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Enhanced delivery of viral particles to the striatum and cortex

a technology of viral particles and striatum, which is applied in the direction of viruses/bacteriophages, genetic material ingredients, drug compositions, etc., can solve the problems of affecting the effectiveness of aav vector distribution, affecting the effective treatment of neurologic disorders, and simple injections, etc., to increase the safety and efficacy of ced a reflux-resistant cannula, improve the safety and efficacy, and improve the safety. the effect of the

Inactive Publication Date: 2019-04-18
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for delivering a recombinant adeno-associated viral (rAAV) particle to the central nervous system of a mammal for the treatment of neurological disorders. The rAAV particle is administered to the striatum, which is involved in many neurological disorders such as Parkinson's disease and epilepsy. The method involves delivering the rAAV particle to the putamen and caudate nucleus of the striatum. The rAAV particle can be engineered to express a heterologous nucleic acid that is important for the treatment of these disorders. The invention provides an improved procedure for achieving widespread expression of the rAAV vector in the cortex and striatum. The rAAV particle can be administered to at least one site in the caudate nucleus and two sites in the putamen, with a ratio of rAAV particles administered to the putamen to rAAV particles administered to the caudate nucleus of at least 2:1. The rAAV particle can undergo retrograde or anterograde transport in the cerebral cortex, and the heterologous nucleic acid can be expressed in various brain regions such as the frontal cortex, occipital cortex, and thalamus. The method is safe and effective for treating neurological disorders.

Problems solved by technology

Effective treatment of neurologic disorders has been hindered by problems associated with the delivery of AAV vectors to affected cell populations.
This delivery issue has been especially problematic for disorders involving the cerebral cortex.
Simple injections do not distribute AAV vectors effectively, relying on diffusion, which is effective only within a 1- to 3-mm radius.

Method used

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  • Enhanced delivery of viral particles to the striatum and cortex
  • Enhanced delivery of viral particles to the striatum and cortex
  • Enhanced delivery of viral particles to the striatum and cortex

Examples

Experimental program
Comparison scheme
Effect test

example 1

d GFP Expression after Intrastriatal AAV1 Vector Delivery

[0201]The ability of AAV1 to efficiently target both striatal and cortical structures in the Rhesus monkey brain when delivered via convection-enhanced delivery (CED) was evaluated. AAV vectors containing GFP cDNA under the control of cytomegalovirus enhancer / chicken beta-actin (CBA) promoter were infused into the caudate and putamen of 9 adult male Rhesus monkeys using CED (see, e.g., Bankiewicz et al., (2000) Exp. Neurol. 164:2-14 and WO 2010 / 088560).

[0202]Methods

Surgical Delivery

[0203]Nine adult male Rhesus macaques (Macaca mulatta; 8.9-11.9 kg) were included in this study. All animals received an infusion of AAV vector bilaterally into caudate nucleus and putamen by means of MRI-guided CED (Richardson, R. M. et al. (2011) Neurosurgery 69:154-163; Richardson, R. M. et al. (2011) Stereotact. Funct. Neurosurg. 89:141-151; Richardson, R. M. et al. (2011)Mol. Ther. 19:1048-1057). Immediately prior to surgery, animals were anest...

example 2

d GFP Expression after Intrastriatal AAV2 Vector Delivery

[0238]The ability of AAV2 to efficiently target both striatal and cortical structures in the Rhesus monkey brain when delivered via convection-enhanced delivery (CED) was evaluated. AAV vectors containing GFP cDNA under the control of cytomegalovirus enhancer / chicken beta-actin (CBA) promoter were infused into the caudate and putamen of 8 adult Rhesus monkeys using CED according to the methods described in Example 1 above.

[0239]Infusion of AAV2 into the striatum by CED resulted in GFP expression in the injected regions (caudate and putamen) (FIG. 4C), substantia nigra (FIG. 4D), and a large number of cortical regions of the Rhesus monkey brain (FIGS. 4A-D). Expression of GFP in the striatum of AAV2 injected animals appeared slightly more restricted and localized when compared to striatal coverage with AAV1 vectors. The expression of GFP within the NHP striatum was comprehensive but relatively contained within the gray matter b...

example 3

lity of GFP Expression after Intrastriatal AAV1 and AAV2 Vectors Made by Triple Transfection or Producer Cell Line Process

[0240]To date the majority of preclinical studies utilize AAV vectors made by Triple Transfection followed by purification using cesium chloride gradients or column chromatography. Thus, to evaluate the impact of vector production on biodistribution in vivo, two methods of vector production Triple Transfection (TT) or Producer Cell line (PCL), were compared. AAV1 and AAV2 vectors generated by these two different manufacturing platforms were administered via CED, and their distribution within the Rhesus monkey brain was compared.

[0241]Infusion of AAV1-GFP vectors made by triple transfection yielded equivalent GFP distribution and coverage when compared to AAV1-GFP vectors made by the producer cell line process. GFP distribution was comparable between AAV1-GFP (TT) (FIGS. 5C&D) and AAV1-GFP (PCL) (FIGS. 5A&B) vectors 30 days following injection into the striatum of...

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Abstract

Provided herein are novel methods for delivering recombinant adeno-associated viral (rAAV) particles to the central nervous system of a mammal (e.g., a human). In aspects, the methods involve administering rAAV particles containing a heterologous nucleic acid to the striatum and causing expression of the heterologous nucleic acid in at least the cerebral cortex and the striatum of the mammal.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a National Phase application under 35 U.S.C. § 371 of International Application No. PCT / US2016 / 017210 filed Feb. 9, 2016, which claims priority to U.S. Provisional Application No. 62 / 114,544, filed Feb. 10, 2015, and U.S. Provisional Application No. 62 / 220,997, filed Sep. 19, 2015, each of which is incorporated herein by reference in its entirety.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE[0002]The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 159792012700SeqList.txt, date recorded: Aug. 9, 2017, size: 1 KB).FIELD OF THE INVENTION[0003]The present invention relates to the delivery of AAV gene therapy vectors to the brain, e.g., the striatum and / or cortex.SUMMARY OF THE INVENTION[0004]Adeno-associated virus (AAV)-based vectors have become the preferred vector system for neurologic gene t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K9/00C12N7/00
CPCA61K48/0075A61K9/0085C12N7/00C12N2750/14143C12N15/86C12N2750/14122C12N2750/14152A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00A61K48/005
Inventor STANEK, LISA M.SHIHABUDDIN, LAMYA
Owner GENZYME CORP
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