A pilot study of recombinant insulin-like growth factor-I in seven multiple sclerosis patients

Abstract

The purpose of this open-label, crossover study was to determine the safety and efficacy of recombinant insulin-like growth factor-I (rhIGF-I) using magnetic resonance imaging (MRI) and clinical measures of disease activity in seven multiple sclerosis (MS) patients. Monthly clinical and MRI examinations were performed during a 24-week baseline and a 24-week treatment period with rhIGF-I. The primary outcome measure was contrast enhancing lesion (CEL) frequency on treatment compared to baseline. Secondary outcome measures included clinical and MRI measures of disease activity including. white matter lesion load (WMLL), magnetization transfer ratio (MTR), TI-Hypointensity volume, cervical spine cross-sectional area and proton magnetic resonance spectroscopic (MRS) imaging for determining regional metabolite ratios. rhIGF-I (Cephalon) was administered at a dose of 50 mg subcutaneously twice a day for 6 months. rhIGF-I was safe and well tolerated with no severe adverse reactions. There was no significant difference between baseline and treatment periods for any MRI or clinical measures of disease activity. Although rhIGF-I did not alter the course of disease in this small cohort of MS patients, the drug was well tolerated. Further studies using rhIGF-I alone or in combination with other therapies may be of value because of the proposed mechanism of action of this growth factor on the oligodendrocyte and remyelination. Multiple Sclerosis (2002)8,24-29

Keywords

Key words: contrast insulin-like growth factor magnetization transfer MRI multiple sderosis proton MRS TI hypointensities white matter lesion load

Get full access to this article

View all access options for this article.

References

Lucchinetti CF

Bruck W.

Rodriguez M.

Lassmann H.

Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol1996; 6: 259-74.

Lucchinetti CF

Bruck W.

Parisi , J.

Scheithauer, B.

Rodriguez M.

Lassmann H.

A quantitative analysis of oligodendrocytes in multiple sclerosis lesions

Brain1999; 122: 2279-95.

Zhao GJ

Koopmans RA

Li DK

Bedell L.

, Paty DW Effect of interferon beta-1b in MS: assessment of annual accumulation of PD/T2 activity on MRI. UBC MS/MRI Analysis Group and the MS Study Group . Neurology2000; 54: 200-206.

Paty DW

Li DK

Interferon beta-1b is effective in relapsingremitting multiple sclerosis: II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group [see comments]. Neurology199343: 662-67.

Li DK

Paty DW

Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-betala in relapsing-remitting multiple sclerosis. Prevention of relapses and disability by interferon-betala subcutaneously in multiple sclerosis. Ann Neurol1999; 46: 197-206.

Jacobs LD

Cookfair DL

Rudick RA

, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) [see comments]. Ann Neurol1996 ; 39: 285-94 [published erratum appears in Ann Neurol 1996 Sep; 40: 480].

Simon JH

Jacobs LD

Campion M.

, et al. Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol1998; 43: 79-87.

Johnson KP

Brooks BR

Cohen JA

, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology1995; 45: 1268-76.

Webster HD

Growth factors and myelin regeneration in multiple sclerosis. Mult Scler1997; 3: 113-20.

10.

McMorris FA

McKinnon RD

Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain Pathol1996; 6: 313-29.

11.

Li W.

Quigley L.

Yao DL

, et al. Chronic relapsing experimental autoimmune encephalomyelitis: effects of insulin-like growth factor-I treatment on clinical deficits, lesion severity, glial responses, and blood brain barrier defects. J Neuropathol Exp Neurol1998; 57: 426-38.

12.

Lovett-Racke AE

Bittner P.

Cross AH

Carlino JA

Racke MK

Regulation of experimental autoimmune encephalomyelitis with insulin-like growth factor (IGF-1) and IGF-1/IGFbinding protein-3 complex (IGF-1/IGFBP3). J Clin Invest1998; 101: 1797-1804.

13.

Liu X.

Linnington C.

Webster HD

, et al. Insulin-like growth factor-I treatment reduces immune cell responses in acute non-demyelinative experimental autoimmune encephalomyelitis. J Neurosci Res1997; 47: 531-38.

14.

Yao DL

Liu X.

Hudson LD

Webster HD

Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis . Proc Natl Acad Sci USA1995; 92: 6190-94.

15.

Yao DL

Liu X.

Hudson LD

Webster HD

Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. Life Sci1996; 58: 1301-1306.

16.

Liu X.

Yao DL

Webster H.

Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis . Mult Scler1995; 1: 2-9.

17.

Lai EC

Linnington C.

Webster HD

, et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF Study Group. Neurology1997; 49: 1621-30.

18.

Borasio GD

Robberecht W.

Leigh PN

, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology1998; 51: 583-86.

19.

Holly JM

Gunnell DJ

Davey Smith G.

Growth hormone, IGF-I and cancer. Less intervention to avoid cancer? More intervention to prevent cancer?

J Endocrinol1999; 162: 321-30.

20.

Grimberg A.

Cohen P.

Growth hormone and prostate cancer: guilty by association?

J Endocrinol Invest1999; 22: 64-73.

21.

Ellis MJ

Jenkins S.

Hanfelt J.

, et al. Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat1998; 52: 175-84.

22.

Richert ND

Ostuni JL

Bash CN

Duyn JH

McFarland HF

Frank JA

Serial whole-brain magnetization transfer imaging in patients with relapsing-remitting multiple sclerosis at baseline and during treatment with interferon beta-1b . Am J Neuroradiol1998 ; 19: 1705-13.

23.

Duyn JH

Gillen J.

Sobering G.

van Zijl PC

Moonen CT

Multisection proton MR spectroscopic imaging of the brain. Radiology1993; 188: 277-82.

24.

DeCarli C.

Maisog J.

Murphy DG

Teichberg D.

Rapoport SI

Horwitz B.

Method for quantification of brain, ventricular, and subarachnoid CSF volumes from MR images. J Comput Assist Tomogr1992 ; 16: 274-84.

25.

Ostuni JL

Levin RL

Frank JA

DeCarli C.

Correspondence of closest gradient voxels—a robust registration algorithm . J Magn Reson Imaging1997; 7: 410-15.

26.

McFarland HF

Frank JA

Albert PS

, et al. Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis . Ann Neurol1992; 32: 758-66.