We may be on the cusp

We may be on the cusp of potential breakthroughs in lipid-targeted treatment of AMD. Genome wide association studies (GWAS) of AMD patients have demonstrated polymorphisms in multiple genes involved in cholesterol homeostasis (). Some examples are ATP-binding cassette transporter member 1 (ABCA1), which plays a key role in RCT, and genes such as hepatic lipase (LIPC) and cholesteryl ester transfer protein (CETP), which are involved in regulating HDL. Of interest, polymorphisms identified through GWAS suggest that lipid regulation and deposition in the eye is complex and may require targeted strategies beyond modulation of a single lipid class. Such strategies may include microRNA (miR) silencing approaches that target specific miRs, such as miR33, to regulate cholesterol synthesis and RCT; Liver X receptor (LXR) agonists to enhance RCT; and CETP modulators to alter serum HDL and particle size (). These novel treatment approaches may synergize with other existing strategies such as statins to reduce cholesterol synthesis. Given the complexity of cholesterol homeostasis, each of these pathways will need careful investigation for efficacy and safety in animal models and randomized clinical trials that are adequately powered to probe these associations. Individualized therapy may be required depending on the pathways affected in each individual. It is biologically plausible that different pathways lead to drusen formation even though the ultimate phenotype is similar. If successful, this approach will usher in a new era in AMD therapy where disease can be targeted at an earlier stage. Acknowledgments The author would like to acknowledge Jonathan B. Lin for help with the illustration. This work was supported by NIH Grants R01EY019287, P30EY02687 (Vision Core Grant); the Carl Marshall Reeves and Mildred Almen Reeves Foundation; Research to Prevent Blindness; the Lacy Foundation; the American Federation for Aging Research; the Schulak Family Gift Fund for Retinal Research; the Jeffrey Fort Innovation Fund; and the Robert Machemer Foundation.
In an elegantly written paper, Haahr and colleagues from Odense, Denmark, document the first phase 1 trial using autologous adipose-derived regenerative GS-7340 fumarate in patients with erectile dysfunction following radical prostatectomy. These results have long been awaited. In 2010, Tom Lue\'s group at UCSF published the first preclinical data on adipose tissue derived stem cell treatment in a rat model of cavernous nerve neuropraxia (a model that accurately and efficiently represents the pathophysiology of erectile dysfunction following nerve-sparing radical prostatectomy) (). Now six years later, the first clinical trial studying injection of regenerative cells derived from adipose tissue is published in EBioMedicine (). The advent of the first clinical data forces us as a scientific community to contemplate on whether or not we are ready for clinical translation of stem cell therapy for a non-lethal disease. Safety The trial described is a phase 1 trial, indicating that the primary goal of the project was to evaluate the safety of (in this case) intracavernous injection of autologous unexpanded processed lipo-aspirate, which also has been named adipose stromal vascular fraction (SVF), or as the authors propose, adipose-derived regenerative cells. These cells where harvested using the automated processing Celution® 800/CRS system (Cytori Therapeutics, San Diego, California, USA). Since the harvesting, processing and injection are typically done in one session, it is of capital importance that we gain insight into the contents of the resulting product. The authors clearly showed that the number of injected cells is a direct derivative of the volume of the lipo-aspirate. Furthermore, they show that the age of the patient has no significant influence on the number of cells per gram of adipose tissue in the final processed product. Whether the regenerative capacity of the cellular lysate is impaired with increasing age remains to be elucidated. The composition of the cellular mixture was thoroughly investigated and it was shown that 1.5 (±SD: 0.8)% of the cells where fibroblastoid colony forming units, a subset of which probably represents true mesenchymal stem cells. The authors state that 26% are stromal cells and the markers that are used to define stromal cells in the stromal vascular fraction cells are indeed compliant with the criteria set forth in a position paper by Bourin et al. on behalf of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT) (Bourin et al., 2013). However the true stem cell population within can only be identified by additional criteria including plastic adherence, the ability to differentiate into adipocytes, osteocytes and chondrocytes and a subset of surface markers that is different from those used in the current study. However, the benefits of direct processing possibly outweigh the risks of contamination and possible dedifferentiation of autologous cell cultures. The most important fact is that an overview was given on the contents of the final injected product. The number of cells ranged between 8.4 and 37.2 million cells and is therefore quite variable from patient to patient. The variability in cell number administered would no doubt have direct effects on the clinical outcome. The optimal concentration must be determined in later efficacy studies, and preliminary analyses of the correlation between concentration of cellular lysate, safety, as well as erection recovery were not presented by the authors.