It is becoming increasingly clear that some rare diseases share characteristics in terms of both symptoms and underlying pathogenesis. Birt-Hogg-Dubé (BHD) syndrome is an excellent example of this. BHD shares kidney symptoms with the cancer syndromes Von Hippel Lindau (VHL) and tuberous sclerosis complex (TSC); lung symptoms with Lymphangioleiomyomatosis (LAM); and skin symptoms with TSC and Familial Multiple Discoid Fibromas (FMDF). Overactive mTOR signalling has been implicated in all of these syndromes, and consequently mTOR inhibitors have been trialled as treatments for a number of different symptoms associated with these syndromes.
The mTOR signalling pathway is an important regulator of metabolism and homeostasis, modifying cellular function in response to nutrient availability (Laplante and Sabatini, 2012). Rapamycin (also known as Sirolimus) is made by a species of bacterium native to Easter Island, and inhibits the mTOR pathway by preventing the activation of mTORC1 (Sehgal, 2003). Sirolimus received FDA-approval in 1999 to be used as an immunosuppressant during organ transplant procedures (Sehgal, 2003). Two derivatives of Sirolimus – Everolimus and Temsirolimus – also have FDA approval.
A number of clinical trials have shown Sirolimus to be effective in the treatment of the kidney angiomyolipomas characteristic of TSC and LAM and indeed, mTOR inhibitors are now commonly used to treat non-syndromic kidney cancer (Mihaly et al., 2012). Interestingly, Sirolimus partially reverses the cystic kidney phenotype seen in a mouse model of BHD (Baba et al., 2008).
In 2011, the MILES trial showed that Sirolimus halted the progression of cyst formation in the lungs of LAM patients (McCormack et al., 2011). However, Sirolimus did not reverse the damage done to the lungs by LAM, and once patients stopped taking the drug, their disease progressed. Pre-clinical data shows that in the mouse model of LAM, combined therapy with Sirolimus and simvastatin – which is a licensed cholesterol lowering drug – not only halted the progression of LAM, but seemed to partially reverse the lung damage in these animals (Goncharova et al., 2012).
Wee et al. recently described the case of two siblings with FMDF. Although the causative gene has not been found, topical treatment with Sirolimus for 8 weeks reduced the size and redness of the skin lesions, suggesting that mTOR dysregulation was an underlying cause. A reduction in the severity of TSC-associated skin lesions has also been reported in several studies (Dabora et al., 2011; Hofbauer et al., 2008; Micozkadioglu et al., 2010). A clinical trial to test whether topical Sirolimus is an effective treatment for the fibrofolliculomas found in BHD has been conducted and the results are currently under evaluation.
Aside from skin, lung and kidney lesions, two recent small studies show that Sirolimus and Everolimus are effective therapies for epileptic seizures and glioneuronal brain tumours which effect children with TSC (Canpolat et al., 2013; Capellano et al., 2013. Clearly, the dysregulation of mTOR signalling can cause myriad disease symptoms, and has even been linked to ageing and Alzheimer’s Disease (Johnson et al., 2013; Tang et al., 2013). Thus, although rigorous clinical testing must be done for each new indication, and hopefully Sirolimus and its derivatives may prove an effective therapy – either alone or in combination with other drugs – for a wide range of diseases, including BHD.
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