). UniQure Biopharma B.V. conducted an open label trial of intraparenchymal multi-site injection of an AAV2/5 based vector (Deiva et al., 2021), resulting in persistent expression of the NAGLU gene in the CNS and reduction of heparan sulfate in CSF. However, the therapy did not result in complete correction of heparan sulfate levels. Three of the four children enrolled in the study presented with an initial decline in developmental quotient, but a later follow-up demonstrated that 100% of children displayed better neurocognitive function over time than predicted from natural history studies (Tardieu et al., 2017). The youngest patient treated at 20 months of age continues to improve in neurocognition, suggesting that earlier treatment is likely to correlate with better outcomes (Tardieu et al., 2017). Despite this promising clinical outcome, further clinical development in MPS IIIB has been terminated by UniQure Biopharma B.V. due to business reasons unrelated to the safety/efficacy profile of the drug (Clinicaltrials.gov). Similarly, Abeona Therapeutics conducted an open-label dose escalation therapy designed for MPS IIIB using an rAAV9.CMV.hNAGLU vector delivered with a single intravenous (IV) injection that preliminarily showed declining HS levels in the CSF and plasma, and an overall reduction in liver volume (AbeonaTherapeutics.com) (NCT03315182). However, this trial was terminated in 2022 for business reasons unrelated to the safety profile of the drug, leaving the MPS IIIB field with no active AAV gene therapy clinical trials (Clinicaltrials.gov).

Adeno-Associated Virus Vector Engineering and Its Ability to Advance Adeno-Associated Virus Gene Therapy

The ability to engineer AAV vectors has vastly improved our ability to enhance the delivery of transgene products with increased transduction and tissue specificity. There are over 100 documented AAV serotypes isolated from humans, non-human primates, and other species (Colon-Thillet et al., 2021). Capsid serotypes, tropisms, vector dose, and routes of administration determine the transduction profile and efficacy of AAV gene therapy (Colon-Thillet et al., 2021).

Since numerous rare genetic disorders, including MPS IIIB, cause some form of neurological dysfunction, the ability for a capsid to safely cross the blood-brain barrier following a relatively non-invasive IV administration has been extensively investigated in preclinical small and large animal studies. AAV9 and AAV-rh10 can cross the blood-brain barrier, but the proportion of vector entering the CNS is relatively low. As a result, high IV doses of AAV are required to effectively target CNS structures, increasing both cost and risk of off-target effects of the therapy (Song et al., 2022). Therefore, it is important to evaluate potential adverse side effects, toxicity, and the benefit-to-risk ratio to make sure that AAV gene therapy will improve quality of life in patients (Verdera et al., 2020; Song et al., 2022).

Our group recently published a study that directly infused the CNS with a novel, engineered AAV8 capsid to deliver the transgene Naglu in an MPS IIIB mouse model (Li et al., 1999; Verdera et al., 2020; Rouse et al., 2022). AAV8 has shown an extensive and broad transduction throughout the brain when injected into neonatal mice (Gilkes et al., 2021). Our AAV8 capsid modifications were designed to evade protein degradation pathways, thereby improving the intracellular trafficking of the vector and transgene expression in neurons and CNS support cells (Heldermon et al., 2007, 2013; Gilkes et al., 2021). This capsid, called AAVtcm8-coNAGLU, was evaluated using two different routes of administration: an intracisternal magna injection and an intracisternal six-site injection. There are several options for CNS routes of administration in humans, each has pros and cons. The intracisternal magna route does not traverse parenchyma structures and reaches the CSF flow increasing transduction but comes with risk of medullary injury and is not a routine procedure currently (Perez et al., 2020; Sadekar et al., 2022). The intracisternal six-site route carries significantly more risk as an invasive surgery and the injection crosses the parenchyma increasing risk of damage; however, the potential transduction profile is broad.

In neonatal mice, both routes caused sustained increases in NAGLU at or above normal physiological levels (5.5-fold higher levels of NAGLU in all areas of the brain, reaching as high as 193-fold higher near the site of infusion), normalization of heparan sulfate, and sustained decreases in compensatory secondary lysosomal enzyme activity. Moreover, we also observed correction of NAGLU activity in peripheral organs, including the liver. The ability of AAV8 to reach both the CNS and the liver is instrumental to curing for MPS IIIB and this therapeutic benefit should be considered for translation into the clinic (Gilkes et al., 2021). Finally, the clinical goal is always to improve quality of life, which can be represented in preclinical studies by clear and measurable behavioral outcomes. Our treatment with AAVtcm8-coNAGLU corrected hearing, shifted circadian activity back to normal time periods, and extended lifespan by > 640 days. Together, these data suggest that engineering novel AAV capsids, such as tcm8, is a promising approach for treating MPS IIIB.

Immune Responses to Adeno-Associated Virus

Although gene therapy has made monumental strides in the past decade, challenges for practical applications in the clinic still exist. In humans, exposure to AAV affects the innate and the adaptive immune systems (Arjomandnejad et al., 2023; Figure 3). In early life, the immune system is exposed to naturally occurring AAV’s that activates a T-cell response and creates immunity to those serotypes (Verdera et al., 2020). Recent clinical trials have highlighted this immunity, due to the limitations it poses for AAV gene therapy. Specifically, patients with pre-existing anti-AAV serotype antibodies are typically excluded from clinical trials because of the high likelihood of an immune response to the AAV vector that may negate the therapeutic benefit of the transgene by causing inflammation (Colon-Thillet et al., 2021; Gorovits et al., 2021). Pre-existing immunities can exclude as many as 50% of the potential patient population within a study (Bulaklak and Gersbach, 2020).

Figure 3.

Immune systems response to AAV exposure.

Innate immune system response and the adaptive immune system response to AAV exposure key steps and information. Created with BioRender.com. AAV: Adeno-associated virus.

Alternatively, in the rare case that patients are not excluded from the trial, anti-AAV antibodies may weaken the therapeutic benefit, potentially requiring an increased dose that enhances the risk for off-target adverse side effects of the therapy (Becker et al., 2022). Since AAV is a naturally occurring virus in the human population, there is a significant portion of the populace that has already been exposed to several AAV capsids depending on location and age (Piechnik et al., 2020). Both age and geographic location have been shown to influence the seroprevalence of neutralizing antibodies. However, younger patients tend to have less exposure to AAVs and are therefore better candidates for AAV gene therapy (Piechnik et al., 2020). This makes the window in which patients have little or no seropositivity extremely short.

The innate immune systems response to AAV begins with the uptake of AAV by antigen-presenting cells followed by the recognition of a foreign pathogen by pattern recognition receptors which are expressed on macrophages and dendritic cells, and can be classified into families, which include toll-like receptors (Chen et al., 2022; Arjomandnejad et al., 2023). These receptors trigger a signaling cascade that initiates the response and activation of the innate immune system (Rabinowitz et al., 2019). The ultimate result of the assembly of antigen-presenting cells is the initiation of the adaptive immune system (Chen et al., 2022).

It is important to consider the interaction of pre-existing anti-AAV antibodies and the dose of AAV gene therapy. Following the innate immune response, the adaptive immune response initiates an antigen specific response that eliminates pathogens and creates an immunological memory with B and T-cells (Martino and Markusic, 2020). Cytotoxic T-cells are responsible for inflammation that impacts target organs, limiting the overall therapeutic benefits of gene therapy (Verdera et al., 2020). The neutralizing antibody (NAb) response is critical to the therapeutic outcome of any AAV therapy. NAbs can effectively bind to AAV and prevent transduction of target cells (Calcedo and Wilson, 2013). NAb titers as low as 1:5 have been shown to completely block vector transduction within the liver when delivered intravenously in mice and non-human primates. In humans, low NAb titer levels have been shown to have the capacity to neutralize relatively high (2 × 10¹² vg/kg) dose vector levels (Mingozzi and High, 2013). Unsurprisingly, clinical trials have shown that a lower dose results in a milder inflammatory response that can be managed with immunosuppressive agents (Ronzitti et al., 2020). On the other hand, there have been cases where high dose vector delivery has led to fatalities. A recent clinical trial treating X-linked myotubular myopathy delivered a high dose AAV8 vector (3 × 10¹⁴ vg/kg) that caused the deaths of three patients by causing liver failure and sepsis (He et al., 2021). Potential solutions to these types of responses include the use of an immune suppressive regimen that has the ability to inhibit the adaptive immune response (creating opportunities for re-dosing of the vector), plasmapheresis, the use of novel engineered vectors to target delivery to organs with high cell turnover rates, or to reduce the side effects of AAV vectors by increasing tissue specificity. It is important to note that these solutions are not without drawbacks, both immunosuppressants and plasmapheresis leave patients vulnerable to infection. Plasmapheresis is the process of removing substances from plasma, by filtering out free antibodies and circulating immune complexes, while the process can reduce NAb levels to undetectable ranges it does require multiple cycles to sufficiently reach those levels (Earley et al., 2022). This is one potential solution to overcoming seropositivity, which would allow total patient populations to be treated not just seronegative patients. Developing solutions like this not only advances the gene therapy landscape but more importantly it allows for additional patients to be treated and potentially cured.

Future of Mucopolysaccharidoses Type IIIB and Gene Therapy

MPS IIIB is a devastating genetic disorder affecting thousands of children all over the globe [National Organization for Rare Disorders]. Despite this, no approved cure exists and treatments are mostly limited to supportive and palliative care (Gilkes and Heldermon, 2014). Future research faces several obstacles that must be addressed and considered by both scientific, regulatory, and medical communities and agencies.

Newborn screening has become a valuable tool for the early detection, and therefore early treatment, of severe and progressive disorders. Due to the progressive nature of MPS IIIB, it is critical that newborn screening include this rare lysosomal storage disease. Current techniques that precede newborn screening include both invasive and non-invasive procedures. One common invasive procedure used to test for genetic abnormalities is amniocentesis, in which a sample of amniotic fluid is taken to test the DNA of the fetus. Research into non-invasive prenatal testing has led to the development of screening prenatal cell-free DNA, which poses no risk to mother or baby (Breveglieri et al., 2019). Cell-free DNA can be used to determine fetal sex, aneuploidies, some monogenetic disorders, and has the potential to sequence whole fetal genomes. However, additional research into cell-free DNA is required to determine the benefit it might bring for screening MPS subtypes (Breveglieri et al., 2019). It is important that any newborn screening used to detect MPS and treatments of MPS IIIB patients following birth become more accessible and affordable. The advancement of AAV gene therapy to the clinic will, at the very least, reduce the need for recurring doses like with ERT. Finally, the low prevalence of both patients, dearth of MPS IIIB clinical trials, and short clinical trial timeframes makes it extremely difficult to demonstrate cognitive improvement with experimental therapies. In order to definitively say that an effective cure for MPS IIIB has been found, the scientific, regulatory, and medical fields must address these challenges.

Conclusions

Potential cures and therapies for MPS IIIB have been extensively studied, tested, and expanded upon for the last 20 years, but the field still faces numerous challenges that must be overcome before finding a cure. The use of novel engineered capsids in AAV gene therapy is one promising solution for treating MPS IIIB by bypassing pre-existing anti-AAV antibodies, enhancing transduction profiles, and reducing off-target side effects with increased target specificity. Our study using the tcm8 AAV capsid has managed to overcome several of these barriers, including, but not limited to, improving hearing and significantly extending lifespan in the MPS IIIB mouse model (Rouse et al., 2022). More research and testing are required to further tailor and enhance this therapy to determine its potential efficacy in humans.