JP-2022533451-A5 -

Dates

Publication Date

20230530

Application Date

20200521

Description

Other Embodiments Although the present invention has been described along with embodiments for carrying it out, the foregoing description is intended to be illustrative and does not limit the scope of the invention, and it is understood that the present invention is defined by the appended claims. Other embodiments, advantages, and modifications are contained in the following claims. The present invention includes the following embodiments. [1] A composition comprising a human codon-optimized polynucleotide encoding human presenilin 1 (PSEN1). [2] The composition according to [1], wherein the human codon-optimized polynucleotide encoding human PSEN1 is at least 95% identical to SEQ ID NO: 9, and at least one codon is optimized for the wild type. [3] The composition according to [1] above, wherein the human codon-optimized polynucleotide encoding human PSEN1 contains Sequence ID No. 9. [4] A composition according to any one of [1] to [3] above, comprising exosomes or lipid-based nanoparticles (LNPs) (for example, formulated using them for delivery). [5] A composition comprising a vector for expressing human PSEN1 in cells, comprising a human codon-optimized polynucleotide according to any one of [1] to [3] above, which is operably linked to a promoter. [6] The composition according to [5] above, wherein the vector is a viral vector. [7] The composition according to [6] above, wherein the viral vector is an adeno-associated virus (AAV) vector. [8] The composition according to [7] above, wherein the AAV vector is AAV9 or AAVrh10. [9] The composition according to [6] above, wherein the viral vector is a lentiviral vector or a retroviral vector. [10] The composition according to [5] above, wherein the promoter is a panneuronal promoter. [11] The composition according to [10] above, wherein the panneurial promoter is a synapsin I promoter. [12] The composition according to [5] above, wherein the promoter is a neuronal cell subtype-specific promoter. [13] The composition according to [12], wherein the neuronal cell subtype-specific promoter is the alpha-calcium/calmodulin kinase 2A promoter. [14] A method for treating a neurodegenerative disease, disorder, or condition, comprising the step of administering a composition according to any one of [1] to [13] above to a human subject in need of treatment, wherein the subject has one or more mutations in at least one allele of PSEN1, preferably mutations encoding a dominant-negative PSEN1 protein isoform. [15] The method according to [14] above, wherein the neurodegenerative disease, disorder, or condition is Alzheimer's disease. [16] The method according to [15] above, wherein the Alzheimer's disease is familial Alzheimer's disease. [17] The method according to [15] or [16] above, wherein the subject has the E280A, Y115H, L166P, C410Y, Δex9, G548, D257A, R278I, L435F, G384A or L392V mutation in the PSEN1 gene, or the N141I, G206A, H163R, A79V, S290C, A260P, A426P, A431E, R269H, L271V, C1410Y, E280G, P264L, E185D, L235V or M146V mutation in the PSEN1 gene. [18] The method according to [15] above, wherein the Alzheimer's disease is sporadic Alzheimer's disease. [19] The method according to [15] above, wherein the Alzheimer's disease is late-onset or early-onset Alzheimer's disease. [20] The method according to [14] above, wherein the neurodegenerative disease, disorder, or condition is frontotemporal dementia, memory loss, cognitive decline, or cognitive impairment. [21] The method according to [20] above, wherein the cognitive impairment is mild cognitive impairment (MCI). [22] The method according to any one of [14] to [20] above, wherein the composition is administered to the target CNS in need of treatment. [23] The method according to [22] above, wherein a polynucleotide encoding the PSEN1 and/or PSEN2 gene or mRNA is administered to the CNS by intravenous delivery, subarachnoid delivery, intracisional delivery, intraventricular delivery, or stereotactic intraparenchymal injection into a specific brain region, optionally into the cisterna magna, ventricles, or lumbar spinal cavity, or by direct injection into the hippocampus or cortical area.