First Causal Therapy for SMA Patients

VPA has been shown to significantly increase SMN protein levels in fibro-blast cell lines treated with drug amounts ranging from 0.5 ^M to 50 ^M (Brichta et al. 2003). VPA is an FDA-approved drug that has been used in the therapy of epilepsy for more than three decades (Zaccara et al. 1988). More recently, VPA has also gained importance as anticonvulsant in manic depression, migraine, and dementia (Papatheodorou et al. 1995; Mathew et al. 2000; Lonergan et al. 2004). Although it is known that VPA up- or downregulates about 2% of genes (Pazin and Kadonaga 1997), severe side effects are relatively rare. Based on these data, a pilot trial with VPA in

10 parents of SMA patients, each of them carrying one SMN1 and one to four SMN2 copies, has been initiated for a period of four months (VPA serum level 80 ^g/ml). In 6 of the 10 SMA parents an increase in FL-SMN2 mRNA levels of 40 to 300% was determined. Particularly significant was the increase of SMN protein levels in 7/9 carriers raising from 1.8-fold to 13.8-fold under VPA treatment (Brichta et al. 2004).

Individual experimental curative approaches in 20 patients with type I,

11 and III SMA treated with VPA (serum level 70-80 ^g/ml) revealed elevated FL-SMN2 mRNA levels in 7 patients and unchanged or even decreased levels in 13 patients. (Brichta et al. 2006). An improvement of the clinical picture after 5-6 months of treatment was observed in about 50% of the patients (Wirth, unpublished data). Some patients presented decreased L-carnitin levels which were compensated by substitution with acetyl-carnitin. Observation of patients with unchanged/decreased FL-SMN2 transcript levels underscores the need for a biomarker. However, so far we do not know if SMN expression in blood reflects SMN expression in a-motor neurons and correlates with muscle strength. Therefore, long-term clinical trials in SMA patients that correlate SMN expression in blood with individual motor function tests are required. Two large trials with VPA/L-carnitin are in progress: in type I SMA patients in Germany (, and in type II and III SMA patients in the United States (

A pilot trial with PBA in SMA patients already revealed promising results (Brahe et al. 2005). However, only phase III placebo-controlled clinical trials will provide the final proof for a potential use of HDAC inhibitors in SMA therapy.

In summary, VPA and PBA seem thus far to be promising compounds due to their excellent bioavailability, good penetration of the blood-brain barrier, and comparatively rare side effects at therapeutic doses. Clinical phase II and III trials are ongoing to ascertain whether the drugs are suitable for SMA therapy (Brahe et al. 2005; and www. However, searching for further compounds is necessary due to the fact that in rare cases VPA and PBA cause severe liver and pancreas damage, interdicting further treatment. Out of the second generation HDAC inhibitors, SAHA is already under clinical phase II investigation for cancer treatment and recently has been shown to cross the blood-brain barrier with no observation of dose-limiting toxicity (Kelly et al. 2003).

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