Phase 1/2 clinical trial of systemic gene transfer of scAAV9.U1a.hSGSH for MPS IIIA demonstrates 2 years of safety, tolerability, and biopotency

Flanigan, Kevin M.; Simmons, Tabatha R.; McBride, Kim L.; Kunkler, K.L.; Alyward, S.; Couce, María L.; Oreiro, Maria Teresa; Smith, Nicholas J.; Jaensch, Louise; Fuller, Maria; Ruiz, Juan; Truxal, Kristen V.

doi:10.1016/j.ymgme.2018.12.122

Cited by 2 publications

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“…Our studies in nonhuman primates (NHPs) showed acute development of thrombocytopenia and transaminitis, which, in some cases, evolved into a lethal syndrome of hemorrhage and shock (9,10). Acute elevations in liver enzymes and/or reductions in platelets have been observed in most high-dose AAV clinical trials (11)(12)(13)(14). Although infrequent, severe toxicities were characterized by anemia, renal failure, and complement activation (12,13).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

et al. 2020

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Delivering adeno-associated virus (AAV) vectors into the central nervous system of nonhuman primates (NHPs) via the blood or cerebral spinal fluid is associated with dorsal root ganglion (DRG) toxicity. Conventional immune-suppression regimens do not prevent this toxicity, possibly because it may be caused by high transduction rates, which can, in turn, cause cellular stress due to an overabundance of the transgene product in target cells. To test this hypothesis and develop an approach to eliminate DRG toxicity, we exploited endogenous expression of microRNA (miR) 183 complex, which is largely restricted to DRG neurons, to specifically down-regulate transgene expression in these cells. We introduced sequence targets for miR183 into the vector genome within the 3′ untranslated region of the corresponding transgene messenger RNA and injected vectors into the cisterna magna of NHPs. Administration of unmodified AAV vectors resulted in robust transduction of target tissues and toxicity in DRG neurons. Consistent with the proposal that immune system activity does not mediate this neuronal toxicity, we found that steroid administration was ineffective in alleviating this pathology. However, including miR183 targets in the vectors reduced transgene expression in, and toxicity of, DRG neurons without affecting transduction elsewhere in the primate’s brain. This approach might be useful in reducing DRG toxicity and the associated morbidity and should facilitate the development of AAV-based gene therapies for many central nervous system diseases.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

et al. 2020

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“…Dose escalation entails three groups from low dose (0.5 × 10e13 vg/kg), mid‐dose (1 × 10e3 vg/kg) to high dose (3 × 10e13 vg/kg). Preliminary data at 24, 12, and 6 months post‐injection from the three dose‐escalating groups, respectively, highlighted a provisional acceptable safety in all patients with significant time‐ and dose‐dependent reduction of HS levels and liver volume, and stabilisation or improvement of adaptive behaviour and/or cognitive function 134 . Study ABT‐003 (NCT04088734) is another clinical trial enrolling 12 MPS IIIA patients with a DQ lower than 60 in middle and advanced phases of the disease.…”

Section: In Vivo Adeno‐associated Viral Gene Therapymentioning

confidence: 95%

“…Preliminary data at 24, 12, and 6 months post-injection from the three dose-escalating groups, respectively, highlighted a provisional acceptable safety in all patients with significant time-and dose-dependent reduction of HS levels and liver volume, and stabilisation or improvement of adaptive behaviour and/or cognitive function. 134 Study ABT-003 (NCT04088734) is another clinical trial enrolling 12 MPS IIIA patients with a DQ lower than 60 in middle and advanced phases of the disease. Recruited patients will receive a single dose corresponding to the high dose of the Transpher A study, that is, 3 × 10e13 vg/kg.…”

Section: Clinical Trialsmentioning

confidence: 99%

Novel therapies for mucopolysaccharidosis type III

Yılmaz

Davison

Jones

et al. 2020

J of Inher Metab Disea

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Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile‐onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease‐modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno‐associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first‐in‐man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease‐modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.

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Phase 1/2 clinical trial of systemic gene transfer of scAAV9.U1a.hSGSH for MPS IIIA demonstrates 2 years of safety, tolerability, and biopotency

Cited by 2 publications

References 0 publications

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates

Novel therapies for mucopolysaccharidosis type III

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