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Gene therapy for neurodegenerative disorders

Inactive Publication Date: 2013-10-31
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about using recombinant viruses to deliver genes to the central nervous system (CNS) and treat neurodegenerative diseases, such as spinal muscular atrophy (SMA). The invention is based on the discovery that both conventional recombinant AAV (rAAV) virions and self-complementary AAV (scAAV) vectors can successfully deliver genes to the CNS and show promise in treating neuropathologies. The invention provides a highly desirable method for treating a variety of neurodegenerative disorders, including SMA. The invention also provides a recombinant AAV virion comprising an scAAV vector, as well as a pharmaceutical composition and a method of administering it to a subject with a motor neuron disorder.

Problems solved by technology

The lack of SMN results in motor neuron degeneration in the ventral (anterior) horn of the spinal cord, which leads to weakness of the proximal muscles responsible for crawling, walking, neck control and swallowing, and the involuntary muscles that control breathing and coughing (Sumner C. J., NeuroRx (2006) 3:235-245).
Currently, there are no effective therapies for SMA.
However, while modulating SMN2 in vitro increased SMN levels and reconstituted nuclear gems in SMA cell lines, efficacy studies with small molecule drugs have not translated to measurable improvements in the clinic (Oskoui et al., Nerotherapeutics (2008) 5:499-506).

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Significant Increase in Survival with Treatment Using AAV-Mediated SMN1 Delivery

[0192]SMA mice on postnatal day 0 (P0) were injected intracerebroventricularly with AAV-hSMN1 into both cerebral lateral ventricles and by direct spinal cord injection into the upper lumbar spinal cord for a total dose of 5.0 e10 genome copies per mouse. Treated and untreated SMA mice were randomly separated into either a survival cohort in which all the mice were left undisturbed and sacrificed at a humane end point, or into an age-matched cohort in which all the mice were sacrificed at 16 days for age-matched comparisons with end-stage untreated SMA mice.

[0193]In the survival cohort, SMA mice treated with AAV-hSMN1 showed a significant increase in median lifespan to 50 days (p<0.0001), compared to 15 days in untreated SMA controls (FIG. 1). All of the treated SMA mice were alive at 15 days, and 87.5% of the treated SMA mice were alive at 19 days compared to 0% in untreated SMA. The Kaplan-Meier curve s...

example 2

AAV-Mediated Expression of SMN in the Spinal Cord and Motor Neuron Counts

[0194]Levels of hSMN protein increased throughout the spinal cord following CNS administration of AAV-hSMN1. In AAV-treated SMA mice at 16 days, there was an approximate 34.0- and 3.6-fold increase in hSMN protein levels in the injected lumbar segment compared to untreated SMA and wild-type mice, respectively (FIG. 2A). The increase in hSMN protein expression extended into the other segments, which included a >2.0-fold increase above wild type levels in the thoracic and cervical spinal cord at 16 days (FIGS. 2B and 2C). In the second group, hSMN protein expression was sustained in AAV-treated SMA mice at 58-66 days. The injected lumbar and neighboring thoracic and cervical regions was approximately 2.5-, 2.2- and 1.2-fold higher than age-matched WT controls, respectively.

[0195]Immunostaining of tissue sections showed hSMN protein in the dorsal and ventral horns of the spinal cord in treated SMA mice at 16 and 5...

example 3

Effects of AAV Treatment on Myofiber Size, the NMJ, and Behavior

[0199]The quadriceps (proximal), gastrocnemius (distal) and intercostal (respiratory) muscles were chosen for analysis because they show marked degeneration. In untreated SMA mice at 16 days, myofibers were small and the majority of individual cells contained a cross-section area of 2 (FIG. 5A). Less than 10% of the myofibers from the untreated SMA mice contained a cross-section area of more than 200 um2. In contrast, the distribution of myofiber sizes in AAV-hSMN1 treated SMA mice was similar to wild type, and many cells possessed a cross-section area of more than 200 and more than 400 μm2 at 16 and 58-66 days, respectively (FIGS. 5A and 5B). The overall average at 16 days showed that the myofibers from treated SMA mice were more than 2-fold larger than those from untreated SMA mice (FIG. 5C). Furthermore, the average myofiber cross-section area in treated SMA mice at 58-66 days was 67%, 76%, and 82% that of wild type ...

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Abstract

Compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and / or spinal cord, are disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of PCT / US2010 / 001239 filed Apr. 27, 2010, which claims the benefit under 35 USC §119(e)(1) of U.S. Provisional Application Nos. 61 / 174 / 982, filed May 2, 2009 and 61 / 268,059, filed Jun. 8, 2009, which applications are incorporated herein by reference in their entireties.TECHNICAL FIELD[0002]The present invention relates generally to gene delivery methods. In particular, the invention relates to compositions and methods for treating disorders affecting motor function, such as motor function affected by disease or injury to the brain and / or spinal cord.DESCRIPTION OF THE INVENTION[0003]Gene therapy is an emerging treatment modality for disorders affecting the central nervous system (CNS). CNS gene therapy has been facilitated by the development of viral vectors capable of effectively infecting post-mitotic neurons. The central nervous system is made up of the spinal cord and the brain. The spinal cord condu...

Claims

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Application Information

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IPC IPC(8): C12N15/86
CPCC12N15/86A61K38/1709A61K48/005C12N2750/14143C12N2750/14171A61K31/7088A61P21/00A61P21/02A61P25/00A61K48/00C12N15/00C12N15/861C12N15/8645A61K48/0075C12N7/00C12N2750/14133A61K48/0008C07K14/4702C12N2750/14121
Inventor PASSINI, MARCO A.SHIHABUDDIN, LAMYACHENG, SENG H.
Owner GENZYME CORP
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