Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.
SUMMARY Forty patients presenting with first episode genital herpes were randomly allocated to seven day treatment with oral acyclovir alone, placebo alone, oral acyclovir plus co-trimoxazole, or placebo plus co-trimoxazole. Patients receiving acyclovir had significantly shorter periods of viral shedding (p<0001),pain (p=003), and times to lesion healing (p< O0O5).Averaged over all patients there was no evidence that co-trimoxazole affected any of the variables, though in women cotrimoxazole was associated with a shorter time to lesion healing (p<0-0l). Furthermore, the combination treatment gave significantly shorter times to lesion healing than acyclovir alone, placebo alone, or placebo and co-trimoxazole (p=O0O1) and good trends elsewhere (external lesions and duration of pain). Neither drug was associated with any adverse events or toxicity or influenced the subsequent recurrence rate.
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