Injection of single-stranded or self-complementary adeno-associated virus 9 into the cerebrospinal fluid
Inventors
DONSANTE, Anthony • Kozarsky, Karen • Boulis, Nicholas Matthew • Riley, Jonathan Patrick
Assignees
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Publication Number
US-12070510-B2
Publication Date
2024-08-27
Expiration Date
Abstract
It is disclosed herein that ssAAV and scAAV vectors of the same serotype administered by injection into the cerebrospinal fluid (CSF) via the intracerebroventricular (ICV) or intrathecal (cisternal or lumbar) route exhibit different cellular tropisms in the central nervous system. Thus, a subject can be treated by injection into the CSF of ssAAV or scAAV vector encoding a therapeutic protein, such as an ssAAV9 or scAAV9 vector. The therapeutic protein can be targeted to specific cells using these vectors. In some embodiments, scAAV9 is utilized to achieve superior transduction in the hippocampus, cerebellum and cerebral cortex where both neurons, particularly Purkinje neurons, and glial cells (such as astrocytes) are transduced. In other embodiments, ssAAV9 is utilized to minimize transduction of astrocytes. In further embodiments, an immunosuppressive agent is also administered to the subject.
Core Innovation
The disclosed invention provides a method for treating a human subject diagnosed with a CNS disorder by administering a scAAV9 encoding a therapeutic protein via injection into cerebrospinal fluid. The administration is performed through an intracerebroventricular, intrathecal cisternal route, or an intrathecal lumbar route at a flat dose of about 1.2×10^14 GC.
The method is described for Spinal Muscular Atrophy, using SMN1 as the therapeutic protein, and includes treating the CNS disorder and alleviating a symptom of the CNS disorder in the human subject. The independent claims define pediatric age ranges of 3 to 12 years old and 9 to 36 months old.
The description further connects this CSF delivery approach with differences in CNS cellular tropism between ssAAV9 and scAAV9 for the same serotype. scAAV9 is described as providing superior transduction of hippocampus, cerebellum, and cerebral cortex, with transduction of both neurons and astrocyte-like cells, including S100β+ astrocytes.
Claims Coverage
The partial claim set contains two independent claims, both focused on CSF injection of scAAV9 encoding SMN1 for treating Spinal Muscular Atrophy, with specified flat dosing and age ranges. The independent claims share the core inventive framework of the route and the therapeutic construct, while differing in the defined pediatric age ranges.
Cerebrospinal fluid administration of scAAV9 encoding SMN1 via specified CSF routes
Administering by injection into the cerebrospinal fluid to the human subject via an intracerebroventricular, intrathecal cisternal, or intrathecal lumbar route an effective amount of a scAAV9 encoding a therapeutic protein, wherein the therapeutic protein is SMN1.
Flat dose of scAAV9 at about 1.2×10^14 GC
Administering an effective amount of a scAAV9 encoding a therapeutic protein at a flat dose of about 1.2×10^14 GC.
Treating Spinal Muscular Atrophy in children 3 to 12 years old
Treating the CNS disorder wherein the CNS disorder is Spinal Muscular Atrophy and the human subject is 3 to 12 years old, thereby treating the CNS disorder and alleviating a symptom of the CNS disorder in the human subject.
Treating Spinal Muscular Atrophy in children 9 to 36 months old
Treating the CNS disorder wherein the CNS disorder is Spinal Muscular Atrophy and the human subject is 9 to 36 months old, thereby treating the CNS disorder and alleviating a symptom of the CNS disorder in the human subject.
Across the two independent claims, the shared inventive concept is CSF injection of scAAV9 encoding SMN1 using intracerebroventricular, intrathecal cisternal, or intrathecal lumbar routes at a flat dose of about 1.2×10^14 GC, with Spinal Muscular Atrophy treatment and symptom alleviation. The independent claims distinguish patient eligibility by defining two different pediatric age ranges.
Stated Advantages
Treating the CNS disorder and alleviating a symptom of the CNS disorder in the human subject.
Reducing the risk of encephalitis in the subject.
Documented Applications
Use of CSF delivery of scAAV9 and comparison with ssAAV9 to support CNS transduction behavior, including targeting of hippocampus, cerebellum, and cerebral cortex.
Treatment application described for Spinal Muscular Atrophy in human subjects, with transduction of brain region cells described for hippocampus, cerebellum, and cerebral cortex.
Use of immunosuppressive co-administration as disclosed to mitigate risks associated with astrocytosis and encephalitis.
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