Gene Therapy for Mucopolysaccharidoses Type IIIB Requires More Testing, Research

A new review published in Neural Regeneration Research examines the state of treatment for mucopolysaccharidoses type IIIB (MPS IIIB), a rare genetic lysosomal disorder in which buildup of heparan sulfate (HS) polysaccharides within cell lysosomes leads to debilitating neurological dysfunction¹; it is caused by mutated N-acetyl-alphaglucosaminidase (Naglu).

Also known as Sanfilippo syndrome, this rare genetic syndrome has no known cures, and current treatments are expensive and limited in supply. However, adeno-associated virus (AAV) gene therapy technology shows great promise of a cure.

Medical team meeting to discuss research

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The authors of this review, who have previously published on AAV gene therapy in a murine model, “a codon-optimized triple mutant AAV 8 vector that restores N-acetyl-alpha-glucosaminidase levels, auditory function, and lifespan,” searched PubMed for studies published between 1999 and 2013 that focused on investigations of MPS IIIB therapies. For this search, they used the search terms MPS IIIB, heparan sulfate, glycosaminoglycans, natural history MPS IIIB, AAV, neutralizing antibodies (NAb), NAb and TAb (total antibodies), AAV gene therapy, pre-natal testing, newborn screening, and MPS on PubMed. In addition, they searched Clinicaltrials.gov using the terms MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, and MPS.

They noted that because malfunctioning HS leads to irreversible central nervous system (CNS) damage, MPS IIIB’s neurological symptoms “highlight the need for a CNS-directed therapeutic approach.”

Overall, they write that early treatment to prevent irreversible neurological dysfunction and organ damage is the best way to improve outcomes among patients who have MPS IIIB. However, because symptom complexity makes it difficult to diagnose the genetic disorder, they recommend newborn screening (NBS), underscoring that several NBS panels from around the world include lysosomal storage diseases² and noting that mass spectrometry multiplex assays, which now are able to detect MPS IIIB markers,³ may help facilitate NBS of MPS IIIB.

Gene therapy, stem cell therapy, and enzyme replacement therapy (ERT) have all been investigated to treat MPS IIIB. Principal challenges to success in this endeavor are treatment cost, lack of treatment longevity, and effectively targeting neurological dysfunction.

Hematopoietic stem cell transplants (HSCT) have had disappointing results, with administration among older patients showing the method unable to reverse neurological dysfunction or prevent additional neurocognitive decline.⁴ Murine models have shown some success, the authors wrote, with lentiviral gene therapy and HSCT, but progress has been disappointing.

Effective in theory, ERT is limited by its ability to cross the blood–brain barrier, effectively target neurological dysfunction, a short and unsustainable half-life, and a high price tag (upwards of $500,000).⁴ Previous research also shows minimal improvement in neurocognitive capacity and HS reduction in cerebral spinal fluid.

AAV gene therapy for MPS IIIB treatment, however, has several advantages compared with HSCT and ERT. It is shown to be highly specific, has demonstrated safety and low pathogenicity, and could potentially induce lifelong gene expression.^5,6 The first AAV gene therapy was approved by the FDA in 2017, and 2 additional therapies were approved in 2019, the review authors wrote. Although there are no gene therapies approved for MPS IIIB, 4 trials have been conducted (NCT03315182, NCT02754076, NCT02493998, NCT03227042), and previous research has produced results that include reduced HS in CSF, improved neurocognitive function, and persistent expression of the NAGLU gene.

One potential drawback is the large intravenous dose of an AAV gene therapy required to optimally target CNS structures, the study authors write, and this can have a 2-fold impact: high cost and high risk.

“It is important to evaluate potential adverse side effects, toxicity, and the benefit-to-risk ratio,” they emphasized, “to make sure that AAV gene therapy will improve quality of life in patients.”

They added that several challenges remain to effectively applying gene therapies in this space, such as implementation of NBS, lack of clinical trials in MPS IIIB, a small patient population, and short clinical timeframes.

“More research and testing are required,” they concluded, “to further tailor and enhance this therapy to determine its potential efficacy in humans.”

References

1. Rouse CJ, Jensen VN, Heldermon CD. Mucopolysaccharidosis type IIIB: a current review and exploration of the AAV therapy landscape. Neural Regen Res. 2024;19(2):355-359. doi:10.4103/1673-5374.377606
2. Chien YH, Lee NC, Chen PW, et al. Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns. Orphanet J Rare Dis. 2020;15(1):38. doi:10.1186/s13023-020-1322-z
3. Khaledi H, Gelb MH. Tandem mass spectrometry enzyme assays for multiplex detection of 10-mucopolysaccharidoses in dried blood spots and fibroblasts. Anal Chem. 2020;92(17):11721-11727. doi:10.1021/acs.analchem.0c01750
4. Taylor M, Khan S, Stapleton M, et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses: past, present, and future. Biol Blood Marrow Transplant. 2019;25(7):e226-e246. doi:10.1016/j.bbmt.2019.02.012
5. Albert K, Voutilainen MH, Domanskyi A, Airavaara M. AAV vector-mediated gene delivery to substantia nigra dopamine neurons: implications for gene therapy anddisease models. Genes (Basel). 2017;8(2):63. doi:10.3390/genes8020063
6. Maurya S, Sarangi P, Jayandharan GR. Safety of Adeno-associated virus-based vector-mediated gene therapy-impact of vector dose. Cancer Gene Ther. 2022;29(10):29:1305-1306. doi:10.1038/s41417-021-00413-6