The movement of cholesterol, which is unestrified, is largely due to the activation of the NPC 1 protein. In cases where inactivation of mutation of this protein occurs, one may be suffering from Niemann-Pick type C disease. So what is this disease? Niemann-Pick Type C disease is a serious but rare nuerogenerative disorder. It is very common to children at or approaching adolescence. The disease is estimated to infect one out of every 160,000 children (Patterson 2009). NPC is regarded as a malfunction in the body’s cholesterol metabolism. NPC is also is sometimes referred to as childhood Alzheimer. This owes to the fact that there is a resemblance in the brains of both the Alzheimer and NPC patients. Even though there has not been a specific treatment for this disease, research has led to development of highly effective therapies and medications. Such include medications that keep seizures, tremors and abnormal limb posturing under control. A tremendous step in fighting NPC disease is the discovery of cyclodextrin. 2-hydroxypropyl-_-cyclodextrin also known as CYCLO has shown significant and positive results when administered to patients of NPC disease and may be the needed cure to stop it (Patterson 2009).
Cyclodextrin is a sugar compound, first discovered in 1891 by A.Villers. At the moment, it is used in the food industry in preparation of cholesterol free products. This is to help reduce the amount intercellular cholesterol, which is the main culprit in NPC, through reduction of o the size of the lysosomes and hence reducing cholesterol. This results to prolonging life of a child or adult who is suffering from the death sentence of NPC (Dietschy 2008).
Delayed clinical onset, a reduction in the intraneural cholesterol and GSL storage, free sphingosine accumulation and reduced markers of neurogeneration came because of administering CYCLO to NPC mice. This increased the lifespan of the mice for a longer time compared to any previous treatment. NPC results from intercellular cholesterol accumulation. This accumulation is eliminated by use of cyclodextrin since it showed reduction in the level of cholesterol when administered to the mice (Dietschy 2008).
The treatment of the mice usually started at P7 and continued for a period of 2weeks with everyday injection of the CYCLO drug. Administration of the drug was by subcutaneous or intraperitoneal with the former method proving to be more efficacious. On testing after 2 weeks, accumulation of cholesterol in the cerebral neuron cortex had been eliminated. This was done by comparison of the Purkinje cell for both treated and untreated mice. The untreated mice showed traces of cholesterol accumulation while the CYCLO treated ones lacked cholesterol storage. Allopregnanolone administered to the mice did not show significant reduction in the levels of cholesterol nor did the lifespan of the mice improve but when the allopregnanolone was combined with cyclodextrin, it led to an increased lifespan (Lau e.tal 2009).
The movement of cholesterol in NPC protein is interfered with by the decrease in the synthesis of testosterone. This eventually causes a disruption in neurosteriodogenesis. The growth, differentiation, and survival of neurons are as a result of neurosteroids. Therefore, an interruption in neurosteriodogenesis leads to NPC neurological phenotype like tremor. The harshness of the disease can be checked by significant reduction of the uptake of the lipoprotein cholesterol. This is very efficient in stopping the absorption of sterol via the intestinal walls lowering the amount of cholesterol reaching the liver. This leads to an improvement of hepatic functions (Lau e.tal 2009).
Through the excretion of sterol out of the brain via the blood-brain barrier causes a reduced amount of apoE-associated C that can be absorbed by the neurons and thus slows neurogeneration causing an increased lifespan. From the experiments and the results done on NPC mice using 2-hydroxypropyl-_-cyclodextrin (CYCLO), shows a reduction in the amount of cholesterol accumulation and a significant increased lifespan. CYCLO treatment shows amazing effects on the neurons but the mechanism by which it occurs is not clear. Contrary to what may be thought, CYCLO does not pass through the blood brain barrier for it contains large molecules.
On the other hand, CYCLO leads to the circulation of hydro cholesterol in the bloodstream, which creates a temporary void that promotes the egress of cholesterol from the brain. However, use of cyclodextrin as pharmaceutical agents’ vehicles enables their entry in to the brain. As suggested by Diestchy, on entrance in to the brain, cyclodextrin gets endocystosed by neurons, complexes with cholesterol and facilitates movement proteins in storage in association with NPC2 protein ((Dietschy 2008).).
As at now, there are ongoing researches on the use of cyclodextrin as a treatment of NPC disease by various medical research institutes. For instance, Therapeutics for Rare and Neglected Disease (TRND) is on the verge of implementing a safe and effective therapy for NPC 1 patients recognized by the United States Food and Drug Administration (FDA). Their research is divided into two phases. In the first phase, dosing procedure is being determined for treatment of NPC 1 patients. Administration by intracerebroventricular (ICV) administration through an Ommaya reservoir is what is being considered. Phase II, which is highly dependent on its predecessor, involves evaluation of the effectiveness of the treatment (Beaudet 2010).
Cyclodextrin is also being tested in other diseases apart from NPC. This includes HIV, Ebola virus and Alzheimer's disease. Research has shown that by removing the cholesterol from the HIV membrane using cyclodextrin, the virus that causes AIDS is prevented from damaging the body’s immune system. Thus, a vaccine from cyclodextrin is being developed to help fight HIV (Vanier& Millat 2012).
Addi and Cassi were diagnosed with Niemann Pick Type C disease, a rare and very costly case called for efforts from across the globe to raise the required amount of money. This particular case involves twins who have been diagnosed with Niemann type C disease and according to Dr. Caroline Hastings; hydroxypropyl-beta-cyclodextrin has been used to diagnose the rare disease. Dr, Hastings undertook extensive research to save the twins (Naureckiene 2011). Many families lost their children to the disease save for Addi and Cassi. The root behind the success of their diagnosis was the willingness and hard work, by Dr. Hastings and Dr. Hugh. People across the globe attribute all the success to their selflessness and their endurance and urge to save lives.
2-hydroxypropyl-_-cyclodextrin (CYCLO) has been repeatedly tested and applied in the treatment of the Niemann Pick type C condition. However, it various tests also indicate that the medication has certain drawbacks in various health aspects of humans. CYCLO reduces the problems, which imply that the storage abilities lysosomes are reduced. The various impacts affect the organs such as the liver, spleen. Various cases have involved paralysis of the nervous system and dementia. During the tests, β-cyclodextrin and Methyl-β-cyclodextrin are used. Their main role is to eliminate the impacts cholesterol in the cells. This effect was enhanced using cultured cells and the assimilation and development of the affinity by these cells to take lipids and as well release them according to the given cellular needs (Naureckiene 2011).
Clinical trials for cyclodextrin are usually done after the preclinical trials. Preclinical trials are usually done on animals such as mice. These animals are administered with the cyclodextrin and monitored for a certain period before the final tests and outcomes are analyzed. The FDA is the body that approves from clinical trials since it involves administering the drug to human subjects through the brain or through the spine by injection. TRND (Therapies for Rare and Neglected Diseases) and the NIH team carry out most clinical trials. This has been scheduled to take place at the fall of 2012. This will be conducted by Dr. Denny Porter and RN Nicole Yanjanin. The clinical trials will be carried out at National Institute for Health. The method selected to administer the drug will be the use of the Ommaya port. This will enable infusion of cyclodextrin into children and young adults’ brains. This is expected efficacy of this method is very high in terms of crossing the BBB (blood brain barrier).
The orphan drug status is a status given to particular drugs that are undergoing development in the pharmaceutical industry by giving them incentive to encourage biotech companies to work on cure on for rare diseases, through tax reductions and exclusive rights to the cure for the specific condition for a seven years period. Niemann-Pick Type C (NPC) definitely falls under this category. An orphan disease is one that affects less than 200,000 people and about 500 diagnosed ever in the world.
Research on Cyclodextrin as a treatment for NPC1 disease is ongoing at research centers like TRND. This owes to the fact that tests on mice have shown significant results including a prolonged lifespan. CYCLO eliminates the accumulation of cholesterol on the cell membrane. This has led to testing of CYCLO on the HIV virus whereby cyclodextrin was introduced into the cell membrane of an HIV virus. This has shown success since the cholesterol was successfully removed from the cell membrane preventing the cell from affecting the body’s immune. Clinical trials to test the efficacy of cyclodextrin in crossing the blood brain barrier are underway under the control of FDA. Therefore, cyclodextrin is an important drug which will be the turning point in the medical field offering cure to various diseases.
Works cited
Patterson, M.C. et al. Niemann-Pick disease type C: a lipid trafficking disorder. In The Metabolic and Molecular Bases of Inherited Disease (eds. Scriver, C.R.,2009
Beaudet, A.L., Sly, W.S. & Valle, D.) 3611–3633 (McGraw-Hill, New York, 2010).
Vanier, M.T. & Millat, G. Niemann-Pick disease type C. Clin. Genet. 64, 269–281 (2012).
Naureckiene, S. et al. Identification of HE1 as the second gene of Niemann-Pick C
disease. Science 290, 2298–2301 (2011).
Liu B, Li H, Repa JJ, Turley SD, Dietschy JM Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J Lipid . 2008
Lau AA, Crawley AC, Hopwood JJ, Hemsley HM. Open field locomotor activity and anxiety-related behaviors in mucopolysaccharidosis type IIIA mice. 2009
