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ARTICLES: E. J. Sorenson, A. J. Windbank, J. N. Mandrekar, W. R. Bamlet, S. H. Appel, C. Armon, P. E. Barkhaus, P. Bosch, K. Boylan, W. S. David, E. Feldman, J. Glass, L. Gutmann, J. Katz, W. King, C. A. Luciano, L. F. McCluskey, S. Nash, D. S. Newman, R. M. Pascuzzi, E. Pioro, L. J. Sams, S. Scelsa, E. P. Simpson, S. H. Subramony, E. Tiryaki, and C. A. Thornton Subcutaneous IGF-1 is not beneficial in 2-year ALS trial Neurology 2008; 71: 1770-1775 [Abstract] [Full text] [PDF]

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Subcutaneous IGF-1 is not beneficial in 2-year ALS trial

Charles L. Howe, Rachel A. Bergstrom, Bruce F. Horazdovsky   (23 February 2009)

Reply from the authors

Eric J. Sorenson, AJ Windbank,JN Mandrekar,WR Bamlet,SH Appel,C Armon,PE Barkhaus,P Bosch,K Boylan,WS David,E Feldman,J Glass,L Gutmann,J Katz,W King,CA Luciano,LF McCluskey,S Nash,DS Newman,RM Pascuzzi,E Pioro,LJ Sams,S Scelsa,EP Simpson,SH Subramony,E Tiryaki,CA Thornton   (23 February 2009)

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial 23 February 2009
Charles L. Howe, Mayo Clinic College of Medicine 200 First St SW, Rochester, MN 55905, Rachel A. Bergstrom, Bruce F. Horazdovsky Send Correspondence to journal: Re: Subcutaneous IGF-1 is not beneficial in 2-year ALS trial howe.charles{at}mayo.edu Charles L. Howe, et al.	We congratulate Sorenson et al. for their well-executed IGF-1 trial in ALS patients. [1] While the title appropriately reflects the subcutaneous mode of IGF-1 delivery, the paper fails to distinguish this critical limitation. What is the bioavailability in CSF and brain parenchyma in humans treated twice daily with 0.05 mg/kg IGF-1? Animal studies indicate that subcutaneous delivery of ~0.8 mg/kg IGF-1 results in a maximal CSF concentration of 3 ng/mL IGF-1 at 2-hr post-injection. [2] This equates to 0.4 nM IGF-1 in CSF at peak. The Sorenson et al. trial dose was 16-fold lower, suggesting that the maximal CSF concentration in patients would be 0.025 nM. The Kd of the IGF-1 receptor is 0.15 nM. [3] Therefore, at 0.025 nM, only 14% of high affinity and less than 1% of low affinity receptors will be occupied. Likewise, the concentration of IGF-1 in CSF overestimates the bioavailable concentration within the brain parenchyma. IGF-1 injected into the lateral ventricle of rats exhibits a half-life of only 12 minutes in the CSF and penetrates no further than 2 mm into the periventricular parenchyma. [4] Extending this to the calculations above, it is likely that less than 2 pM IGF-1 could be achieved within 1-2 mm of the ventricle. Since this concentration gives no more than 1% of high affinity receptor occupancy, and since the majority of target neurons are located a centimeter or more from the ventricles and central canal, the concept of peripheral delivery of tolerable levels of IGF-1 is predestined to fail therapeutically. In addition, peripheral delivery of IGF-1 is known to upregulate circulating levels of IGF binding proteins that sequester IGF-1. This may effectively nullify the therapy, especially over the course of two years. ALS patients and controls exhibit 0.8-0.95 nM IGF-1 [5], or approximately 36 times more endogenous IGF-1 in the CSF than is likely derived from peripheral delivery, suggesting that subcutaneous delivery is biologically irrelevant. Until we adopt a new paradigm for safely providing growth factors to neurons under spatial and temporal control and at physiologically relevant levels, it is premature to conclude, as Sorenson and colleagues did, that “insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis”. [1] References 1. Sorenson EJ, Windebank AJ, Mandrekar JN, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770-1775. 2. Armstrong CS, Wuarin L, Ishii DN. Uptake of circulating insulin-like growth factor-I into the cerebrospinal fluid of normal and diabetic rats and normalization of IGF-II mRNA content in diabetic rat brain. J Neurosci Res 2000;59:649-660. 3. Masters BA, Raizada MK. Insulin-like growth factor I receptors and IGF-I actions in neuronal cultures from the brain. Ann N Y Acad Sci 1993;692:89-101. 4. Nagaraja TN, Patel P, Gorski M, Gorevic PD, Patlak CS, Fenstermacher JD. In normal rat, intraventricularly administered insulin-like growth factor-1 is rapidly cleared from CSF with limited distribution into brain. Cerebrospinal Fluid Res 2005;2:5. 5. Bilic E, Bilic E, Rudan I, et al. Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol 2006;13:1340-1345. Disclosure: The authors report no disclosures.
Reply from the authors 23 February 2009
Eric J. Sorenson, Mayo Clinic Department of Neurology, Rochester, MN 55905, AJ Windbank,JN Mandrekar,WR Bamlet,SH Appel,C Armon,PE Barkhaus,P Bosch,K Boylan,WS David,E Feldman,J Glass,L Gutmann,J Katz,W King,CA Luciano,LF McCluskey,S Nash,DS Newman,RM Pascuzzi,E Pioro,LJ Sams,S Scelsa,EP Simpson,SH Subramony,E Tiryaki,CA Thornton Send Correspondence to journal: Re: Reply from the authors sorenson.eric{at}mayo.edu Eric J. Sorenson, et al.	We thank Dr. Howe for his correspondence and agree with his comments. The effectiveness of subcutaneously administered neurotrophic factors—including IGF-1 on the CNS—is still unclear. As Dr. Howe states, there are limitations in administering these agents subcutaneously. There have been many trials in which neurotrophic factors given subcutaneously had no beneficial effect. [6-11] We agree with Dr. Howe that novel delivery mechanisms need to be developed if a sustained affect on the CNS is anticipated. This need has been recognized by many researchers and now a number of delivery systems are being developed. Unfortunately, none have succeeded in providing an effective delivery platform for human studies. Until Ehrlich’s “magic bullet” allows for delivery of an effective agent directly and only to the cell line or lines of interest, we are left with the limitations of present day delivery models. References 6. ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996;46:1244-1249. 7. The BDNF Study Group. A controlled trial of recombinant methionyl human BDNF in ALS: (Phase III). Neurology 1999;52:1427-1433. 8. Beghi E, Chio A, Inghilleri M et al. A randomized controlled trial of recombinant interferon beta-1a in ALS. Italian Amyotrophic Lateral Sclerosis Study Group. Neurology 2000;54:469-474. 9. 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. Neurology 1998;5:583-586. 10. Caroscio JT, Cohen JA, Zawodniak J et al. A double-blind, placebo-controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 1986;36:141-145. 11. Miller RG, Petajan JH, Bryan WW et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Annals of Neurology 1996;39:256-260. Disclosure: The authors report no disclosures.