The ability to develop therapeutics that are able to infiltrate the blood-brain barrier (BBB) is an ongoing, complex task undertaken by scores of biotechnology and pharmaceutical companies around the world. Drugs capable of bypassing the cellular wall and the numerous obstacles of the BBB are generally small, lipid-soluble compounds that typically utilize transmembrane diffusion to cross the BBB. Therapeutics that cross the BBB to treat depression, affective disorders, chronic pain, and epilepsy are among the chosen few currently available, yet research is proving quite promising for a wide range of central nervous system (CNS) conditions, including multiple sclerosis (MS).
MS is a unique inflammatory autoimmune disorder in that it appears to have only one target: the myelin protein of the brain. Symptoms of the disease may include cognitive impairment, vertigo, weakness, numbness, vision impairment, fatigue, neuropathic pain, spasticity, tremor, and paralysis. The disease is progressive and while there are drugs that can slow the progression of the disease or reduce severity and frequency of MS attacks in some patients, there is currently no cure for MS.
In MS, activated myelin-specific lymphocytes and monocytes are able to penetrate the BBB and release cytokines in order to produce an immune response and promote inflammation. In conjunction with CNS cells (microglia), they then destroy the myelin sheaths of nerve axons, leading to nerve demyelination and, eventually, death. The biotech community and pharmaceutical industry are largely focused on breaking down the steps of this inflammatory process and stopping it in its tracks. Following are some examples of novel drug therapies in various phases of clinical trials that breach the BBB in order to allow for safer, more effective treatment of MS.
Drugs that Deplete Lymphocytes
Fingolimod® (FTY720) (Novartis). Fingolimod® is a monoclonal antibody that prevents certain lymphocytes from leaving lymph nodes and entering the blood stream, thereby reducing the chances of triggering an immune response, as mentioned in the above paragraph. A recent study of Fingolimod® showed a reduction of relapse rate of 38%-52% in MS patients.
CLARITY® (Cladribine) (Ortho Biotech). A recent study of CLARITY® for the treatment of MS showed a greater than 50% reduction in annualized relapse rates in patients with relapse-remitting MS.
Drugs that Act as Immunomodulators
Zenapax® (Daclizumab) (Biogen Idec). Zenapax® is a monoclonal antibody that works by blocking receptors that promote the growth of T cells activated against myelin and migration across the BBB. The role of Zenapax® with regard to MS is somewhat unclear; however, studies are ongoing.
ALLEGRO® (laquinimod) (Teva). ALLEGRO® reduces the passage of lymphocytes into the CNS and shifts the focus of cytokines from inflammation to regulation. Just months ago, the FDA put ALLEGRO® on the Fast Track on the approval process to treat MS.
Drugs that Reduce Inflammation
CLARITY® (BG-12) (Merck Serono). Inflammation within the CNS is believed to cause the localized lesions of the brain and spinal cord. CLARITY® has been found to significantly reduce such lesions. In a recent study conducted by Merck Serono, the manufacturer of the drug, CLARITY® was found to reduce annualized relapse rate by 55%-58%.
Ibudilast® (MN-166) (Medicinova). Ibudilast®, which has been used extensively in Japan for the treatment of asthma, is showing great promise in the treatment of lesions associated with the inflammatory aspects of MS. In a recent study, Ibudilast® sustained disability progression was approximately 50% less likely in patients receiving Ibudilast® and the formation of new lesions was significantly reduced.
These drug therapies that are able to breach the BBB in order to treat various diseases of the CNS will be watched closely by many people for a variety of reasons. Searching the Web you will find many people looking for financial information, to keep up with the business world, or simply out of interest in science. The underlying reason most of us follow these innovations, however, is that we’d like to see that those things we fear most – those diseases that could affect us or someone we love- could potentially not be that fearful after all.
