Comparative Efficacy and Safety of Multiple Routes of Direct CNS Administration of Adeno-Associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human Arylsulfatase A cDNA to Nonhuman Primates
Open accessAbstract
Metachromatic leukodystrophy (MLD), a fatal disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA), is associated with an accumulation of sulfatides, causing widespread demyelination in both central and peripheral nervous systems. On the basis of prior studies demonstrating that adeno-associated virus AAVrh.10 can mediate widespread distribution in the CNS of a secreted lysosomal transgene, and as a prelude to human trials, we comparatively assessed the optimal CNS delivery route of an AAVrh.10 vector encoding human ARSA in a large animal model for broadest distribution of ARSA enzyme. Five routes were tested (each total dose, 1.5 × 10(12) genome copies of AAVrh.10hARSA-FLAG): (1) delivery to white matter centrum ovale; (2) deep gray matter delivery (putamen, thalamus, and caudate) plus overlying white matter; (3) convection-enhanced delivery to same deep gray matter locations; (4) lateral cerebral ventricle; and (5) intraarterial delivery with hyperosmotic mannitol to the middle cerebral artery. After 13 weeks, the distribution of ARSA activity subsequent to each of the three direct intraparenchymal administration routes was significantly higher than in phosphate-buffered saline-administered controls, but administration by the intraventricular and intraarterial routes failed to demonstrate measurable levels above controls. Immunohistochemical staining in the cortex, white matter, deep gray matter of the striatum, thalamus, choroid plexus, and spinal cord dorsal root ganglions confirmed these results. Of the five routes studied, administration to the white matter generated the broadest distribution of ARSA, with 80% of the brain displaying more than a therapeutic (10%) increase in ARSA activity above PBS controls. No significant toxicity was observed with any delivery route as measured by safety parameters, although some inflammatory changes were seen by histopathology. We conclude that AAVrh.10-mediated delivery of ARSA via CNS administration into the white matter is likely to be safe and yields the widest distribution of ARSA, making it the most suitable route of vector delivery.
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Overall gross and microscopic pathology showed no effects of the dose/volume of vector beyond focal superficial parenchymal loss due to surgical intervention, similar to that observed in previous studies with PBS-treated controls.
“Overall gross and microscopic pathology showed no effects of the dose/volume (5 × 1013 gc and 1 mL of vector per CSF site) of vector beyond focal superficial parenchymal loss due to surgical intervention, similar to that observed in previous studies with PBS-treated controls.31”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [31]
The Results report superficial cortical loss and needle-track changes in PBS-treated controls, consistent with surgical injury. But the Discussion says additional inflammatory and degenerative lesions occurred in vector-treated animals, not PBS controls, and that vector involvement was probable. The Results also give a total dose of 1.5 × 10¹² genome copies per animal, not 5 × 10¹³ per CSF site. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredStatistical comparisons were considered significant if p < 0.01 because of the small sample size (n = 3/group) and daily variations in cell numbers and serum chemistries.
“Due to the small sample size (n = 3/group) and daily variations in cell numbers and serum chemistries, statistical comparisons were considered to be significant if p < 0.01.31,37,38”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [31]
The Results (page unavailable) report statistical comparisons of serum chemistry and blood-count measurements. They describe n=2 monkeys per route, except n=1 for the intraarterial route, rather than n=3 per group. The passages do not state a p<0.01 significance threshold or attribute one to daily variation in cell numbers and serum chemistries. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges and establish upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.
“The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges (total 65 blood samples from 29 individual male NHPs) and establish the upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.31,35”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [31]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe vector-administered groups (all routes) did not differ from the sham controls in any parameter of general assessment or comprehensive blood profile, remaining within the historic ranges.
“The vector-administered groups (all routes) did not differ from the sham controls (n = 2) in any parameter of general assessment or comprehensive blood profile (complete blood count and chemistry panel), remaining within the historic ranges obtained from previous studies (Supplementary Figs. S10 and S11).31,35”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [31]
The Results (page not available) report no behavioral difference between PBS and vector-treated animals across routes and no adverse trends in blood tests. However, they also report significant differences in a few blood parameters versus PBS controls and transient postsurgical enzyme elevations. The claim overstates the findings by saying that no parameter differed and that values remained within normal ranges throughout. (LLM, conf=0.90)
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- Authors
- Rosenberg, J. B., Sondhi, D., Rubin, D. G., Monette, S., Chen, A., Cram, S., De, B. P., Kaminsky, S. M., Sevin, C., Aubourg, P., & Crystal, R. G.
- Affiliations
- Cornell University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Inserm (FR)
- Corresponding author
- Crystal, Ronald G.
- ORCID
- Venue
- Human Gene Therapy Clinical Development
- Publisher
- SAGE Publications
- Published
- 2014-09
- Volume
- 25
- Issue
- 3
- Pages
- 164-177
- ISSN
- 2324-8637 (ISSN-L)
- 2324-8645
- PMC
- PMC4227442
- OpenAlex
- W2315403871
- Cited by
- 58
- References
- 55
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 2 · 2016: 8 · 2015: 3 · 2014: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Gene Therapy Clinical Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- National Institute of Neurological Disorders and Stroke (U01NS066920)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- metachromatic leukodystrophy, arylsulfatase A, adeno-associated virus gene therapy, convection-enhanced delivery, mannitol, lysosomal enzyme replacement, nonhuman primate model, vector safety
- MeSH terms
- Dependovirus, Animals, Central Nervous System, Cerebroside-Sulfatase, Gene Expression Regulation, Genetic Vectors, Humans, Leukodystrophy, Metachromatic, Primates, Genetic Therapy, Gene Transfer Techniques, DNA, Complementary, Transgenes, Serogroup
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