mer’s disease is known to disrupt this function

mer’s disease is known to be the most common form of dementia, such as impaired judgment or ability to make decisions, memory and changes in thinking and other brain functions. Approximately 200,000 Americans under the age of 65 have younger-onset Alzheimer’s disease. In the of 2001, Dr. Tuszynski and his colleagues at the University of California,initiated a clinical trial of nerve growth factor (NGF) gene therapy in Alzheimer Disease , the first phase of an experimental gene therapy protocol for Alzheimer’s disease. The main goal of this clinical trial was to determine whether a nervous system growth factor(NGF) prevents or reduces cholinergic neuronal degeneration in patients with Alzheimer disease. Ten patients with early Alzheimer disease were enrolled in this clinical trial, underwent NGF gene therapy using ex vivo and in vivo gene transfer with survival times ranging from 1 to 10 years after treatment. During the clinical trial eight patients in the first phase 1 ex vivo trial and of two patients in a subsequent phase one in vivo trial were examined. All ten patients were shown a hypertrophy response to NGF gene therapy.  INTRODUCTIONAlzheimer disease is an inherit genetic mutation that can be passed from parent to child and an aggressive brain disorder that is known to damage brain cells, causing memory loss, changing behavior including some other brain functions 1. Alzheimer is a types of dementia which is associated with brain cells damage; in particular the brain region called Hippocampus which is the part of the brain known to be in charge of memories. Note that this brain damage associated with this dementia are permanent, worsen over time and cannot be reverse2. Even though Alzheimer disease is known to be the cause of a rare combination of genetic mutation. However, the genetic reason behind this disease is still a phenomena and is still mostly unexplained. Although, the Genetic cause of the disease is still unknown, the effect this disease have in human brain is very clear. In a healthy human brain electrical process take place thatcauses the human body to function normally. Inside of human brain there are billions a neuron cells constantly communication with one another; these healthy neurons are needed in order to function well. However Alzheimer disease is known to disrupt this function and compromised this brain function overtime which caused loss of memory. In Alzheimer disease abnormalTau separate from the microtubule causing them to fall apart. Which will soon cause fragments of the tau eventually later on would combine and form a tangle inside the neurons and destroy the cells. As this process continues neurons and other brain region would disconnect from each other and they would completely stop communicate and dies. The brain would also shrank and loses it permanent functions. Alzheimer become more dangerous as the disease progress an early diagnosis is often a high change4.Alzheimer progress very slowly most individual affected with Alzheimer are usually live the disease for years before they start to notice symptoms of the disease which make it very difficult to find a cure The people diagnoses with Alzheimer are usually between the ages of 30s to mid-60s this is only representa lower percentage of all the individuals. The reason why the disease largely strikes at this specific age range is still a mystery for scientist5.Because of Alzheimer complication, so it questionable that one or any drug intervention can successfully cure the disease. For over a decade researches have been focus on improvement people to maintain mental function and manage behavioral6. Researches main goal to develop therapies targeting specific genetic, molecular, and cellular mechanisms so that the actual underlying cause of the disease can be stopped or prevented.Nowadays researchers have reached to a point where they are able search beyond treating symptoms and to reflect about addressing underlying disease processes7. For a decade manyongoing therapeutic clinical trials have been developing and testing by scientist and hope these therapeutic drugs might protect certain brain cells and alleviated such as short term-memoryloss8. In The year of 2001, Dr. Tuszynski and his colleagues at the University of California, San Diego School of Medicine initiated a first clinical trial at UC San Diego and the CNPRC,a gene therapy for an adult neurodegenerative disorder . In April 2001, he delivered human nerve growth factor (NGF) gene therapy that might prevent the neuronal degeneration and cell death characteristic of Alzheimer’s disease9.The main goal of this clinical trial was to targets the cellsthat are located deep within part of the brain called cholinergicsystem which supporting memory and cognitive function.  For over the course of this clinical trial, these cells have been shown to react to NGF in primate studies. The researchers hope that the NGF could inhibiting extensive loss of these cells that may slow intellectual decline seen in Alzheimer’s patients9,10,11 A gene therapy that boosts nerve growth factor (NGF) production in cholinergic neurons was safe and appeared to promote neuronal growth in a small study of patients with early Alzheimer’s disease, researcher’s reported12. The NGF protein was used for two main reasons. First NGF is known to be a large and polar protein; therefore it is too large to pass through the blood-brain barrier, making it difficult to inject elsewhere13. Second, NGF broadly circulation throughout the brain might causes adverse effects such as pain and weight loss. Research might introduce the protein simply to surrounding degenerating neurons by precisely injecting NGF into the brain14,15 .HYPOTHESIS”NGF gene therapy play a crucial role in cognition to restore degenerated neurons and slow down the progression ofAlzheimer disease”AIMS1. Due to the regenerative effect on cholinergic neurons that Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer’s disease 2. This research clinical trial (NGF) tests the ability of cells and growth factors to promote regeneration.  MATERIALS AND METHODSTreatment of Alzeimer with NGFIn phase I of this trial, eight patients with mild Alzheimer’sdisease were enrolled in clinical trial over a time period ranging from 2001 to 201116. These eight patients received ex vivotherapy to deliver the NGF gene directly into their brains.Briefly, after the first injection skin biopsies were obtained and examined from each patients, transduced to express human NGF using Moloney leukemia viral (MLV) vectors 10,16. Which isolating connective tissue cells called fibroblasts, genetically modifying them to express the NGF genes, and then implanting the cells into the patients’ basal forebrain. They used this strategy because NGF is too large to cross the blood-brain barrier, and can stimulate other nerve cells, leading to unwanted side-effects such as pain and weight loss 14,15. The first part of the clinical finding of the phase 1 ex vivo gene therapy have been reported , which involves inserting NGF genes into skin fibroblasts and implanting those altered cells into their brains. The second phase I clinical trial ten patients were enrolled in vivo gene therapy from 2005 to 2007, in which an adeno-associated viral vector serotype 2 (AAV2) carrying NGF genes were injected into their brains. The AAV2-NGF was used simply because it is less expensive and some of the most dramatic results have been obtained has shown promise for the treatment of inherited and degenerative diseases in a variety of non-human primate brain for seven years 17,18.Histology and Analyses In order to determine whether degenerating neurons in Alzheimer disease retain an ability to respond to a nervous system growth factor delivered after disease onset. All surgical details regarding the gene delivery have been reported, such as MRI scans of the ten patients in a MRI compatible stereotaxic head frame in order to detect any brain target for cell. During the ex vivo gene delivery study five males and five females were enrolled where cells were stereotaxically implanted into five sites equally spaced over the rostral-to-caudal a total distance of approximately 12 mm. The NGF therapeutic injections were precisely space at ~2.5mm intervals, indicated the distance over which NGF spreads from gene delivery sites in non-human primates 10,17.Statistical analysisStatistical analyses were performed at an individual level using each patient’s own baseline value as a control comparisons within the patients were made using paired t-test with a significance criterion of P<0.05 where the test results were reported as mean ± SEM. The Patients were characteristics per ages, the mean age at diagnosis was 67.5 ± 2.2 years and the mean age at gene transfer was 69.3 ± 2.2 years. Patients survived a mean time period of 5.4 ± 1.0 years after gene transfer 19.Fluorescent Viability DeterminationSeveral sets tissues label were performed in order to evaluate the effect of NGF have in the brain. Firs, Nissl stainwas performed to visualize the fibroblast grafts in ex vivo patients as well as the cellular morphology. NGF antibody: 1:500 dilution for fluorescence, 1:1000 dilution for light-level labeling. Then, p75 which detects the low-affinity NGF receptor and is expressed by NGF-responsive cholinergic neurons of the basal forebrain. Finally, c-fos, to assess activation of cell signaling classically related to NGF signaling. And Phospho-tauimmunolabeling to detect neurofibrillary degeneration20,21 .Antemortem Prediction of Braak stageThe Braak stages of the patients within each control and treatment sample will be determined. These methods were used both in research and for the clinical diagnosis of these diseases and are obtained by performing an autopsy of the patient's brain.During the light level immunolabeling, sections were incubated 0·1M Sodium Periodiate for 20 min and rinsed in 0.1M of TBS, antibodies were also detected by incubating sections in 1.5 µg/ml biotinylated IgG. During the fluorescent immunolabeling section were sections were post-fixed in 2% paraformaldehydeand treated with 0.1M sodium borohydride for 30 min followed by 30 min in 0.5% Sudan black then Sections were incubated in primary antibodies for 72 hr at 4°C. Finally, p75 cells were measured using a stereological microscope, A counting frame of 300×300 µm with 1:4 sample ratio. The p75 cells bodies were performed in three patients that received unilateral transplantation of the autologous fibroblasts expressing NGF19,20,21. Pathological Evaluation of BrainsDuring this clinical trial a pathological evaluation wasperformed in all study subjects. Signs Alzheimer disease wereshowed by ?-amyloid and tau in all patients, as well as NGF-treated subjects and control Alzheimer disease.POSSIBLE PITFALLSBiological response to NGF were reported in the largest parts if the patient's brain. Results cholinergic cell size in p75 labeled sections was measured in three subjects and receivedunilateral delivery of NGF. Cell hypertrophy which is a neuronal response to trophic stimulus was observed in brains of three patients undergoing the ex vivo NGF gene transfer21,23,24.  Further evidence, two patients that underwent AAV2-NGF in vivo gene transfer an activation of growth factor-induced canonical trophic signaling was also observed24. Significant  Alzheimer's disease-related deaths have increased over the past decades in every race, sex, and ethnicity category, howeverthe good news is that even though this disease is progressive and cannot be stopped; much can be done to improve the quality of life for the person with Alzheimer. The key to coping with the awful disease is a willingness to seek information and an openness to accept help and support from others. NGF is a new gene therapy administered to patients with established Alzheimer's disease results in classic trophic responses. This gene therapy could save thousands of lives and it is an open door to expanded clinical programs underway in Alzheimer's disease, Parkinson's disease and other neurological indicati


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