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BEBRF Funded Research Report

Andrew Harrison, M.D.
Michael Lee, M.D.
Linda K. McLoon, Ph.D.
Department of Ophthalmology
University of Minnesota

Background: Botulinum toxin A is a safe and effective method for treating focal dystonias. Local injection causes paralysis at the neuromuscular junction, and function slowly returns over a period of 1-4 months in most individuals. Since sprouting of the paralyzed nerves is thought to be responsible for the initial return of function after botulinum toxin A treatment, we hypothesized that preventing or reducing this botulinum toxin induced sprouting would lengthen the duration of effectiveness of any given dose of botulinum toxin A. Our initial studies last year demonstrated that the sequential injection of botulinum toxin and either antibody to insulin-like growth factor (a-IGF-1R) or corticotrophin releasing factor (CRF) resulted in the prevention of sprouting in the treated orbicularis oculi muscles of adult rabbitsa. This decreased sprouting, with the concomitant slowing or prevention of the formation of new neuromuscular junctions, should result in a prolonged period of time when the focal muscle spasms are reduced. In the absence of an animal model for benign essential blepharospasm, we tested the ability of CRF and either a-IGF-R1 or CRF to maintain decreased force generation capacity in treated muscles. The ability to extend treatment effectiveness for blepharospasm and hemifacial spasm patients would decrease the number of clinic visits, increase patient quality of life, as well as decrease overall lifetime costs.

We have been testing the ability of botulinum toxin A and either co-injected CRF or a-IGF-1R to extend the functional efficacy of botulinum toxin A injections. Two of the drugs tested were CRF and a-IGF-1R. Both were shown to result in a slowing in the return of function by comparing control muscles, muscles treated with botulinum toxin A only, and muscles treated with botulinum toxin A and either a-IGF-IR or CRF. We saw a significant reduction in amount of force generated by muscles that received the double injections compared to botulinum toxin A alone at 2 weeks post injection (Fig 1). Note that the combined injection of botulinum toxin A and CRF was much more effective in maintaining muscle weakness compared to botulinum toxin A only (Fig 1 bottom). Note also that at this dose of botulinum toxin A in rabbit muscle, botulinum toxin A-treated muscles showed a variable response, with some already showing force equal to the saline-treated control muscles (hatched bars in Fig. 1 compared to white bars).

figure 1
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At the one month post-treatment interval significantly decreased force in the muscles treated with both botulinum toxin A and CRF was maintained (Fig 2). We have filed a provisional patent, which we hope will become a full patent for the combination drug treatment. We are also filing for orphan drug status for this combined treatment paradigm, and if granted by the FDA, will allow us to apply for orphan drug development funds from NIH. We will continue, assuming additional funds can be raised, to test different doses of CRF and botulinum toxin A to determine, in our animal studies, the optimum dose, as well as work to develop a human patient-approved drug combination dosage for testing in a Phase I clinical trial. As a result of this process, we have held off publishing these most recent results until after the patent is granted (or at least a decision has been made on our patent application). We believe this approach can make a substantial difference in the number of injections per year, as well as the overall lifetime exposure of patients to botulinum toxin, and we are committed to moving toward clinical testing.

figure 2
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Harrison AR, Berbos Z, Zaldivar RA, Anderson BC, Semmer M, Lee MS, McLoon LK. Modulating neuromuscular junction density changes in botulinum toxin-treated orbicularis oculi muscle. Invest Ophthalmol Vis Sci. 2011;52(2):982-986.
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Originally published in Benign Essential Blepharospasm Research Foundation Newsletter, Volume 31, Number 5, page 4 (2012)

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