Kordower, JH and Olanow, CW. Regulatable promoters and gene therapy for Parkinson's disease: is the only thing to fear, fear itself? Exp Neurol 209: 34-40
ABSTRACT Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research.
- SourceAvailable from: Qingjun Huang
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- "Alzheimer's disease and many other multifactorial cognitive or neurological disorders are rapidly growing public health concerns with potentially devastating effects  . Although numerous studies have described either the etiology of these diseases or compounds that protect neurons, an effective therapy is yet to be developed  . "
ABSTRACT: Learning and memory requires energy-demanding cellular processes and can be enhanced when the brain is supplemented with metabolic substrates. In this study, we found that neuroglial cell metabolic activity was significantly elevated when cultured in the presence of polyhydroxybutyrate (PHB) degradation product 3-hydroxybutyrate (3-HB) and derivatives. We demonstrated that the receptor for 3-HB, namely, protein upregulated in macrophages by IFN-gamma (PUMA-G), was expressed in brain and upregulated in mice treated with 3-hydroxybutyrate methyl ester (3-HBME). We also affirmed increased expression of connexin 36 protein and phosphorylated ERK2 (extracellular signal-regulated kinase 2) in brain tissues following 3-HBME treatment, although these differences were not statistically significant. Mice treated with 3-HBME performed significantly (p<0.05) better in the Morris water maze than either the negative controls (no treatment) or positive controls (acetyl-l-carnitine treatment). Moreover, we found that 3-HBME enhanced gap junctional intercellular communication between neurons. Thus, 3-HB and derivatives enhance learning and memory, possibly through a signaling pathway requiring PUMA-G that increases protein synthesis and gap junctional intercellular communication.Biomaterials 12/2008; 30(8):1532-41. DOI:10.1016/j.biomaterials.2008.12.012 · 8.31 Impact Factor