Compositions and methods using reelin in alzheimer's disease

A composition comprising a reelin protein or a nucleic acid encoding a reelin protein, preferably wherein the reelin protein comprises a H3447R or H3447K mutation and/or a R3454A mutation, optionally H3447R or H3447K in combination with an R3454A mutation.

(canceled)

A composition comprising or consisting of a reelin C-terminal region (CTR), and optionally a carrier, preferably wherein the CTR comprises a H3447R or H3447K mutation and/or a R3454A mutation, optionally H3447R or H3447K in combination with an R3454A mutation, optionally comprising or consisting of a sequence as shown in Table 1.

A method of treating or preventing a neurodegenerative disease in a subject, the method comprising administering to the subject an effective amount of an agent that reduces methylation of the RELN promoter in an amount sufficient to increase RELN expression in the subject, wherein the agent that reduces methylation promoter is:

• (i) a fusion protein comprising a catalytically inactive CRISPR/Cas protein fused to a demethylation domain, and a guide RNA directing the fusion protein to demethylate a cytosine in the RELN promoter, optionally administered as a RNP;
• or
• (ii) a nucleic acid encoding a fusion protein comprising a catalytically inactive CRISPR/Cas protein fused to a demethylation domain, and a guide RNA directing the fusion protein to demethylate a cytosine in the RELN promoter, optionally administered as mRNA or in one or more vectors, optionally viral vectors, optionally adeno associated viral AAV vectors.

A method of treating or preventing a neurodegenerative disease in a subject, the method comprising administering to the subject an effective amount of:

• (i) a CRISPR/Cas protein, a guide RNA directing the Cas protein to the region of a RELN allele comprising H3447 or R3454, and an ssODN comprising a sequence comprising a H3447R or H3447K mutation and/or a R3454A mutation, optionally one or more ssODNs comprising a sequence comprising a H3447R or H3447K in combination with an R3454A mutation, for insertion into the RELN allele, optionally administered as a RNP;
• or
• (ii) a nucleic acid encoding a CRISPR/Cas protein, a guide RNA directing the Cas protein to the region of a RELN allele comprising a H3447, and an ssODN comprising a sequence comprising a H3447R or H3447K mutation and/or a R3454A mutation, optionally H3447R or H3447K in combination with an R3454A mutation for insertion into the RELN allele, optionally administered as naked DNA or mRNA and/or in one or more vectors, optionally viral vectors, optionally adeno associated viral AAV vectors.

A method to assess risk of developing Alzheimer's Disease in a subject, the method comprising determining the presence or absence of an H3447R variant allele in a RELN gene of the subject, wherein the presence of the H3447 variant indicates that the subject has a reduced risk of developing AD as compared to a subject who does not have the H3447R variant.