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Slow intraventricular delivery

Inactive Publication Date: 2009-05-14
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]According to the invention a patient can be treated who has a lysosomal storage disease which is caused by an enzyme deficiency which leads to accumulation of the enzyme's substrate. The enzyme is administered to the patient via intraventricular delivery to the brain. The rate of administration is such that the administration of a single dose consumes more than four hours. Substrate levels in said brain are thereby reduced.

Problems solved by technology

A major challenge to treating LSD (as opposed to treating a liver-specific enzymopathy) is the need to reverse lysosomal storage pathology in multiple separate tissues.
Furthermore, attempts to introduce a replacement enzyme into the brain by direct injection have been limited in part due to enzyme cytotoxicity at high local concentrations and limited parenchymal diffusion rates in the brain (Partridge, Peptide Drug Delivery to the Brain, Raven Press, 1991).

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Animal Model

[0055]ASMKO mice are an accepted model of types A and B Niemann-Pick disease (Horinouchi et al. (1995) Nat. Genetics, 10:288-293; Jin et al. (2002) J. Clin. Invest., 109:1183-1191; and Otterbach (1995) Cell, 81:1053-1061). Niemann-Pick disease (NPD) is classified as a lysosomal storage disease and is an inherited neurometabolic disorder characterized by a genetic deficiency in acid sphingomyelinase (ASM; sphingomyelin cholinephosphohydrolase, EC 3.1.3.12). The lack of functional ASM protein results in the accumulation of sphingomyelin substrate within the lysosomes of neurons and glia throughout the brain. This leads to the formation of large numbers of distended lysosomes in the perikaryon, which are a hallmark feature and the primary cellular phenotype of type A NPD. The presence of distended lysosomes correlates with the loss of normal cellular function and a progressive neurodegenerative course that leads to death of the affected individual in early childhood (The Me...

example 2

“Intraventricular Infusion of rhASM in the ASMKO Mouse II”

[0056]Goal: To determine what effect intraventricular infusion of rhASM has on storage pathology (i.e., sphingomyelin and cholesterol storage) in the ASMKO mouse brain

[0057]Methods: ASMKO mice were stereotaxically implanted with an indwelling guide cannula between 12 and 13 weeks of age. At 14 weeks of age mice were infused with 0.250 mg of hASM (n=5) over a 24 h period (˜0.01 mg / h) for four straight days (1 mg total was administered) using an infusion probe (fits inside the guide cannula) which is connected to a pump. Lyophilized hASM was dissolved in artificial cerebral spinal fluid (aCSF) prior to infusion. Mice were sacrificed 3 days post infusion. At sacrifice mice were overdosed with euthasol (>150 mg / kg) and then perfused with PBS or 4% parformaldehyde. Brain, liver, lung and spleen were removed and analyzed for sphingomyelin (SPM) levels. Brain tissue was divided into 5 sections before SPM analysis (S1=front of brain,...

example 3

“Intraventricular Delivery of hASM in ASMKO Mice III”

[0059]Goal: to determine lowest efficacious dose over a 6 h infusion period.

[0060]Methods: ASMKO mice were stereotaxically implanted with an indwelling guide cannula between 12 and 13 weeks of age. At 14 weeks of age mice were infused over a 6 period at one of the following doses of hASM: 10 mg / kg (0.250 mg; n=12), 3 mg / kg (0.075 mg; n=7), 1 mg / kg (0.025 mg; n=7), 0.3 mg / kg (0.0075 mg; n=7), or aCSF (artificial cerebral spinal fluid; n=7). Two mice from each dose level were perfused with 4% parformaldehyde immediately following the 6 h infusion to assess enzyme distribution in the brain (blood was also collected from these to determine serum hASM levels). The remaining mice from each group were sacrificed 1 week post infusion. Brain, liver, and lung tissue from these mice was analyzed for SPM levels as in study 05-0208.

TABLE 3GroupTreatmentnASMKO0.250 mg(10 mg / kg)12ASMKO0.075 mg(3 mg / kg)7ASMKO0.025 mg(1 mg / kg)7ASMKO0.0075 mg(.3 mg...

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Abstract

Neurological diseases, including lysosomal storage diseases, can be successfully treated using intraventricular delivery of the therapeutic agents to bypass the blood-brain barrier. Similarly, diagnostic agents and anesthetic agents can be delivered to the brain in this manner. The administration can be performed slowly to achieve maximum effect. Such administration permits greater penetration of distal portions of the brain.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of PCT Application No. PCT / US2007 / 03382, filed Feb. 8, 2007, which claims priority under 35 U.S.C. § 119 (e) to U.S. Provisional Application Ser. No. 60 / 771,451 filed Feb. 9, 2006 the contents of which are hereby incorporated by reference into the present disclosure in their entirety.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to delivery of agents to the brain. In particular it relates to brain diagnosis, treatment, and imaging.[0003]A group of metabolic disorders known as lysosomal storage diseases (LSD) includes over forty genetic disorders, many of which involve genetic defects in various lysosomal hydrolases. Representative lysosomal storage diseases and the associated defective enzymes are listed in Table 1.TABLE 1Lysosomal storage diseaseDefective enzymeAspartylglucosaminuriaAspartylglucosaminidaseFabry.alpha.-Galactosidase AInfantile Batten Disease*(CNL1)Palmitoyl Protein Thio...

Claims

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Application Information

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IPC IPC(8): A61K38/43A61P43/00
CPCA61K31/00A61K9/0024A61P1/16A61P11/00A61P13/12A61P23/00A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P3/00A61P3/08A61P43/00A61P3/10A61K9/0085C12N9/16C12N15/86C12N2750/14143
Inventor DODGE, JAMESPASSINI, MARCO A.SHIHABUDDIN, LAMYACHENG, SENG H.
Owner GENZYME CORP
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