# US 2019/0169246 A1 · Reelin compositions for treatment of neurological disorders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0169246 A1
- Document ID: US20190169246A1
- Status: Published application
- Kind: A1
- Application number: 16/264,896
- Filed: 2019-02-01
- Published: 2019-06-06
- Earliest claimed: 2016-08-03
- Assignees: University of South Florida
- Inventors: Edwin J. Weeber
- Web page: https://patentgrep.com/patent/US20190169246A1

## CPC

- C07K 14/473: {alpha-Glycoproteins}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 35/761: Adenovirus
- A61K 38/1709: {from mammals}
- A61K 48/0066: {Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61K 48/0083: {characterised by an aspect of the administration regime}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 14/47: from mammals
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/62: DNA sequences coding for fusion proteins
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- C07K 2319/00: Fusion polypeptide
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Changes in Reelin levels as well as Reelin signaling alter cognitive function. This can be accomplished by administering a therapeutically effective amount of a repeat fragment of Reelin, or a construct formed from fragment repeats of Reelin to a patient or subject. Changes to Reelin levels can be used to treat various neurodegenerative diseases, neuronal insults, or stroke, such as fragile X syndrome, William's syndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia, Alzheimer's disease, and schizophrenia. Reelin can also be used to alter dendritic spine density, diminished long-term potentiation, and diminished synaptic plasticity and associative learning deficits. Constructs formed from repeat region 3 of full length Reelin and repeat region 5 of full length Reelin, or repeat region 3 of full length Reelin and repeat region 6 of full length Reelin have been found particularly useful.

## Claims

### Claim 1

A method of treating a symptom of a disease or disorder of the nervous system, comprising:
administering a therapeutically effective amount of a Reelin vector comprising a recombinant Reelin fragment or Reelin splice fragment and a CMV promoter inserted into a viral vector to a patient in need thereof, wherein the disease or disorder of the nervous system is a neuronal insult or neuronal disorder.

### Claim 2 (depends on 1)

The method of claim 1, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 (SEQ ID NO. 2), Reelin fragment repeat R4 (SEQ ID NO. 3), Reelin fragment repeat RS (SEQ ID NO 4), Reelin fragment repeat R6 (SEQ ID NO. 5), Reelin fragment repeat R3 through R4 (SEQ ID NO. 6), Reelin fragment repeat R3 through R5 (SEQ ID NO 11), Reelin fragment repeat R3 through repeat region R6 (SEQ ID NO 10), Reelin fragment repeat R4 through R5 (SEQ ID NO 7), Reelin fragment repeat R5 through R6 (SEQ ID NO 8), Reelin fragment repeat R3 joined to Reelin fragment repeat R5 (SEQ ID NO 12), Reelin fragment repeat R3 joined to Reelin fragment repeat R6 (SEQ ID NO. 9), and Reelin fragment repeat R4 joined to repeat RE, or combinations thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 (SEQ ID NO. 2), Reelin fragment repeat R4 (SEQ ID NO. 3), Reelin fragment repeat R5 (SEQ ID NO 4), and Reelin fragment repeat R6 (SEQ ID NO. 5), or combinations thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 through R4 (SEQ ID NO. 6). Reelin fragment repeat R3 through R5 (SEQ ID NO 11), Reelin fragment repeat R3 through repeat region R6 (SEQ ID NO 10), Reelin fragment repeat R4 through RS (SEQ ID NO 7), Reelin fragment repeat R5 through R6 (SEQ ID NO 8), Reelin fragment repeat R3 joined to Reelin fragment repeat R5 (SEQ ID NO 12), and Reelin fragment repeat R3 joined to Reelin fragment repeat R6 (SEQ ID NO. 9), or combinations thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the neuronal disorder is selected from the group consisting of fragile X syndrome, William's syndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism, Reelin deficiency, bipolar disorder, depression, and schizophrenia.

### Claim 6 (depends on 1)

The method of claim 1, wherein the neuronal insult is traumatic brain injury.

### Claim 7 (depends on 1)

The method of claim 1, wherein the symptom of a disease or disorder of the nervous system is selected from the group consisting of a deficiency in dendritic spine density, diminished long-term potentiation, diminished synaptic plasticity and associative learning deficits.

### Claim 8 (depends on 1)

The method of claim 1, wherein the effective amount of the Reelin vector is administered to the patient intracerebrally by bilateral injection at a dose of between about 1 □L to about 2 □L of a composition of the Reelin vector for each 30 to 36 g of patient mass to obtain a concentration of Reelin in the CNS fluid of between about 10 μM to about 5 nM.

### Claim 9 (depends on 1)

The method of claim 1, wherein the viral vector is selected from the group consisting of AAV-9, AAV-5, AAV-4, and AAV-1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the viral vector is selected from the group consisting of an AAV-9 vector or an AAV-5 vector.

### Claim 11

A composition comprising, a Reelin vector comprising, a recombinant Reelin fragment or Reelin splice fragment and a CMV promoter inserted into a viral vector.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 (SEQ ID NO. 2), Reelin fragment repeat R4 (SEQ ID NO. 3), Reelin fragment repeat R5 (SEQ ID NO 4), Reelin fragment repeat R6 (SEQ ID NO. 5), Reelin fragment repeat R3 through R4 (SEQ ID NO. 6), Reelin fragment repeat R3 through R5 (SEQ ID NO 11), Reelin fragment repeat R3 through repeat region R6 (SEQ ID NO 10), Reelin fragment repeat R4 through R5 (SEQ ID NO 7), Reelin fragment repeat RS through R6 (SEQ ID NO 8), Reelin fragment repeat R3 joined to Reelin fragment repeat R5 (SEQ ID NO 12), Reelin fragment repeat R3 joined to Reelin fragment repeat R6 (SEQ ID NO. 9), Reelin fragment repeat R4 joined to repeat R6, or combinations thereof.

### Claim 13 (depends on 11)

The composition of claim 11, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 (SEQ ID NO. 2), Reelin fragment repeat R4 (SEQ ID NO. 3), Reelin fragment repeat R5 (SEQ ID NO 4), Reelin fragment repeat R6 (SEQ ID NO. 5), or combinations thereof.

### Claim 14 (depends on 11)

The composition of claim 11, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat R3 through R4 (SEQ ID NO. 6), Reelin fragment repeat R3 through R5 (SEQ ID NO 11), Reelin fragment repeat R3 through repeat region R6 (SEQ ID NO 10), Reelin fragment repeat R4 through R5 (SEQ ID NO 7), Reelin fragment repeat R5 through RE (SEQ ID NO 8), Reelin fragment repeat R3 joined to Reelin fragment repeat R5 (SEQ ID NO 12), Reelin fragment repeat R3 joined to Reelin fragment repeat RE (SEQ NO. 9), or combinations thereof.

### Claim 15 (depends on 11)

The composition of claim 11, wherein the recombinant Reelin fragment or Reelin splice fragment is selected from the group consisting of Reelin fragment repeat region R3 joined to repeat region RE (SEQ ID NO 10) or repeat region R3 joined to repeat region R5 (SEQ ID NO 12).

### Claim 16 (depends on 11)

The composition of claim 11, wherein the viral vector is selected from the group consisting of AAV-9, AAV-5, AAV-4, and AAV-1.

### Claim 17 (depends on 16)

The composition of claim 16, wherein the viral vector is selected from the group consisting of an AAV-9 vector or an AAV-5 vector.

### Claim 18 (depends on 1, 11)

The method of claim 1, further comprising administering the Reel in vector of claim 11.