The CRISPR/Cas9 system is a prokaryotic defense mechanism that in bacteria confers resistance to foreign DNA by recognizing and cutting specific sequences. CRISPR/Cas9 has also been used in recent research as a low-cost genome editing tool with tremendous potential. Given that CGD is a disease of a single genetic anomaly, it might be an easy target for Cas9 mediated repair. In fact, previous studies have given a proof-of-principle approach to gene therapy using CRISPR/Cas9 in induced pluripotent stem cells, showing that genotypic and phenotypic correction of CGD is possible (Flynn et al. 2015). Future avenues of research must include a delivery mechanism for CRISPR/Cas9 systems into bone marrow for correction of hematopoietic stem cells. Possible research could involve the application of micelles expressing certain bacterial or fungal lipids or antigens such that they are phagocytosed, which would allow the CRISPR/Cas9 system to enter the cell.
Prevention of granuloma formation
A component of CGD pathology is the formation of chronic granulomata. However, translational research into manipulating the underlying mechanisms of granuloma formation is lacking. Yepes et al. recently explored a combination therapy of edelfosine and praziquantel in schistosomiasis, a parasitic disease that stimulates granulomatous reactions by the immune system (Yepes et al. 2015). Praziquantel kills the schistosomes, which treats the parasitic infection. Edelfosine, however, is an oncodrug that targets the Fas5 death receptor. Edelfosine in combination showed a significant size reduction in granulomata and a downregulation of Th1, Th2 and Th17 post-infection responses (Yepes et al. 2015). This research, although seemingly unrelated to CGD, shows a drug effecting the cellular immune response that underlies granuloma development. If a drug were to be developed with a similar mechanism of action and was shown to function in CGD patients, it could be used to reduce the severity of chronic granuloma formation and prevent blockages in hollow organs.
Increasing intracellular peroxide
Thyroid hormones are synthesized in the presence of hydrogen peroxide (Ohye and Sugawara 2010). The synthesis of hydrogen peroxide occurs by the enzyme dual oxidase 2 (DUOX2). The DUOX family is closely related to the NADPH oxidases but is expressed exclusively in the thyroid (Ohye and Sugawara 2010). The formation of superoxide by NADPH oxidase is as a precursor to hydrogen peroxide, which is converted into antimicrobial compounds by myeloperoxidase. Because CGD causes a NADPH oxidase defect that prevents superoxide production, it may be interesting to examine whether expressing DUOX2 in phagocytes would confer antimicrobial activity, since hydrogen peroxide is also a precursor to antimicrobial compounds generated during respiratory burst. If possible, the expression of DUOX2 in CGD-derived phagocytes would likely restore the ability to kill invading pathogens.