7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy

Abstract

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline b-galactosidase (b-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where b-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and b-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

GM1 Gangliosidosis: Mechanisms and Management

“…Since neuronal storage is an obvious and severe lesion, secondary demyelination resulting from neuroaxonal pathology was formerly the sole explanation. 126 This is further supported by the near-universal agreement that oligodendrocytes do not store GM1 ganglioside 24,126,146 and the resulting hypothesis that unaffected oligodendrocytes would produce healthy myelin that is destroyed by neuronal pathology. However, other signs of severe oligodendrocyte pathology have become evident with ultrastructural (Figure 1C and D) and histological evaluation, including decreased numbers of mature oligodendrocytes 24,126 and increased cell death (TUNEL-positive).…”

“…Recent literature has addressed the role of myelin pathology in GM1 and other neuropathic LSDs. Studies involving children, 24,126,128 dogs, 144 mice, 145 and cats 146 with GM1 have universally reported decreased myelin in the CNS, with a reduction in Luxol Fast Blue staining being the most commonly reported evidence of this pathology. 24,126,146 Some studies have measured myelin using X-ray diffraction 145 or noted ultrastructural abnormalities with transmission electron microscopy (TEM) such as fewer myelinated axons 126 and unraveling of myelin sheaths (Figure 1A and B).…”

“…Studies involving children, 24,126,128 dogs, 144 mice, 145 and cats 146 with GM1 have universally reported decreased myelin in the CNS, with a reduction in Luxol Fast Blue staining being the most commonly reported evidence of this pathology. 24,126,146 Some studies have measured myelin using X-ray diffraction 145 or noted ultrastructural abnormalities with transmission electron microscopy (TEM) such as fewer myelinated axons 126 and unraveling of myelin sheaths (Figure 1A and B). 146 The mechanism(s) behind myelin abnormalities and their effects on disease pathogenesis is an emerging discussion topic in the literature, with three main hypotheses considered: dysmyelinogenesis (failure to form myelin properly), primary demyelination (dysfunction or destruction of myelin after proper formation), or secondary demyelination (due to axonal degeneration).…”

“…24,126,146 Some studies have measured myelin using X-ray diffraction 145 or noted ultrastructural abnormalities with transmission electron microscopy (TEM) such as fewer myelinated axons 126 and unraveling of myelin sheaths (Figure 1A and B). 146 The mechanism(s) behind myelin abnormalities and their effects on disease pathogenesis is an emerging discussion topic in the literature, with three main hypotheses considered: dysmyelinogenesis (failure to form myelin properly), primary demyelination (dysfunction or destruction of myelin after proper formation), or secondary demyelination (due to axonal degeneration). Since neuronal storage is an obvious and severe lesion, secondary demyelination resulting from neuroaxonal pathology was formerly the sole explanation.…”

“…Noninvasive or minimally invasive methods to track GM1 disease progression include blood-based biomarkers, cerebrospinal fluid biomarkers, magnetic resonance spectroscopy, and neuroimaging. 3,22,25,59,60,146,151,152 For neuropathic diseases, analysis of biomarkers can provide a picture of disease progression and insight into the efficacy of therapeutics.…”