Drugs and therapies

There is currently no treatment available for any of the symptoms for BHD syndrome. However, more clinical research and a better understanding of the basic biology will facilitate development of drugs and other therapies to treat, and eventually cure, BHD syndrome.

For example, screening drug libraries could identify novel therapeutic compounds. Additionally, candidate drugs, already known to target a relevant pathway (e.g. mTOR signalling) or a phenotypically similar disorder (e.g. TSC or VHL), could be tested. If FDA approved drugs proved effective in the treatment of BHD they could be rapidly repurposed. Indeed, the antibiotic mithramycin can inhibit the growth of FLCN-null cells and might, therefore, prove to be an effective treatment for BHD-associated RCC (Lu et al., 2011). Additionally, work from the same lab showed that RNAi knock down of Slingshot2 (SSH2) lead to the activation of apoptosis genes Caspase 3 and Caspase 7 and decreased cell viability in FLCN-null cells, but not FLCN-expressing isogenic cells, suggesting that therapies targeting SSH2 activity might also prove to be an effective treatment for these cancers (Lu et al., 2013). Similarly, combined autophagy inhibition and Paclitaxel treatment promoted apoptosis specifically in FLCN-null cells, but not FLCN-expressing cells (Zhang et al., 2013).

The NIH recently announced a new clinical trial (NCT02504892) for the mTOR inhibitor everolimus in BHD patients with RCC. Everolimus is an approved treatment for sporadic metastatic RCC but has not been specifically trialled in BHD-associated and sporadic chromophobe RCC.

Gene and stem cell therapy hold much promise in the treatment of a wide variety of disorders. Early experiments show that FLCN function can be successfully reinstated in FLCN-null cells (Wong and Harbottle, 2013), meaning that in the future it may be possible to re-introduce a functional copy of the FLCN gene into FLCN-null or -heterozygous cells, either preventatively or curatively. However, these technologies are still developing, and currently there is only one FDA-approved gene therapy and only one FDA-approved stem cell treatment – Glybera to treat lipoprotein lipase deficiency and  cord blood stem cell transplant to treat blood disorders and cancers – available, although a number of both types of treatment are currently undergoing clinical trial.