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Comprehensive Tumor Gene Panel: Experience of a Cancer Survivor

Shivani Mehra (name changed) couldn’t have asked for a more fulfilling life. A loving husband, two amazing kids, a successful job as a financial consultant, supportive family and friends, she had everything and much more. All that changed shortly after her 40th birthday, when she noticed some of the early signs of an impending storm. A battery of tests later she was diagnosed with lung adenocarcinoma, a type of non-small cell lung cancer and the most common type of lung cancer among non-smokers.

Shivani’s oncologist Dr. Verma (name changed) quickly realized that time was not a luxury for her and ordered molecular and immunohistochemistry (IHC) tests to determine course of treatment. Since EGFR gene mutation by RT-PCR method and ALK and ROS-1 expression by IHC test turned out to be negative, he ruled out targeted therapy and decided on conventional chemotherapy. Unfortunately, her conditioned kept worsening as her tumor progressed. The Mehra family eventually realized that their perfect life was never going to be the same and hoped for a miracle.

Dr. Verma decided to give another shot at targeted therapy and sent her biopsy tissue to MedGenome Labs Ltd for a comprehensive tumor gene panel test. This next generation sequencing based test that allows screening of variations across 175 genes associated with response or resistance to specific targeted therapies in various types of cancer, revealed a rare neurotrophic tyrosine receptor kinase (NTRK3) gene fusion. NTRK gene fusions are known as oncogenic drivers and treatment of patients carrying NTRK gene fusion mutations is achieved by first generation tyrosine receptor kinase (TRK) inhibitors which are associated with high response rate. Dr. Verma facilitated the procurement of the targeted drug. Shivani’s family finally breathed a sigh of relief as she responded well to the drug and is now slowly but steadily progressing towards recovery.

With the advancement in molecular medicine, understanding of pathology of life-threatening diseases has expanded and a combination of information available through research and technology has revolutionized genomics-driven therapeutic approaches in various diseases including cancers.

MedGenome Labs Ltd offers a wide range of molecular tests that help to determine genomic profile-based targeted therapy and helps to assess prognosis and treatment to patients at baseline, progression or recurrence.

Shivani doesn’t dread the inevitable anymore, the days of uncertainty have been overcome. She is thankful to her doctor for his guidance and perseverance, to the molecular test that changed the course of action and to the access to life saving medicine, all of which turned out to be game-changers for her.

Every cancer survivor has a story to narrate – a story of pain, precariousness, panic and of empathy, solidarity, resolve, hope and gratitude. And every survivor’s story restores the faith that there is light at the end of dark tunnel.

Genetic Screening for Breast Cancer

Breast cancer is the most common type of cancer affecting women across the globe. Breast cancer is both genetically and histopathologically heterogeneous, and the mechanisms underlying breast cancer development is largely unknown1. Age is one of the significant risk factors in breast cancer. The incidence is increased by pregnancy but is permanently lowered by high parity. Breast cancer incidence is reduced by early first childbirth and the longer the women breastfeed the more they are protected against breast cancer2.

About 5% of breast cancers are found to have an underlying genetic cause and they follow autosomal dominant inheritance pattern 3. Mutations in two specific tumor suppressor genes BRCA1 and BRCA2 have been implicated in 80% to 90% of all hereditary and breast and ovarian cancers4. Ernst & Young report 2015 on cancer states that the low density of diagnostic facilities and the absence of mass screening programs is a major hurdle for timely diagnosis in India5.

The breast cancer incidences in India have grown over the years and have steadily increased and as many as 1,00,000 new patients are being detected every year6. Histologically, breast tumors can be classified on the basis of the location of origin into ductal tumors, lobular tumors, and other subtypes. Ductal tumors develop in breast ducts and represent 80% of tumors. Lobular tumors develop inside the lobes and they account for 10 to 15% of the cases, while other subtypes represent less than 10% of cases diagnosed per year7.

Breast cancers are classified as:

Ductal Carcinoma in situ (DCIS): This condition is considered non-invasive or pre-invasive breast cancer. DCIS means the cells that line the ducts have become cancerous.

Lobular Carcinoma in situ (LCIS): In this condition, cancer cells are seen growing in the lobules of the milk-producing glands of the breast, but they hardly grow through the wall of the lobules and hence are non-invasive.

When the DCIS and LCIS become invasive they are termed as Invasive Ductal Carcinoma (IDC) and Invasive Lobular Carcinoma (ILC) respectively. IDC is the most common kind of breast cancer.

Genetics of Breast Cancer

Those who inherit the risk of breast cancer are associated with the type of gene involved. For instance, mutations in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant pattern8. Even though breast cancer is common in women, the mutated genes can be inherited either from the mother or father. Mutations in some of the other genes such as PTEN, TP53, STK11, ATM, CDH1, and CHEK2 have also been found to increase the risk of breast cancer 9.

MedGenome Solutions

Apart from BRCA1 and BRCA2 gene analysis, MedGenome’s hereditary cancer mutation panel covers all the major genes implicated in and associated with breast cancer such as EPCAM, MLH1, MSH2, MSH6, and PMS2, PTEN, STK11, and TP53. It is advisable that women with an abnormal breast cancer gene be screened twice a year as they have a much higher risk of developing cancer in the time between yearly screenings9.


  1. Pharmacogenomics: An Introduction, edited by R Chakravarthy, 2006, ICFAI University Press.
  2. Guy Bradley-Smith, Sally hope, Helen V. Firth, Jane A. Hurst, Oxford handbook of Genetics, OUP, 2011.
  3. Peter S Harper, Practical Genetic Counselling, Edward Arnold Publishers Limited, 2004.
  4. S. K. Singh, Cancer genetics and genomics, Surendra Publications, 2010.
  5. Call for Action: Expanding cancer care in India, Ernst & Young, 2015.
  6. Imran Ali, Waseem A. Wani, and Kishwar Saleem, Cancer Scenario in India with Future Perspectives, Cancer Therapy Vol. 8, 56-70, 2011.
  7. Bruna Karina Banin Hirata et al., Molecular markers for breast cancer: Prediction on tumor behavior, Disease Markers, Volume 2014.

Spina Bifida Birth Defect

Spina bifida is part of a group of birth defects called neural tube defects. It is an embryonic structure that eventually develops into the baby’s brain, spinal cord, and surrounding tissues. The neural tube normally develops early in the pregnancy and closes by the 28th day after conception. In babies with spina bifida, a portion of the neural tube fails to develop or close properly, causing defects in the spinal cord and in the bones of the spine.

Spina bifida, which literally means ‘cleft spine’, is characterized by the incomplete development of the brain, spinal cord, and/or meninges (the protective covering around the brain and spinal cord)1, 2. Rates of the different types of spina bifida vary significantly from country to country with 0.1 to 5 per 1000 births. On average in developed countries, it occurs in about 0.4 per 1000 births. In the United States, it affected about 0.7 per 1000 births and in India about 1.9 per 1000 births3,4.

Spina bifida most often occurs in three forms, categorized by severity of occurrence2. They are:

Type one: Myelomeningocele

Myelomeningocele is the most serious and more common of the two forms of cystic spina bifida. In this condition, the cyst not only contains tissue and cerebrospinal fluid but also nerves and a part of the spinal cord. The spinal cord is damaged or not properly developed. As a result, there is always some paralysis and loss of sensation below the damaged region. The amount of disability is highly dependent on where the spina bifida is, and the amount of affected nerve tissue involved. Bladder and bowel problems occur in most people with myelomeningocele, as the nerves come from the bottom of the spinal cord, so are always below the lesion.

Type two: Meningocele

In this form, the sac contains meninges (tissues which cover the brain and spinal cord) and cerebrospinal fluid, which bathes the central nervous system. The development of the spinal cord may be affected, but impairment is usually less severe than myelomeningocele. Meningocele is the least common form of spina bifida.

Type three: Spina Bifida Occulta (hidden form)

This is a mild form of spina bifida, which is very common. Estimates vary but between 5% and 10% of people globally may have spina bifida occulta. It must be emphasized that for the vast majority of those affected, having spina bifida occulta is of no consequence whatsoever. Often people born with this, only become aware that they are afflicted with this, after having a back x-ray for an unrelated problem. However, for a few (about 1 in 1,000) there can be associated problems.

Genetics of Spina Bifida

Spina bifida is a complex condition likely caused by the interaction of multiple genetic and environmental factors. Changes in genes related to folate processing and genes involved in the development of the neural tube have been studied as potential risk factors for spina bifida. However, the best-studied gene of these is MTHFR. This gene provides instructions for making a protein that is involved in processing the vitamin folate (also called vitamin B9). A shortage (deficiency) of this vitamin is an established risk factor for neural tube defects5.

Prenatal Diagnosis

Prenatal diagnosis is most commonly carried out by screening methods such as second-trimester test (16-18 weeks of gestation) Maternal Serum Alpha-fetoprotein (MSAFP) screening and fetal ultrasound. The MSAFP screen measures the level of a protein called alpha-fetoprotein (AFP), which is made naturally by the fetus and placenta. During pregnancy, a small amount of AFP normally crosses the placenta and enters the mother’s bloodstream. If abnormally high levels of this protein appear in the mother’s bloodstream, it may indicate that the fetus has an ‘open’ (not skin-covered) neural tube defect.

The MSAFP test, however, is not specific for spina bifida and requires correct gestational dates to be most accurate; it cannot definitively determine that there is a problem with the fetus. Amniocentesis may also be used to diagnose spina bifida. Although amniocentesis cannot reveal the severity of spina bifida, finding high levels of AFP and other proteins may indicate that the disorder is present1.

Postnatal Diagnosis

Mild cases of spina bifida (occulta, closed) not diagnosed during prenatal testing may be detected postnatally by plain film X-ray examination. Individuals with the more severe forms of spina bifida often have muscle weakness in their feet, hips, and legs that result in deformities that may be present at birth. Doctors may use Magnetic Resonance Imaging (MRI) or a Computed Tomography (CT) scan to get a clearer view of the spinal cord and vertebrae. If hydrocephalus is suspected, the doctor may request a CT scan and/or X-ray of the skull to look for extra cerebrospinal fluid inside the brain1.


  3. Bhide, P; Sagoo, GS; Moorthie, S; Burton, H; Kar, A (July 2013). “Systematic review of birth prevalence of neural tube defects in India.”. Birth defects research. Part A, Clinical and molecular teratology 97 (7): 437–43.
  4. Kondo, A; Kamihira, O; Ozawa, H (January 2009). “Neural tube defects: prevalence, etiology and prevention.”. International journal of urology: official journal of the Japanese Urological Association 16 (1): 49–57.

Genetics of Lung Cancer

Lung cancer is the most common cause of death due to cancer, with a global estimate of nearly one death in five people (1.59 million deaths, 19.4% of the total). There was an estimate of 1.8 million new cases in 2012 (12.9% of the total), 58% of which occurred in the less developed regions. Because of its high fatality (the overall ratio of mortality to incidence is 0.87). Due to the relative lack of variability in survival in different world regions, the geographical patterns in mortality closely follow those in incidence1,2. Cancer is neither rare anywhere in the world, nor mainly confined to developed countries. Striking differences in the patterns of cancer from region to region are observed. As opposed to the 5 years survival of 52% in all cancers, lung cancer survival rates continue to be poor 3.

In India, approximately 63,000 new lung cancer cases are reported each year. One of the major contributors to lung cancer is believed to be tobacco use and hence, is called a smoker’s disease. However, a significant number of patients with lung cancer have no history of smoking. Major gender, clinicopathological, and molecular differences in lung cancers arising in never-smokers strongly suggest a disease distinct from the more common tobacco-associated forms of lung cancer3.

Genetics of Lung Cancer

Lung cancer is comprised of two main histologic subtypes: Non-small-cell Lung Cancer (NSCLC) and Small-cell Lung Cancer (SCLC). Subsets of NSCLC may be characterized by recurrent driver mutations in multiple oncogenes like ALK, BRAF, EGFR, HER2, MET, KRAS, NRAS, and PIK3CA among others4.

Specialized molecular and genetic testing for these kinds of cancer would prove to be very useful in the detection and accurate treatment.

In general, hereditary lung cancer occurs more frequently in women, non-smokers, and those with early-onset lung cancer. Overall, it has been estimated that 1.7% of lung cancers up to the age of 68 are hereditary. Trend analysis reveals that patients of NSCLC, especially lung adenocarcinoma, are more likely to have a history of lung cancer than those with SCLC. Also, people with a BRCA2 mutation have a higher risk than others, of developing lung cancer5.

MedGenome’s Solutions

MedGenome, a provider of clinical genomics solutions for personalized healthcare, offers comprehensive genetic diagnostic solutions for early detection of lung cancer. The solutions provided range from single gene testing for EGFR to testing a panel of genes (oncogenes and tumor suppressor genes) implicated in the onset of the disease.

Our Hereditary Cancer Panel covers all the major genes linked to lung cancer. Early detection of cancer is the most important step in ensuring a favorable prognosis, and timely surgical intervention can reduce the risk of developing cancer by up to 85%.


  2. Behera, D. “Epidemiology of lung cancer–Global and Indian perspective.”Journal, Indian Academy of Clinical Medicine 13.2 (2012).
  3. Noronha V, Dikshit R, Raut N, Joshi A, Pramesh C S, George K, Agarwal J P, Munshi A, Prabhash K. Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-center experience. Indian J Cancer 2012;49:74-81
  4. Lovly, C., L. Horn, W. Pao. 2014. Molecular Profiling of Lung Cancer. My Cancer Genome
  5. (Updated March 31).

World Immunization Day

Every year, 10th November is celebrated as World Immunization Day. According to the WHO, immunization prevents between 2 and 3 million deaths every year and now protects children not only against diseases for which vaccines have been available for many years, such as Diphtheria, Tetanus, Polio and Measles, but also against diseases such as Pneumonia and Rotavirus Diarrhoea, two of the biggest killers of children under age of five.

World Immunization Day is observed with the aim of highlighting vaccination as a low-tech, cost effective, high impact solution to preventing illness and disease in individuals of all ages. Vaccinations prevent susceptibility to illnesses which can result in serious complications and even death. If exposure to a disease occurs in a community, there is little to no risk of an epidemic if people have been immunized.

Recent advances in medical science have resulted in enhanced protection bestowed by vaccination. Some diseases that once killed thousands of children, have been eliminated completely and others are close to extinction– primarily due to safe and effective vaccines. Polio is a prime example of the great impact that vaccines have had in India. Polio was once India’s most-feared disease, causing death and paralysis across the country, but today, thanks to vaccination, as of 2014, India has been declared polio-free by the WHO, and has been removed from the list of endemic countries. Another example of the benefits of vaccination is the eradication of smallpox worldwide, because of which immunization against the disease is no longer a necessity. Regular and effective immunization may be able to ensure that many such diseases the plague may be eradicated soon.

Even though some diseases, such as polio, rarely affect people in developed nations, all of the recommended childhood immunizations and booster vaccines are still needed. Travellers may inadvertently bring these diseases into developed nations and infect people who have not been immunized. Without the protection via immunizations, these diseases may quickly spread through the population, causing epidemics. The same is true the other way wherein a traveller is entering a new country and immunization can help fight the common disease agents at the destination. Non-immunized people living in healthy conditions are not protected from disease. The immune system can fight a disease better and faster if the individual has had the infection before or has been immunized.

Some vaccine-preventable diseases can result in prolonged disabilities and can take a financial toll because of lost time at work, medical bills or long-term disability care. In contrast, getting vaccinated against these diseases is a good investment and usually covered by insurance.

A small number of people may be susceptible to diseases, such as those with impaired immune systems. These people may not be able to get vaccinations or may not develop immunity even after having been vaccinated. Their only protection against certain diseases is for others to get vaccinated so the illnesses are less common. Vaccines are only given to children after a long and careful review by scientists, doctors, and healthcare professionals. The benefits of vaccination cannot be emphasized enough, and it is safe to say the discomfort or pain caused by the side effects of the vaccine pale in comparison to the tremendous pain and illness caused by the diseases that these vaccines prevent.

Diabetes is a Growing Burden in the Society – Latest Scientific Advances Can Help Us Manage it Better

Metabolic disorders occur when abnormal chemical reactions disrupt the systematic breakdown of food into usable forms of nutrients for the body. Such disorders results in an imbalance in the hormones required by one to stay healthy. Diabetes, one such metabolic disorders, is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body’s systems, like vascular dysfunction, heart failure, neuronal damage, kidney failure, and blindness.

Globally, 387 million people suffer from Diabetes; this number is estimated to be 592 million by 2035. 77% of people with diabetes live in low- and middle-income countries. In 2012, diabetes was the direct cause of 1.5 million deaths. In 2014, this number rose to 4.9 million, with 9% of adults, 18 years and older suffering from diabetes. The number of people with type 2 diabetes is increasing in every country and the greatest number of people with diabetes are between 40 and 59 years of age. 179 million people with diabetes are still undiagnosed 1,2.

India has more diabetics than any other country in the world, according to the International Diabetes Foundation, and an estimate shows that around 1 million Indians die of diabetes every year; the average of an individual to be affected by diabetes is 42.5 years3. The disease currently affects more than 62 million Indians, which is more than 7.1% of India’s adult Population4. According to the Indian Heart Association, India is the diabetes capital of the world with a projected 109 million individuals with diabetes by 20355.

Research and Treatment

Traditionally insulin therapy has been the primary treatment option for diabetic patients. The goal of insulin therapy is to maintain blood sugar levels within the stipulated range. The insulin regimen chosen is dependent on factors like the type of diabetes the patient is afflicted with as well as his/her lifestyle. Depending on its onset peak and duration, insulin types can range between rapid-acting, short-acting, intermediate-acting and long-acting7. Aggressive and often temporary use of insulin therapy at disease onset in type 2 diabetes is associated with effective glycemic control with minimal weight gain and hypoglycemia. A more timely and selective introduction of insulin replacement therapy, as β-cell function progresses, could facilitate the achievement and maintenance of normal glycemic levels and thus reduce disease-associated complications8.

Recent years have seen many advances in the field of diabetes research and treatments. Diabetes is a vascular disease that leads to many end-organ complications, including dialysis and legal blindness among driving adults. One way to treat diabetes and these symptoms are with organ transplantation. The entire cornea can be replaced, with new surgical techniques also developed to just replace the damaged portion. In addition to kidney transplantation, type 1 diabetic patients could also receive a kidney-pancreas transplant at the same time. This can remove the need for insulin administration. Other recent advances include innovations like glucose-monitoring devices, insulin pumps, and artificial pancreas. In addition to lifestyle therapy, the statin class of drugs are prescribed for diabetic patients with cardiovascular disease to manage a dangerous form of cholesterol known as LDL or low-density lipoprotein, according to the American Diabetes Association6.

Genetics and Genetic Testing of Diabetes

About 2%-5% of diabetes have underlying genetic causes. An example of this kind of diabetes, is Maturity Onset Diabetes of the Young (MODY), a monogenic form of diabetes caused by mutations in the autosomal dominant gene that disrupt insulin production. MODY1 and MODY3 are the most common forms. In contrast, common forms of diabetes like Type 1 and Type 2 have genetic causes, but no distinct pattern of inheritance. They result from interactions of multiple gene variants (and are hence also called polygenic forms of diabetes), each exerting only a modest effect, and the environment. Hence the gene variants implicated in common forms of diabetes can be regarded more as susceptibility genes, and not disease genes per se9.

Predictive genetic testing for diabetes is now a reality. Babies with diabetes are now being immediately genetically tested for all implicated genes while previously they would only get genetic testing years after diabetes was diagnosed, after which the genes would be tested one at a time. Crucially, this means that the genetic diagnosis is made early, giving the doctor information on how best to treat the patient and inform them of the medical problems the patients are likely to develop in the future.

This is a paradigm shift in how genetic testing fits in with the patients’ clinical symptoms. In the past, symptoms were used to select which gene would be tested – now the early comprehensive gene testing means that the genetic result predicts clinical features that have not yet developed. This helps the doctors to anticipate the likely problems for their patients and put the appropriate care in place to reduce their impact10.

MedGenome’s Solutions

MedGenome, a provider of clinical genomics solutions for personalized healthcare, is committed to the development of comprehensive genetic diagnostic solutions. To this end, it has a genetic testing panel for MODY and neonatal diabetes, which tests for over 30 genes that are associated with the disease, such as ABCC8, AKT2, INS, and INSR. Early disease detection can enable better disease management thereby making a healthy lifestyle possible.


  3. Gale, Jason (November 7, 2010).”India’s Diabetes Epidemic Cuts Down Millions Who Escape Poverty”. Bloomberg.
  4. Diabetes can be controlled in 80 percent of Cases in India”.
  5. Indian Heart Association Why South Asians Facts Web. 30 April 2015.

Pancreatic Cancer – Important Facts

The pancreas is a gland, located behind the stomach, which produces digestive juices and hormones that regulate blood sugar. Pancreatic cancer is the twelfth most common cancer in the world (along with kidney cancer), with 338,000 new cases diagnosed in 2012. The early stages of this cancer do not usually produce symptoms, so the disease is generally advanced when it is diagnosed. The estimated 5-year prevalence of people in the world living with pancreatic cancer is 4.1 per 100,000. This cancer is almost always fatal, and is the seventh most common cause of death from cancer. About 55 per cent of pancreatic cancer cases occurred in more developed countries, with the highest incidence of pancreatic cancer being in Northern America and Europe; and the lowest incidence in Africa and Asia1.

Adenocarcinoma is the most frequent type of pancreatic cancer; slower-growing endocrine tumors account for only a small fraction of the total burden of disease. As for nearly all cancers, incidence rates of pancreatic cancer vary among countries, with approximate 5- to 7-fold differences between countries with the lowest and highest incidence; rates reported from African countries are low because of insufficient data3.

In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and an estimated 40,560 people will die of this disease2. The global annual incidence rate for pancreas cancer is about 8/100,000 persons3.

Genetics of Pancreatic Cancer

Pancreatic cancer has been associated with a number of environmental exposures and factors. One such factor is smoking. Established results show that smoking contributes to atleast 20-30% of all pancreatic cancers. Passive smoking also can increase the risk of pancreatic cancer, since environmental tobacco smoke (ETS) contains the same toxins like nicotine, carbon monoxide, ammonia and benzene. Other factors associated with pancreatic cancer are alcohol consumption, diet, obesity, diabetes mellitus, blood type and exposure to certain types of drugs like medication.

A genetic predisposition to the disease is a major risk factor for pancreatic cancer. Activation of the oncogene KRAS, with simultaneous inactivation of the tumor suppressor genes p53, DPC4, p16 and BRCA2 have been associated with the onset of pancreatic cancer. 90% of all cases of pancreatic cancer have p16 mutations, 70% have p53 mutations, and 55% have DPC4 mutations 4.

Around 10% of pancreatic cancers are hereditary, many of which occur as part of rare medical syndromes such as familial breast cancer, Peutz-Jeghers syndrome, familial melanoma, hereditary colon cancer, hereditary pancreatitis, Ataxia telangiectasia and familial pancreatic cancer5.

MedGenome’s Solutions

MedGenome, a provider of clinical genomics solutions for personalized healthcare, offers comprehensive genetic diagnostic solutions for early detection of pancreatic cancer. The solutions provided range from single gene testing to testing a panel of genes (oncogenes and tumor suppressor genes) implicated in the onset of the disease.

Our Hereditary Cancer panel covers all the major genes linked to pancreatic cancer like KRAS, TP53 and STK11. Early detection of cancer is the most important step in ensuring a favorable prognosis, and timely surgical intervention can reduce the risk of developing cancer by up to 85%.


  3. Yadav, Dhiraj, and Albert B. Lowenfels. “The epidemiology of pancreatitis and pancreatic cancer.”Gastroenterology6 (2013): 1252-1261.

Gene Therapy: a promising potential treatment modality for LCA

Leber congenital amaurosis (LCA) is a congenital retinal disorder that primarily affects the retina. It occurs in 2 to 3 among 100,000 new-born and accounts for 10%-18% of all inherited blindness or severe visual impairment in children that can alleviate or worsen over a period of time. It is characterized by nystagmus, hyperopia, keratoconus, photophobia, cataract, and glaucoma, and Franceschetti’s oculo-digital sign, behaviour associated with pressing, rubbing or poking of eyes with fingers or knuckles resulting in deep-set eyes and keratoconus.1, 2 Certain genetic subtypes of LCA are also known to cause early onset of renal failure.

With more than 13 identified types of LCA, each type can be differentiated by their impairment pattern, eye abnormalities, and genetic cause. Mutation in more than 25 genes.3 that are required for normal development and function of retina can result in the disease and early visual impairment. The genes may be associated with either the development of photoreceptor cells, involved in phototransduction or normal functioning of cilia. While mutations in genes RPE65, CRB1, GUCY2D, and CEP290 are known to contribute majorly, mutations in other genes are also known to cause LCA. Below is the table showing genes and its proportion of contribution in LCA.4

Gene Occurrence
SPATA7, CRB1, NMNAT1, RD3, LRAT, TULP1, KCNJ13, and IQCB1Not certain
IMPDH1Rare cause of dominant LCA

Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.

LCA follows autosomal recessive pattern of inheritance and can be diagnosed by Electroretinography (ERG), a technique measuring electrical activity of retina. Children with LCA show lower or absence of the activity. With no surgical or medical therapy available currently, LCA is regarded as an incurable disorder and is mainly managed through symptomatic and supportive. Additionally, refractive error correction, utilization of low-vision aids is also known to benefit affected individuals. However, with several clinical trials underway at institutions like Moorfields Eye Hospital at the University College of London, Universities of Pennsylvania and Florida, and Children’s Hospital of Philadelphia showing positive results of gene therapy for LCA2 caused RPE65 mutation is showing up as a potential treatment option.5

Detection of RPE65 mutations is done using molecular genetic testing using sequencing technologies with clinical symptoms and signs providing vital information about the genes to test for and their order.6 Identifying the genetic cause of an inherited

disease, genetic diagnostics helps by confirming the clinical diagnosis, availing appropriate therapeutic methods, and enables clinicians to determine the prognosis and progression of the disorder.7

Gene therapies treat disease by inactivating or replacing defective gene or by introducing a novel gene. Viruses, especially Adeno-associated viruses (AAV) are commonly used for introduction of genes due to their simple structure and biology. Belonging to parvovirus family, AAV need co-infection on other viruses such as adenovirus for replication. Although less immunogenic on comparison chances of triggering an immune response are present. Thus, delivering appropriate dosage without eliciting an immune response that could be dangerous to patient or render the therapy ineffective is a challenge. Among the 12 identified serotypes, AAV1 to AAV 12, AAV2, AAV4, and AAV5 are exclusive for retinal disorders, AAV2 being more common.

Small size of eye allows for small amounts of vector usage and immunological advantage offered by the blood-ocular barrier in eye make it ideal for gene therapy. Various studies are being conducted to check the effectiveness of the therapy in retinal diseases caused by RPE65 variants using AAV vectors for introducing normal copy of the gene subretinaly. Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.

Gene therapy gained further impetus as a potential treatment in 2017 with U.S. Food and Drug Administration (FDA) approving Luxturna (voretigene neparvovec-rzyl) by Spark Therapeutics, Inc for treating eye disorders caused by RPE65 mutations. Using recombinant AAV vector, Luxturna helps in restoring the normal vision in children and adults by delivering a normal copy of the gene directly to retinal cells that allows for the expression of a protein responsible for converting light to an electrical signal in the retina.8 A phase 3 study conducted on 31 subjects showed that patients who received Luxturna demonstrated significant improvement in effectively finishing the obstacle path even at low illumination in contrast to control group.

In order to analyse the efficacy and safety of unilateral and subretinal injections of AV2 and 4 Le Meur, et al, Molecular Therapy, carried out a study on 9 subjects having RPE65 gene mutation associated LCA. Visual activity and general and ocular tolerance in nine subjects were assessed for a year after administering of the vectors in either low or heavy dosages. In an ancillary study which included six of the above subjects assessment was followed up for 2 to 3.5 years. At the end all of them showed good tolerance for the vector; and visual field improvement and stabilization, enhanced visual acuity in subjects with nystagmus, and cortical activation along with visual field and pathways was observed during Functional magnetic resonance imaging (fMRI) evaluation.9

India also is slowly catching up on gene therapy with currently 10 centres across India concentrating on genetic therapies for various disorders ranging from head and neck cancer, haemophilia, leukaemia, cervical cancer to eye disorders.10 Narayana Nethralaya, an eye hospital in Bengaluru, has set up a Centre for Regenerative Medicine, Genetics and Gene Therapy that will be focused on providing genetic care to patients, especially those having LCA.11, 12 Government of India is also encouraging the gene therapy research in India by providing financial assistance through organizations like Department of Science and Technology (DST), Department of Biotechnology (DBT), and Indian Council of Medical Research (ICMR), etc.9

Gene therapy is potential treatment modality that holds promise of curing a disease at the root cause than just alleviating the symptoms. It could be an effective treatment option of future if more research and clinical studies are conducted to analyse the safety and efficacy of the therapy and regulatory authorities to develop policies in streamlining the process.10

Reference :

  1. Kumaran N, Ripamonti C, Kalitzeos A, et al. Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis. IOVS. 2018;59(1):85-93.
  2. Leber Congenital Amaurosis. American Association for Pediatric Ophthalmology and Strabismus. Accessed 5 June 2018.
  3. Kumarn N, Smith AJ, Michaelides M, Ali R, Bainbridge J. Gene therapy for Leber congenital amaurosis. Expert Rev Ophthalmol. 2018;13(1):11-15. Epub ahead of publication.
  4. Weleber RG, Francis PJ, Trzupek KM, Beattie C. Leber Congenital Amaurosis. In: Ardinher HH. Seattle (WA): University of Washington, Seattle; 1993-2018.
  5. Leber Congenital Amaurosis. Foundation Fighting Blindness. 2018. Accessed 5 June 2018.
  6. Leber Congenital Amaurosis. National Organization for Rare Disorders, Inc. 2018. Accessed 5 June 2018.
  7. What are the types of genetic tests? U.S. National Library of Medicine. 2018. Accessed 10 June 2018.
  8. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. U.S. Food and Drug Administration. 2018. Accessed 5 June 2018.
  9. Le Meur G, Lebranchu P, Billaud F, et al. Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis. Mol Ther. 2018;26(1):256-268.
  10. Chodisetty S, Nelson EJ. Gene therapy in India: a focus. J Biosci. 2014 Jun;39(3):537-41.
  11. Ocular Genetics. Narayana Nethralaya. 2018. Accessed 5 June 2018.
  12. Gene Therapy at your Doorstep. 2018. Accessed 5 June 2018.

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