Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in
the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN)
protein as a result of loss or mutation of the SMN1 gene. SMN protein is encoded by two
genes, SMN1 and SMN2, which essentially differ by an single nucleotide in exon 7. As a
result, the majority of the transcript from SMN2 lacks exon 7. According to clinical
severity, SMA was classified to three types, including type I, type II, and type III.
Drugs capable of modifying the transcription pattern of SMN2 to increase the full-length of
SMN mRNA expression and the amount of SMN protein may have therapeutic effects for SMA
patients. In order to test this hypothesis, we used EBV-transformed lymphoblastoid cell lines
derived from the different types of SMA patients to screen the effect of various drugs on
SMN2 gene expression. Hydroxyurea (HU) was found to be effective among the drugs we tested.
HU is an effective therapeutic agent for patients with thalassemia and sickle cell disease
which the toxicity is minimal and is well-tolerated and safely used in children. We had
undergone a small-scaled 33 SMA patients randomized pilot trial (HU treatment for 8 weeks and
then follow up drug-free 8 weeks) to evaluate the effect of HU in SMA patients and we got a
promising preliminary data. We found that HU could significantly increase in the manual
muscle testing scores at 4 weeks, and full-length SMN mRNA level in the 30mg/kg/day subgroup
at 8 weeks relative to baseline, and it is safe under the dose 30mg/kg/day.
In this study, we plan to enroll 60 type II and III SMA patients and conduct a single-center,
randomized, double-blind, placebo-controlled, prospective trial of two-year duration to
evaluate the efficacy and safety of HU.The primary end points are the changes in full-length
SMN expression, SMN protein, motor function and lung function in SMA patients. We also design
a safety monitoring system to investigate the adverse effects and to assure the patients'
safety. We hope we can find and prove the efficacy and safety of HU in SMA patients and set
up a evaluating model for multi-center trials in the future.
Phase:
Phase 2/Phase 3
Details
Lead Sponsor:
Kaohsiung Medical University Chung-Ho Memorial Hospital