Daily Archives: July 18, 2021

A Charlotte baby became the first at UNC Medical Center in Chapel Hill, N.C. to receive a breakthrough gene therapy treatment for spinal muscular atrophy (SMA), after his condition was discovered through the Early Check newborn screening pilot study.

It was a pregnancy that went relatively smooth. No red flags. No urgent ultrasounds. But, for this one family of Charlotte, N.C., that sense of apprehension was always lurking.

It was like I was waiting for the other shoe to drop. After all that we went through with our first child, once we had our son, it seemed too easy to feel like everything was normal, said the mom, who wishes to be anonymous.

Their first child was born with health issues that went undetected during the moms pregnancy, and it was a surprise at birth.

So, my pregnancy with my second child, my son, was super simple aside from the fact that I would consider myself slightly traumatized from what happened with my oldest. Other than that, the pregnancy was easy and enjoyable, she said.

Their son was born February 25th, 2021, perfect in every way, at least on the outside. Around this time the parents received an envelope in the mail informing them about Early Check, a pilot study focused on screening newborns for rare health conditions, and how parents could sign their babies up prenatally or postnatally.

After speaking with our pediatrician, and realizing how enrolling our son in this study could make a difference, we decided to register, said the mom, whose intuition also played a role in her familys decision. Little did she know her gut decision would allow her child to live a more normal life.

The pilot study is in collaboration between RTI International, North Carolina State Laboratory of Public Health (NCSLPH), and three major universities the University of North Carolina at Chapel Hill, Duke University and Wake Forest University. Among many other rare conditions, Early Check launched screening for spinal muscular atrophy (SMA) in October 2018 throughout the spring of 2021.

With Early Check, we started including SMA because it wasnt a part of the general newborn screening for the state, so it was a pilot to see how it could work and to see if we could identify this condition in newborns, said Cynthia Powell, MD, pediatric geneticist, UNC site principal investigator for Early Check.

Results No Parent Wants to Hear

When their baby was three-weeks-old, the parents registered their son to be a part of the study. Four days later, they received a phone call.

It was one of those really nice spring days, a Friday afternoon. We were out getting ice cream and when we got back in the car, we both had missed calls. After listening to the voicemail, my stomach dropped, the mom said.

Their son received an abnormal newborn screening result for SMA, a rare genetic disorder caused by deficiency of the survival motor neuron protein (SMN1), resulting in progressive degeneration and irreversible loss of cells in the spinal cord and brainstem. Without treatment, the decreased level of the SMN protein leads to muscle weakness, and wasting atrophy of muscles used for movement. Most babies diagnosed with this disorder will have weak mobility, typically shown in the extremities, such as limp legs and arms, before six-months of life. This debilitating and often fatal muscle weakness can lead to an individual not being able to perform the basic functions of life, like breathing and swallowing, eventually leading to death by two or three-years-old. SMA is the leading cause of infant mortality from a single gene disorder, and its prevalence is one per 10,000 births globally.

This is a pretty devastating genetic disease, said Zheng (Jane) Fan, MD, pediatric neurologist, co-investigator for the Early Check pilot study. The severity of the disease depends on the genetic mutation subtype. For SMA babies, they have no copies of the SMN1 gene. Their disease severity depends on the number of copies of the SMN2 gene, which serves as a backup copy for the SMN1 gene, she said.

The Early Check results showed that the son had an absent SMN1 gene. A follow-up appointment was scheduled for the family to visit UNC School of Medicines Clinical & Translational Research Center (CTRC) the following Tuesday for confirmatory testing and to see how many copies of the SMN2 gene were present. For the parents, it was a long, grueling three days full of questions about whether or not their son was going to live.

We basically mourned the loss of our son that entire weekend before our visit to Chapel Hill, said the dad.

The confirmatory testing tells how many copies of the SMN2 gene are present. If there are three or more copies of the SMN2 gene, a baby could have a moderate form of SMA, whereas if there are two or less copies of SMN2, it could lead to a more severe form. Results showed that the son had three back-up copies of the SMN2 gene.

All the types of SMA are caused by the same gene variant, but are different in severity that will influence the age of onset and how quickly and severe it will manifest. Classification is based on the clinical age of onset and rate of regression, said Yael Shiloh-Malawsky, MD, pediatric neurologist and associate professor in the UNC Department of Neurology. With the more severe form, a child will never gain the milestone of sitting. This is Type I. Type II are kids who will be able to sit, but will never gain independent walking and later on can lose the ability to sit without help. Type III are children who gain walking, and later on will have decline in their strength.

Just looking at the child with the naked eye, no one could tell that he had a debilitating disorder forming on the inside. No symptoms were shown at all. For this particular case, the son fell within the Type II range.

For babies with Type I or II, the recommendation is to start treatment as soon as possible, said Dr. Fan.

We didnt even think treatment was an option, said the mom as her eyes begin to fill with tears.

During our first appointment with Dr. Fan, she showed us videos of children jumping rope and running. Children who had SMA, but received treatment. We never thought our son was going to be able to do any of those things, her voice trembled.

Life-Saving New Treatments for SMA

New medical advances are changing the course of SMA by helping thousands of children diagnosed with the disease experience better outcomes. For this family specifically, treatments were narrowed down to two choices; Spinraza, an FDA approved drug at $125,000 per one dose that is continued every four months for the duration of the individuals life, or they could choose the recent FDA approved gene therapy called Zolgensma, a $2-million dollar one-time treatment.

Time was of the essence. With SMA, once symptoms start to appear, its a red flag that motor neurons have already been lost. A decision needed to be made quickly.

After discussions with our pediatrician, Dr. Fan, Dr. Shiloh, and other medical professionals, we decided to choose Zolgensma, said the mom.

Zolgensma, the first gene therapy approved to treat children with SMA less than two-years-old, is a one-time intravenous infusion that takes about an hour. It involves a safe virus, AAV9, that delivers a fully functional human SMN1 gene to the targeted motor neurons, which in turn improves muscle movement and function, and also improves survival and quality of life.

Multiple testing went underway to see if the child was eligible for the Zolgensma treatment.

If the baby had antibodies against the AAV9 virus, then the gene therapy wouldnt have been effective, Dr. Fan said. This is because once the therapy penetrates the blood, the antibodies would kill the virus, even though the virus was harmless and carrying potentially life-saving cargo.

Luckily, test results showed that the baby did not have antibodies against the virus. It took two weeks for the treatment to be approved from insurance and to be delivered to UNC Childrens Hospital. Then on April 21st at eight-weeks-old, the baby became the first at UNC Medical Center to receive the life-saving gene therapy treatment.

I have a real appreciation for our doctors. They are so brilliant and they want to use that towards the good of our children. Theres hope, said the dad.

From checking in, receiving the treatment, to monitoring for side effects, the whole process took about seven hours. After staying in town for a couple days, the family headed back home. However, the son was monitored continuously to check for potential side effects the biggest being elevated liver enzymes, due to an inflammatory response.

This baby tolerated the gene therapy treatment well, with no apparent side effects and his liver enzymes remained in normal range throughout the monitoring period, Dr. Fan said.

For children diagnosed with SMA Type II, muscle weakness develops between ages 6 and 12 months. However, because the Early Check newborn screening was available for SMA and the child received the gene therapy early before the onset of symptoms, the outcome is in his favor.

If the child had been born in a different state that already started newborn screening on a population basis, he would have been screened, but because North Carolina hadnt started screening for SMA yet, he wouldve been missed if his family hadnt signed up for the study. Its pretty remarkable, said Dr. Powell.

As of May 1, 2021, SMA has been part of newborn screening statewide, and North Carolina is among the more than 30 states with this screening.

Our expectation is that this child will have normal development, normal strength like any other baby, said Dr. Shiloh-Malawsky.

For now, the parents continue to be observant of their son while being cautiously optimistic.

Its the nature of parenting that youre going to worry about your child, said the mom. I was thinking it was a death sentence when I heard about my sons diagnosis. Were only three months into it, but from what the doctors have said, it doesnt have to be a death sentence. My son can live a fulfilling life. Were grateful for that.

So far, hes right on track for his physical therapy evaluation, and recently, he rolled over for the very first time, she said, and she smiled.

Written by Brittany Phillips, UNC Health Communications Specialist

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Baby First at UNC to Receive Gene Therapy for SMA, Thanks to Early Check Newborn Screening | Newsroom - UNC Health and UNC School of Medicine

COLUMBUS, OHIO A novel method of gene therapy is helping children born with a rare genetic disorder called AADC deficiency that causes severe physical and developmental disabilities. The study, led by researchers at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine, offers new hope to those living with incurable genetic and neurodegenerative diseases.

Research findings are published online in the journal Nature Communications.

This study describes the findings from the targeted delivery of gene therapy to midbrain to treat a rare deadly neurodevelopmental disorder in children with a neurogenetic disease, aromatic L-amino acid decarboxylase (AADC) deficiency characterized by deficient synthesis of dopamine and serotonin.

Only about 135 children worldwide are known to be missing the enzyme that produces dopamine in the central nervous system, which fuels pathways in the brain responsible for motor function and emotions. Without this enzyme, children lack muscle control, and are usually unable to speak, feed themselves or even hold up their head. They also suffer from seizure-like episodes called oculogyric crises that can last for hours.

Remarkably, these episodes are the first symptom to disappear after gene therapy surgery, and they never return, said study co-author Dr. Krystof Bankiewicz, professor of neurological surgery at Ohio State College of Medicine who leads the Bankiewicz Lab. In the months that follow, many patients experience life-changing improvements. Not only do they begin laughing and have improved mood, but many are able to begin speaking and even walking. They are making up for the time they lost during their abnormal development.

The directed gene therapy in seven children ages 4 to 9 who were infused with the viral vector resulted in dramatic improvement of symptoms, motor function and quality of life. Six children were treated at UCSF Benioff Childrens Hospital in San Francisco and one at Ohio State Wexner Medical Center. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future, Bankiewicz said.

During the gene therapy surgery, physicians infuse a benign virus programmed with specific DNA into precisely targeted areas of the brain. The infusion is delivered extremely slowly as surgeons monitor exactly how it spreads within the brain using real-time MRI imaging.

Really, what we're doing is introducing a different code to the cell, said Dr. James Brad Elder, director of neurosurgical oncology at Ohio State Wexner Medical Centers Neurological Institute. And we're watching the whole thing happen live. So we continuously repeat the MRI and we can see the infusion blossom within the desired nucleus.

Researchers believe this same method of gene therapy can be used to treat other genetic disorders as well as common neurodegenerative diseases, such as Parkinsons and Alzheimers disease. Clinical trials are underway to test this procedure in others living with debilitating and incurable neurological conditions.

The directed gene therapy, in these patients, resulted in dramatic improvement of symptoms, motor function and quality of life. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future.

The findings described in this study are the culmination of decades of work by teams from multiple academic institutions, including University of California San Francisco, Washington University in St. Louis, Medical Neurogenetics Laboratory in Atlanta, St. Louis Childrens Hospital and Nationwide Childrens Hospital in Columbus, Ohio.

The research was supported by the National Institute of Neurological Disorders and Stroke and foundational grants, including the AADC Research Trust, the Pediatric Neurotransmitter Disease Association and funding from The Ohio State University.

This work provides a framework for the treatment of other human nervous system genetic diseases. Its our hope that this will be first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner, Bankiewicz said.

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Your Healthy Family: New gene therapy providing hope for those with rare genetic disorders - KOAA.com Colorado Springs and Pueblo News

When she isnt pursuing her favorite heart-pumping activities of running, swimming, or cycling, Sharlene M. Day, a presidential associate professor of cardiovascular medicine and director of Translational Research for the Penn Cardiovascular Institute, is focused on the heart in another way; trying to unlock and treat the mysteries of genetic heart disease.

As part of her research at the Day Lab, Day integrates translational and clinical science to understand the full spectrum of genetic heart disease evolution and progression, from gene mutations in heart muscle cells to ways of predicting negative outcomes in patients. Clinically, she sees patients with hypertrophic cardiomyopathy, a condition where the heart muscle becomes thick making it harder for blood to leave the heart, and other genetic heart conditions at the Penn Center for Inherited Cardiac Disease, such as inherited arrhythmias, high blood cholesterol, Marfan syndrome and familial amyloidosis. Her research program primarily focuses on these same conditions.

A physician scientist, Day completed her residency, followed by a cardiology fellowship, and a postdoctoral research fellowship at the University of Michigan before joining the faculty there, and spent 24 years there before coming to Penn. Day was recruited to Penn Medicine to lead initiatives in translational research within the Cardiovascular Institute and to grow the clinical and academic mission in the Penn Center for Inherited Cardiovascular Disease.

Very early on in my training, I became fascinated with the interplay between genetics and cardiac physiology that manifest in very unique observable cardiac traits and complicated disease trajectories including both heart failure and arrhythmias, also known as irregular heartbeats, says Day.

This story is by Sophie Kluthe. Read more at Penn Medicine News.

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Getting to the heart of genetic cardiovascular diseases | Penn Today - Penn Today

Northern Californias bay area, which includes San Francisco, San Mateo, Santa Clara, Napa, and Marin County, is home to some of the most well-established biopharma companies. The atmosphere is chill, the mood relaxed unless you happen to work for one of these scientific innovators where drive and determination are required to meet the mission.

The Biotech Bay region is home to 3,418 life sciences companies, and 96,574 employees making an average of $151,076. Focuses and technologies range from cell and gene therapy to precision medicine and polymer chemistry, targeting rare diseases along with more pervasive killers. And these seven companies just happen to have a wealth of job openings right now.

Gilead Sciences Inc.

Nestled in Foster City, a small hamlet in San Mateo County, Gilead Sciences is well-known for its achievements in viral diseases, most notably human immunodeficiency virus (HIV).

With a mission of developing novel therapeutics for life-threatening illnesses with unmet medical need, Gilead has an impressive list of FDA-approved medicines. These include Veklury, better known as the COVID-19 therapy, remdesivir, Biktarvy, a single tablet HIV regimen, and Yescarta, a chimeric antigen receptor T cell (CAR-T) drug acquired along with Kite Pharma in 2017.

In 2020, Gilead employed approximately 13,600 individuals. This was an increase of around 2000 (15.25%) from 2019, and the company is growing again.

For those passionate about global access to cancer medicines, Gilead is hiring a Director, Value & Access Strategy Oncology. The successful applicant will have at least 12 years of biopharma experience in market access-related activities bonus points if this is on a regional or country basis. For the more statistically-inclined, Gilead is looking for a Sr. Manager, Biostatistics Oncology.

With well over 300 positions available, opportunities abound to join this Biotech Bay leader.

BioMarin Pharmaceutical Inc.

Established in 1997, San Rafael-based BioMarin specializes in super-rare diseases. BioMarin is targeting cures for diseases like inherited metabolic disorder, Phenylketonuria (PKU), and the rapidly progressing pediatric brain disorder, late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The company also has a strong presence in hemophilia.

With six commercially approved drugs and a market cap of $15.4 billion, BioMarin was cited by Zacks Equity Research as one of four potential biotech takeover targets for 2021. Whether this will be the case, only time will tell, but BioMarin is getting even bigger, with nearly 200 open posts, including:

Associate Director, Global Brand Management - Strategy and Operations. Anyone wanting to make this strategic career move will need to have a minimum of 7 years of pharmaceutical/biotech industry experience.

Senior Associate - Regulatory Affairs. The successful candidate will possess superior decision-making and problem-solving skills and have a tendency to thrive in a cross-functional business environment. A degree in health or life sciences is required; Ph.D. preferred.

Category Manager, Single Use Technology. This job is for those passionate about supply chain operations, with 5-plus years of strategic procurement experience and 3-plus years in the biotech/life sciences industry. BioMarin would prefer someone with an MBA or MS, and a C.P.M.

Arcus Biosciences, Inc.

Founded in 2015, Arcus Biosciences is combining precision therapeutic strategies in an effort to defeat cancers that have thus far eluded medicine. Arcus has clearly been busy over the past six years, with 13 programs in clinical development and five more coming down the discovery pipeline. Targets include a wide range of cancers, including non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer, and colorectal cancer.

Those seeking a position within this unique biopharma company should check out some of the 90-plus jobs currently available. Here are just a couple:

Bioanalytical Scientist. Arcus is actively recruiting a scientist for its Drug Metabolism and Pharmacokinetics (DMPK) department. Interested candidates with a Ph.D. in pharmaceutical sciences or related disciplines should apply.

Principal Investigator/Clinical Biomarkers Translational Science. Arcus is seeking a candidate with expertise in the development, execution, and oversight of biomarker plans for oncology assets.

Associate Director, Clinical Supply. The winner of this position will play a role in all of Arcuss clinical development problems. The desired applicant will have 7-plus years of relevant experience and a Masters degree.

Global Blood Therapeutics

Global Blood Therapeutics (GBT) is comprised of nearly 400 people driven by the mission of delivering life-changing treatments for those with sickle cell disease (SCD) and other severe blood disorders. In late 2019, the FDA approved GBTs oxbryta (voxelotor) as the first treatment to directly inhibit sickle hemoglobin polymerization, the root cause of SCD. Other investigative medicines include a potential treatment to limit the frequency of vaso-occlusive crises (VOCs) and multiple other shots on goal for SCD.

Located on Oyster Point Boulevard in South San Francisco, GBT is looking for new talent to fill more than 80 positions, including:

Director, Clinical Operations. GBT is open to hiring the right person to work remotely from anywhere in the U.S. for this prime leadership position.

Associate Director, Pharmacovigilance Operations. Another remote opportunity for a vigilant leader with 10 or more years of pharmacovigilance experience in an operational and compliance position.

Nektar Therapeutics

San Francisco-based Nektar Therapeutics is focused on curing cancer and autoimmune disease using polymer chemistry, a unique approach to drug design that uses optimized pharmacology to create new molecular entities.

Nektar is leveraging this technology to develop five clinical-stage investigational drugs with partners Bristol Myers Squibb, Biogen, Eli Lilly & Co., and Vaccibody. The companys lead immuno-oncology candidate, bempegaldesleukin, is an IL-2 pathway agonist designed to stimulate the immune system to fight cancer. It is currently being tested in phase III for a number of indications in combination with BMSs OPDIVO. In February, Nektar inked a co-development deal with SFJ Pharmaceuticals to advance bempegaldesleukin in head and neck cancer.

With all of these programs, it is no wonder Nektar is sourcing new talent for more than 50 positions. Here are just a couple.

Clinical Trial Manager. If any (or all) of the above programs appeal, this role might be the right fit. The successful applicant will have eight years of pharmaceutical development experience, with at least two years overseeing trials.

Principal Medical Science Liaison (MSL)-Northeast. A remote opportunity for a creative, technical, and scientifically-minded individual hailing from the Northeast.

Sangamo Therapeutics, Inc.

This genomic medicine company touches on many of biotechs hottest areas including gene therapy, cell therapy, and in vivo genome editing. Sangamos diverse preclinical and clinical-stage pipeline is aimed at solving life-limiting diseases like Hemophilia A, Amyotrophic lateral sclerosis (ALS), Phenylketonuria (PKU), and Fabry disease.

In July 2020, Sangamo entered into a collaboration with Novartis to develop and commercialize gene regulation therapies for three neurodevelopment targets, including autism spectrum disorder. The agreement leverages Sangamos proprietary genome regulation technology, zinc finger protein transcription factors (ZFP-TFs), which aims to upregulate the expression of genes in these disorders.

Anyone wishing to participate in this mission should check out one of Sangamos available positions. A Research Associate III/IV job is one of many associate-level opportunities currently on the board. There are also openings for a few scientist-level positions, including a Research Scientist, Molecular Biology.

Sana Biotechnology

This cell and gene therapy hybrid is developing its cell engineering platform to deliver any payload to any cell in a specific, predictable and repeatable way. Sana is aiming this technology at a wide range of oncologic, genetic, CNS, and cardiovascular targets in a currently all preclinical pipeline.

Sana has been vocal about its culture of inclusion, diversity and equity (IDE), which leadership believes is paramount to its patient-centric culture. By tapping Head of Development Operations, Farah Anwar, as its IDE leader, Sana has ensured that a senior executive is privy to the people dynamics as well the medical ones.

Sana is currently looking to bring on board a Head of Facilities to spearhead its capital project master plan, a Principal Scientist, Genomics Core to advance this key technology, and a Cloud Systems Administrator to oversee the design.

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Biotech Bay is Rich With Opportunity in the Industry's Hottest Spaces - BioSpace

Kriya Therapeutics, based in Redwood City, Calif. and Research Triangle Park, NC,closedon a Series B financing worth $100 million.

Patient Square Capital led the round with participation from new investors Woodline Partners, CAM Capital, Hongkou, Alumni Ventures and others. Existing investors also took part, including QVT, Dexcel Pharma, Foresite Capital, Bluebird Ventures, Transhuman Capital, Narya Capital, Amplo and JDRF T1D Fund.

Kriya is one of BioSpaces NextGen Bio Class of 2021 life sciences startups to watch. In May 2020, it closed on an $80.5 million Series A financing. Its pipeline includes multiple AAV-based gene therapies for type 1 and type 2 diabetes, severe obesity, and other indications.

KT-A112 is a gene therapy to produce insulin and glucokinase for type 1 and 2 diabetes. KT-A522 is a gene therapy administered by salivary gland injection that carries the gene to produce a glucagon-like peptide 1 (GLP-1) receptor agonist for type 2 diabetes and severe obesity. And KT-A832 is a gene therapy that delivers the gene to produce modified insulin growth factor 1 (IGF-1) for type 1 diabetes.

In recent years, we have seen the promise of gene therapy become a reality for the treatment of a number of devastating diseases, said Shankar Ramaswamy, co-founder and chief executive officer of Kriya.

However, the field has been constrained by critical limitations in manufacturing technology, vector design capabilities and cost. Kriya was formed with the mission of revolutionizing how gene therapies are designed, developed and produced by fully integrating advanced manufacturing technologies, computational tools and development capabilities within a single company, Ramaswamy continued.

As part of the financing, Jim Momtazee, managing partner of Patient Square Capital, will join Kriyas board of directors.

We believe that gene therapy will have transformative impact on medicine over time, and companies that are able to integrate platform capabilities delivering better treatments, lower cost and broader applications of the technology are going to drive that innovation, Momtazee said. With that vision, we are incredibly excited to partner with the management team at Kriya to bring multiple important medicines to patients.

In August 2020, the companyannouncedit had secured a manufacturing facility in Research Triangle Park to support its pipeline production. The facility is 51,350 square feet and designed with a fully integrated process development lab, quality control and analytical development capability, pilot production suite, and current good manufacturing practice (cGMP) production infrastructure. It plans to manufacture its gene therapies at the site via its scalable suspension cell culture manufacturing process at up to a 2,000-liter bioreactor scale.

At the time, Britt Petty, Kriyas chief manufacturing officer, said, Manufacturing continues to be a critical bottleneck to the advancement of gene therapies for prevalent diseases. With the establishment of our cGMP manufacturing facility in North Carolina, we are preparing to have the capacity to support our pipeline of programs addressing large patient populations, from initial INDs through late-phase clinical studies. Moreover, we are investing in process innovation and scalable infrastructure with the goal of reducing the costs of goods of our therapies by orders of magnitude.

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Kriya Raised $100 Million in a Series B Round to Advance Gene Therapies - BioSpace

Introduction

Osteoporosis (OP) is a metabolic bone disorder characterized by low bone mass and micro-architectural deterioration of the bone tissue.1 OP increases the risk of bone fractures, which are associated with increased mortality and low quality of life.2 Postmenopausal OP and osteoporotic fractures are common, particularly among older women.3 As there are no signs or symptoms of OP other than bone fractures, risk assessment for OP is necessary to identify individuals at higher risks of future clinical events.4 A diagnosis of OP can be made based on low bone mineral density (BMD) measured by dual-energy X-ray absorptiometry.5 In a meta-analysis of genome-wide association studies, different BMD phenotypes were found to be associated with alpha-L-iduronidase (IDUA) gene polymorphisms.6

IDUA regulation has been demonstrated to affect bone formation. For instance, IDUA-deficient mice progressively developed a high bone mass phenotype with pathological lysosomal storage in cells of osteoblast lineage.7 Histomorphometric quantification further helped identify shortening of bone-forming units in these mice and a reduced quantity of osteoclasts per bone surface.7 In addition, an up-regulation of IDUA was observed in osteoporotic patients compared with healthy older adults.8 Within the IDUA protein, it is hypothesized that the phosphorylation site T366 is indirectly affected by IDUA rs6831280 (A361T) and phosphorylation sites T98 and S102 are affected by IDUA rs3755955 (R105Q).6 To this end, Wang et al recruited 328 OP patients, with or without osteoporotic fractures, to evaluate the association of IDUA gene polymorphisms with BMD and fractures in Chinese elderly patients with OP.9 They found that IDUA rs6831280 polymorphism was associated with BMDs at L2-L4 and total hip BMD.9 In this study, we aim to validate this finding in Chinese women with postmenopausal OP.

Optimal protein and calcium intake, vitamin D supply, and inhibition of smoking and drinking, together with regular weight-bearing physical exercise, are the corner stones for OP and/or osteoporotic fracture prevention.2 Several drugs are licensed to reduce fracture risk by slowing down bone resorption (eg, bisphosphonates and denosumab) or by stimulating bone formation (eg, teriparatide).1 Zoledronic acid (ZA) is an intravenous, highly potent aminobisphosphonate used in patients with primary or secondary OP or low bone mass.10 Its high affinity and long half-life in bones and long duration of action allow for a once-yearly administration.10 Therefore, we intended to explore the role of these two polymorphisms of IDUA gene in OP susceptibility and the therapeutic effect of intravenous ZA administration in Chinese postmenopausal women.

From April 2014 to August 2017, three hospitals (Jintan Hospital Affiliated to Jiangsu University, the Affiliated Changzhou No. 2 Peoples Hospital of Nanjing Medical University, and the Second Affiliated Hospital of Jiaxing University) continuously recruited 660 Chinese postmenopausal women (>1 year since menopause), including 357 OP patients and 303 healthy controls. BMD was measured by trained technicians at the lumbar spine (L2L4) and femoral neck via dual-energy X-ray absorptiometry (Lunar Radiation Corp., Madison, WI, USA). The daily inter-rater variation coefficient was within normal operational standards and in vivo variation coefficient was lower than 1.5%. Based on the definition by the World Health Organization (WHO), the presence of OP was characterized by a BMD T-score of less than 2.5 either at the femoral neck or lumbar spine. Those who had undergone oophorectomy or those who exhibited premature ovarian failure, thyroid disease, rheumatoid arthritis, hypercortisolism, calcium intake disorders, gastrointestinal, and/or renal diseases; those under the age of 40 years; and those who had a history of abnormal bone metabolism or use of medication interfering with bone metabolism were excluded from the investigation.

The annual treatment cost for ZA is equivalent to other oral anti-OP drugs; furthermore, it is easy to use and has good compliance and high bioavailability. Therefore, the OP patients were recommended to use ZA after a kidney function test (creatinine clearance rate 35 mL/min). Each enrolled OP patient received intravenous ZA once a year for 3 years. Intravenous ZA was administered at a dose of 5 mg per 100 mL of 0.9% saline solution with a standardized duration of 30 to 40 min. Patients received 500 mL of intravenous saline before/after ZA infusion. Daily supplementation with calcium (500 mg) and vitamin D (400 IU) was strongly recommended. However, 9 OP patients with severe cognitive impairment, bisphosphonate-related osteonecrosis of the jaw, allergy, and previous ZA contraindications were excluded during treatment. In all, 70 OP patients did not complete the entire treatment process. We finally performed data analysis on 278 OP patients and 303 healthy controls. The response to ZA treatment was evaluated based on the trend of BMD in the lumbar spine. An increase in lumbar spine BMD exceeding 0.05 g/cm2 was indicative of effective treatment, and any results otherwise were suggestive of ineffective treatment. Accordingly, the OP patients were divided into responders and non-responder groups with respect to ZA treatment. Individuals in the control group did not have a previous history of OP and/or fractures and were age matched to the participants with OP. All participants were of Chinese Han ethnicity and were genetically unrelated. Daily physical activity, menstrual history, and family history concerning the incidence of fractures were obtained from all participants. Data regarding calcium and vitamin D intake were also collected through a structured questionnaire. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Written informed consent was obtained from all participants in the study before enrollment. Confidentiality of personal and medical data was conducted in accordance with the Helsinki declaration. The Clinical Ethics Committee of the aforementioned three hospitals [Jintan Hospital Affiliated to Jiangsu University (ID: KY-2014-010), the Affiliated Changzhou No. 2 Peoples Hospital of Nanjing Medical University (ID: [2017] KY008-01), and the Second Affiliated Hospital of Jiaxing University (ID: JXEY-2015SW68)] approved this investigation.

Blood samples collected from each participant were used to genotype polymorphisms. Genomic DNA was isolated from peripheral leukocytes using the TIANamp Blood DNA kit (Qiagen, Hilden, Germany). We selected single nucleotide polymorphisms (SNPs) in the IDUA gene according to the following criteria: minor allele frequency >5% and significant association with BMD or BMD-related risk factors reported in previous studies.

IDUA gene polymorphisms were genotyped via polymerase chain reaction (PCR) and Sanger sequencing (Genesky Biotechnologies Inc., Shanghai, China). The primers used in this study were as follows: rs3755955: 5-CGCAGCATCAGAACCTGCTACT-3 (forward); 5-CGGGTGTTGTTGACCTGGAAG-3 (Reverse); rs6831280: 5-TCTGAAACTGTCCTGTTGACTCAG-3 (forward); 5-ATCAATGTTGAGCAATTGTCAG-3 (Reverse). Five percent of the samples were repeatedly genotyped to ensure the validity of the genotyping methods.

A chi-square test was used to evaluate the differences in categorical variables and percentages were used between two groups. The mean and SD of continuous variables were calculated and tested using Students t-test or an analysis of variance. Deviation from HardyWeinberg equilibrium (HWE) for IDUA gene polymorphisms was assessed among the control individuals using chi-square test. Logistic regression analysis was applied to calculate the odds ratios (ORs) and 95% confidence intervals (95% CI) for evaluating the association between IDUA gene polymorphisms and the risk of OP. A value of P < 0.05 was considered statistically significant. All data were analyzed using SPSS 22.0 software (SPSS Inc., Chicago, USA).

Baseline participant characteristics are shown in Table 1. The case group comprised 278 postmenopausal women with a mean age of 62.788.40 years and BMI of 24.39 kg/m2. Among all participants, most women (65.1%) did not have diabetes; however, the number of women with diabetes differed significantly between groups (P=0.016). There was a significant difference between vitamin D and calcium intake and lumbar spine/femoral neck BMD between participants with OP and healthy controls (P<0.001).

Table 1 Patient Demographics and Risk Factors in Osteoporosis

The genotype distribution information of the two SNPs in IDUA is provided in Table 2. The A allele frequencies of IDUA rs3755955 and rs6831280 polymorphisms were 19.4% and 27.2% among participants, with OP and 13.5% and 21.3% among healthy controls, respectively. The genotype distribution of these two polymorphisms was in agreement with HWE in the healthy control group.

Table 2 Genotype Frequencies of IDUA Gene Polymorphisms in Cases and Controls

Our study demonstrated that the AA genotype or A allele of IDUA rs3755955 polymorphism was associated with an increased risk of OP (AA vs GG: OR, 2.88; 95% CI, 1.087.64; P = 0.034; A vs G: OR, 1.54; 95% CI, 1.132.11; P = 0.007). Similarly, GA+AA genotype had a 1.53-fold higher risk of OP than the GG genotype. Furthermore, IDUA rs6831280 polymorphism conferred susceptibility to OP under the homozygous, dominant, and allelic models. These associations remained significant after adjusting for age, BMI, and diabetes mellitus. Additionally, IDUA rs6831280 polymorphism increased the risk of OP in the recessive model.

We further investigated the association of IDUA gene polymorphisms with the demographic (ie, age and BMI) and clinical data (ie, diabetes and lumbar spine/femoral neck BMD) (Table 3). For rs3755955, the age of the AA genotype carrier was found to be significantly younger than that of the GA/GG genotype carriers. In addition, IDUA rs3755955 polymorphism was significantly associated with lumbar spine BMD, with the AA genotype having the lowest BMD. Furthermore, the femoral neck BMD of the AA genotype carrier in rs3755955 polymorphism was significantly lower than that of GA/GG genotype carriers. However, no significant association with clinical parameters was found for rs6831280 polymorphism.

Table 3 The Biochemical Measurements of the Study Population

We recorded baseline characteristics of responders (61.5% of participants) and non-responders to ZA treatment (Table 4). The mean age and BMI of responders and non-responders were not significantly different (all P > 0.05). Similarly, among responders, there was no significant difference between participants with OP and healthy controls with regard to vitamin D and calcium intake, diabetes status, and lumbar spine/femoral neck BMD.

Table 4 Clinical Characteristics of Patients Treated with Aclasta

Furthermore, this study investigated the effect of these two polymorphisms on the therapeutic effect of intravenous ZA (Table 5). There was no significant difference in the genotypic distribution of rs3755955 polymorphism between responders and non-responders to ZA treatment. However, the incidence of the A allele, GA+AA genotype, or AA genotype of IDUA rs6831280 polymorphism was higher in responders than in non-responders (A vs G: OR, 0.50; 95% CI, 0.330.75; P = 0.001). The findings remained significant after adjusting for age, BMI, and diabetes mellitus. This indicated that ZA treatment was more effective in individuals with the A allele.

Table 5 The Distribution of Genotype Frequencies of IDUA Gene Polymorphisms in Responders and Non-Responders

In this study, we found that IDUA rs3755955/rs6831280 polymorphisms increased the risk of OP in a population of Chinese women. Furthermore, IDUA rs3755955 polymorphism in women with OP was associated with a younger age and lower lumbar spine BMD. Finally, IDUA rs6831280 polymorphism caused differences in individual sensitivity to ZA treatment for OP.

Protein phosphorylation is the most basic, universal, and most important mechanism for regulating and controlling protein vitality and function.11 Protein phosphorylation occurs mainly in two amino acids: serine (including threonine), and tyrosine.11 Gene polymorphisms that create, alter, or destroy phosphorylation sites have been recognized as functional variants for human diseases, such as prostate cancer (TP53 rs1042522)12 and tuberculosis (TLR2 rs5743708).13 Niu et al found that IDUA phosphorylation-related SNPs rs3755955 and rs6831280 exert indirect effects on nearby phosphorylation sites, which could affect the risk of OP.6

Wang et al recruited 172 OP patients with low-traumatic fractures and 156 OP patients without fracture to investigate the relationship of two SNPs (rs3755955 and rs6831280) with BMD and fractures.9 They found that BMDs at lumbar spine L2L4 and total hip among subjects with the GA genotype of rs6831280 polymorphism were lower than those among subjects with the GG or AA genotype carriers.9 IDUA rs6831280, and not rs3755955, polymorphism is a genetic risk factor for osteoporotic fractures.9 Our results revealed that IDUA rs3755955 and rs6831280 polymorphisms increased the susceptibility of postmenopausal women to OP. Individuals with the AA genotype of rs3755955 polymorphism had the lowest lumbar spine BMD compared with GA or GG genotype. Notably, this study focused on the association of IDUA gene polymorphisms with OP, but not with fractures. Furthermore, our study demonstrated that IDUA rs3755955 polymorphism is associated with BMD at lumbar spine, instead of rs6831280 polymorphism reported by Wang et al.9 This inconsistency may be attributed to geographical differences (Northern and Southern), dietary differences, and population heterogeneity. A single infusion of intravenous ZA decreases bone turnover and improves BMD after 12 months in postmenopausal women with OP10 and significantly reduces the risk of vertebral, hip, and other fractures.14 Since IDUA rs3755955 and rs6831280 polymorphisms were associated with lumbar spine BMD, our study evaluated the effect of these SNPs on the sensitivity to ZA. There was no significant difference between responders and non-responders to ZA treatment in the allelic and genotypic distribution of the rs3755955 polymorphism. However, we could not rule out the possibility of false-positive results because of a small sample size. Nevertheless, the A allele frequency of rs6831280 polymorphism in participants with OP was significantly higher than that in healthy controls. Therefore, mutant genotypes were more sensitive to ZA, and the increased treatment effect was significant. To the best of our knowledge, this study is the first to evaluate the association between IDUA gene polymorphisms and ZA treatment, and may serve to guide further studies in this field.

Several potential limitations of our study merit careful consideration. First, the sample size was relatively small, which could have produced false-positive or false-negative results. Second, this study only genotyped two SNPs of the IDUA gene and the coverage of this gene was incomplete. Third, we did not include many risk factors for OP (eg, smoking and history of personal fractures) into consideration because of the limited data availability. Finally, these results should be validated in other populations in China and in other countries.

In conclusion, our group identified a significant association between IDUA gene polymorphisms and OP. Further studies with larger sample sizes in other races and ethnicities are urgently warranted to identify the genetic profile of individuals with OP.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

This study was supported by the National Natural Science Foundation of China (81702179), Funding from Young Talent Development Plan of Changzhou Health Commission (CZQM2020059), Science and Technology Plan Project of Changzhou (CJ20190002), and Zhejiang Medicine and Health Technology Plan (2020KY313).

No potential conflict of interest was reported by the authors.

1. Eastell R, ONeill TW, Hofbauer LC, et al. Postmenopausal osteoporosis. Nat Rev Dis Primers. 2016;2:16069. doi:10.1038/nrdp.2016.69

2. Rizzoli R. Postmenopausal osteoporosis: assessment and management. Best Pract Res Clin Endocrinol Metab. 2018;32(5):739757. doi:10.1016/j.beem.2018.09.005

3. Black DM, Rosen CJ, Solomon CG. Postmenopausal osteoporosis. N Engl J Med. 2016;374(18):1797. doi:10.1056/NEJMx160008

4. Watts NB. Postmenopausal osteoporosis: a clinical review. J Womens Health (Larchmt). 2018;27(9):10931096. doi:10.1089/jwh.2017.6706

5. Baccaro LF, Conde DM, Costa-Paiva L, Pinto-Neto AM. The epidemiology and management of postmenopausal osteoporosis: a viewpoint from Brazil. Clin Interv Aging. 2015;10:583591. doi:10.2147/CIA.S54614

6. Niu T, Liu N, Yu X, et al. Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies. J Bone Miner Res. 2016;31(2):358368. doi:10.1002/jbmr.2687

7. Kuehn SC, Koehne T, Cornils K, et al. Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I. Hum Mol Genet. 2015;24(24):70757086. doi:10.1093/hmg/ddv407

8. Zhou Z, Gao M, Liu Q, Tao MD. Comprehensive transcriptome analysis of mesenchymal stem cells in elderly patients with osteoporosis. Aging Clin Exp Res. 2015;27(5):595601. doi:10.1007/s40520-015-0346-z

9. Wang Q, Tang C, Jia J, Zhang G, Liu Z. Associations of IDUA and PTCH1 with bone mineral density, bone turnover markers, and fractures in Chinese elderly patients with osteoporosis. Dis Markers. 2019;2019:9503762. doi:10.1155/2019/9503762

10. Dhillon S. Zoledronic acid (Reclast((R)), Aclasta((R))): a review in osteoporosis. Drugs. 2016;76(17):16831697. doi:10.1007/s40265-016-0662-4

11. Humphrey SJ, James DE, Mann M. Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol Metab. 2015;26(12):676687. doi:10.1016/j.tem.2015.09.013

12. Fan S, Hao ZY, Zhang M, Liang CZ. Association between the rs1042522 polymorphism in TP53 and prostate cancer risk: an updated meta-analysis. Chronic Dis Transl Med. 2017;3(2):95104. doi:10.1016/j.cdtm.2017.04.001

13. Cubillos-Angulo JM, Arriaga MB, Silva EC, et al. Polymorphisms in TLR4 and TNFA and risk of mycobacterium tuberculosis infection and development of active disease in contacts of tuberculosis cases in Brazil: a prospective cohort study. Clin Infect Dis. 2019;69(6):10271035. doi:10.1093/cid/ciy1001

14. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):18091822. doi:10.1056/NEJMoa067312

Link:
IDUA Gene Variants and Response to Zoledronic Acid Treatment in Chines | PGPM - Dove Medical Press

British-born cardiologist Dr Euan Angus Ashley, 49, is one of the pioneers in the application of gene sequencing in medicine and part of an international network of specialists working tirelessly to make the long-held dream of genetic-based medicines an everyday reality.

Based in California, where he serves as Professor of Medicine and Genetics at Stanford University as well as the Head of Stanford Center for Undiagnosed Diseases, and the founding director of the Center for Inherited Cardiovascular Disease as well as Stanfords Clinical Genomics Program, Dr Ashley has just published new popular science book The Genome Odyssey, which reveals how our understanding of the human genome is now revolutionizing medicine, unlocking the secrets of mystery diseases and leading to powerful new treatments for our most intractable illnesses.

In this exclusive interview, Dr Ashley discusses his fascinating new book, explains why we are currently in a golden age of genomic medicine, and reveals just how fundamentally the rise of genetic healthcare will transform society for the better.

Q. How can our genetics cause illnesses? To what extent would you say that diseases and morbidity ultimately have bad genes to blame?

A. Essentially, all diseases have a genetic component. For some diseases they can be almost entirely explained by one letter change in the genome, for others its half nature and half nurture, and for some others still, a pathogen (like a virus) or the immune system is more to blame than the human genome, which plays a smaller role. Even for those diseases, though, genetic sequencing can help us understand the pathogen or the changes in our immune cells.

Q. As you make clear in your new book, The Genome Odyssey, we are on the cusp of a new era of genetic-based medicine. Why should we be excited about this?

A. We are finally understanding diseases that have remained mysterious for hundreds of years. And that understanding now allows us to develop medicines that can very precisely target those diseases. We sometimes call this precision medicine. Devastating illnesses that affect millions of people around the world like sickle cell disease or haemophilia could in the near future be, essentially, cured. This is not business as usual. This is a revolution.

Q. You say that we will all benefit from genetic medicine in the future. Does this mean that the costs of genetic sequencing and treatments have come down significantly in recent years?

A. Its hard to think of an example where a technology has become as accessible so quickly as is the case with genome sequencing. People often talk about how fast computers advance in their computing power but genome sequencing has advanced much faster. Its like being able to buy a Ferrari for a penny!

Q. What has been your role in the development of genetic-based medicine?

A. Back in 2009 I walked into a colleagues office and he showed me his genome. He was the fifth person in the world to have his genome sequenced. After he started showing me his genome I recognized a few of the genes in which he had variations, and which were known to be associated with hypertrophic cardiomyopathy, an inherited cause of sudden death. I started asking him about his family medical history to see if there were cases of sudden, unexplained deaths. It turned out his family had quite a lot of these incidents, including his cousins son who had died suddenly aged 19 years. Long story short, shortly after, he became the first patient in the world to walk into a doctors office with his genome. And rather terrifyingly at the time, that doctor was me!

Q. The Genome Odyssey provides a fascinating survey of genetic medicine. What motivated you to write it?

A. I love stories. I live in awe of my patients and what they go through living from one day to the next with these challenging diseases. I wanted to tell the stories of these brave individuals in the hope that it would give others strength and inspiration.I am also fascinated by stories of scientists and innovators who break boundaries to push technologies to the limits. I love the fact I get to live among these amazing scientists here in Silicon Valley. I try to emulate them and make discoveries to help humanity.I hoped in the book to weave the very human stories of the patients and families affected by disease together with the stories of the scientists who make those breakthroughs possible. I explain some science along the way but always try to keep it light and anchor each chapter with a remarkable story from a patient so we can understand how those scientific breakthroughs come to affect real people.

Q. In your book you compare doctors involved with genomic medicine as akin to fictional detective Sherlock Holmes. Can you explain the similarity?

A. Solving medical mysteries is exactly like solving crimes. In fact, not many people realize that Sherlock Holmes creator, Arthur Conan Doyle, was himself a physician (an ophthalmologist) and that he based the character of Holmes on a Scottish surgeon with an uncanny eye for detail. In medical or criminal mysteries, you have to survey the scene, interrogate the witnesses, come up with hypotheses, and then test them. What TV shows like House, M.D. and CSI: Crime Scene Investigation have illustrated is that the application of technology to these mysteries raises the odds of solving the case. The genome is a big part of that.

Q. Towards the close of your book you project forward to future applications of genetic medicine. One of these involves identifying and harnessing the genetic powers of superhumans. What do you mean by the term superhuman, and how do you think learning about their genetic codes will help make us all healthier?

A. It turns out that if you study large populations of humans (who are willing to share their health and genetic data) you find out a lot about disease. One of the unusual things you can detect is that some people are remarkably resilient to disease. I discuss a few examples in the book, such as an Olympic athlete, a woman with extremely low cholesterol, and a young boy who didnt feel pain. These genetic superheroes can, in effect, teach us how to make everyone else just a bit more super. And its now a big focus for pharmaceutical companies. More than that, it appears to be paying off. New drugs developed following on from this genomic revolution are coming to market and showing major benefits. In fact, it would be reasonable to say that no drug will likely be developed in the future without someone asking if there is human genetic evidence that it will work. This is a big change from how we used to develop drugs, where we would often test a number of theories in small animals like mice before we ever got near humans.

Q. You mention in your book that the UK is leading the way in the field of genomic medical research. Can you explain more?

A. The UK is, indeed, at the forefront of genomic research globally. In fact, the genetic technology that has been responsible for the genome revolution came together in Cambridge! And a new disruptive sequencing technology is being developed in Oxford. But the UK is also at the forefront of population genetic studies. Without doubt the most influential genetic population study in the world today is the UK Biobank. Literally thousands of papers have been written as a result of the 500,000 UK citizens being willing to share their health and genetic data. I discuss a few examples in the book of insights that have come from the UK biobank research. But those insights are just the beginning. Also in the application of genome sequencing to medical care, Genomics England is one of the worlds most successful endeavourshaving sequenced more than 100,000 individuals with rare disease to try to find answers. Finally, the UK is not resting on its laurels, launching soon a new program called Our Future Health which aims to recruit five million Britons into the largest study of preventive genomics anywhere in the world. Our Future Health is focused on incorporating knowledge of your genome to help you better direct lifestyle and preventive efforts to avoid disease.

Q. You also discuss the development of gene therapy in providing new treatments for such conditions as haemophilia. What are the current challenges in changing genes or gene expression itself within the human body and how will these be overcome?

A. The history of genetic therapy has been long and winding, and many lessons have been learned along the path to the current golden age of genetic therapywith many successes building on the lessons of the last 30 years. The challenges that remain now are to broaden the impact of therapies beyond the organs and organ systems that are easiest to deliver therapies to (the liver, the eye, and cells outside of the body like from our bone marrow). Getting gene therapies to the heart or the brain is much harder than to the liver or eye so we have to work towards new delivery systems using fat particles or inactivated viruses that can help us approach those conditions.

Q. Just how far do you think genetic-based testing and treatment will change the face of medicine in the coming decades?

A. I think genetic testing and treatment will touch every aspect of health and medicine. There isnt a disease without a genetic component. And as we understand that better we will be able to integrate that with knowledge of our environment (it is often said that your postcode might be more important than your genetic code in predicting your future health, but in reality they are inseparable and each provides insight into how best to avoid or treat disease).

Q. The Genome Odyssey is packed with fascinating stories and information on the cutting edge of medical science, but what for you is the most interesting element of the book?

A. Well, the obvious answer is the stunning advances in genome sequencing, the computing that makes analysis of this data possible, and the patients it impacts. But the less obvious answer is that, at various times during writing, I became obsessed with other smaller things, many of which made it into the book in some form like Sherlock Holmes (I read all the books) or Homers Odyssey (that is a looong book) but many of which did not (or if they did, they live in the endnotes). For example, I got deeply obsessed with sentences that only contain the word Buffalo (little known fact: the word can be a verb, noun, and adjective). Related, the origin of Buffalo chicken wings was fascinating to me. Also, the origin of the Human Genome Project and things like the fact that two of the people drawing blood for the original volunteers were identical twins. I love these kinds of trivial and sometimes tangential observations.

Q. What first led you into becoming a doctor, and why did you choose to specialise in both cardiology and rare diseases?

A. For as long as I can remember I have always wanted to be a doctor. My dad was a GP in Glasgow and my mum a midwife, and they used to take me on their house calls when I was little. I was also always fascinated by the heart. I just loved the fact that it moved with rhythm and its movement made sounds like music. Genetics was somehow also in my destiny after my biology teacher gave me a copy of The Selfish Gene by Richard Dawkins when I was in secondary school (he also told my parents I was a buffoon who would never amount to muchchallenge accepted). But it was my nerdy nature and the fact I loved to program computers that really sealed my fate. As genetics became a specialty where you needed large computers to understand the big data, I was drawn to that like a magnet. And Silicon Valley was the place it all seemed to be coming together. So today, I am lucky enough to get to do all this with amazing colleagues in a beautiful and sunny part of the world.

Q. What is the most satisfying part of your vocation?

A. My patients. I live for my patients. And I live in awe of my patients and what they go through. We get to stand next to them for a while as they go through lifes ups and downs but we should never forget that as we move on the next patient they are still there living through the challenges of their disease. So for me everything starts and ends with the patients. But I also love the scientific process. I love the excitement of a new idea. The frisson of the unknown. The anticipation of what might be. I also love the energy of teams. I feed off that energy and try to reflect it back.

Q. Being a doctor must take up most of your time but, in those rare moments that it doesnt, how do you like to unwind?

A. Well, for many years I spent as much time playing saxophone in various jazz bands as I did learning medicine. I still love jazz and play now with my kids (my daughter plays saxophone and my youngest son just started drums). I also love sport and am on a quest to finally understand American sports (whereas football and rugby are engraved in my soul). Im also known for my love of single malt and I enjoy imparting a little piece of Scotland to my California friends who are always eager to learn.

Q. What has been your proudest medical achievement to date, and what are you and your team currently working on?

A. I think seeing what our community around the world has been able to do with genome sequencing technology is very fulfilling. I am proud to have been a small part of that. We are currently working on how to make genome sequencing faster, cheaper, more accurate and, most importantly, more available to everyone who could benefit. But we also want to cure the diseases that cause heart failure and sudden death. Too many people still die unnecessarily, devastating the families left behind. We understand those diseases better now thanks to genome sequencing but the journey towards curing those diseases is just beginning.

The Genome Odyssey: Medical Mysteries and the Incredible Quest to Solve Them (St. Martins Press) by Dr Euan Angus Ashley is out now on Amazon in hardcover, eBook, and audiobook formats, priced 22.99, 9.49, and 20.47 respectively. For more information visit http://www.genomebook.info.

The rest is here:
Charting The Genetic Medicine Revolution: An Interview With Author Of The Genome Odyssey, Dr Euan Angus Ashley - The London Economic

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Foundation Medicine, Inc. today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOneLiquid CDx to be used as a companion diagnostic to aid in identifying patients with MET exon 14 skipping (METex14) in metastatic non-small cell lung cancer (NSCLC) for whom treatment with TABRECTA (capmatinib) may be appropriate. TABRECTA is the first therapy approved by the FDA for adult patients with metastatic NSCLC whose tumors have an alteration that leads to METex14. FoundationOne Liquid CDx analyzes the largest genomic region of any FDA-approved comprehensive liquid biopsy test and was approved by the FDA in August 2020 to report genomic alteration results for patients with any solid tumor.

NSCLC accounts for approximately 85% of lung cancer diagnoses,[1] 3 to 4% of which are associated with METex14.[2] Today's approval adds to the number of therapies for which both of Foundation Medicines FDA-approved comprehensive genomic tests are listed as companion diagnostics. FoundationOneCDx, Foundation Medicines tissue test, was approved as a companion diagnostic for TABRECTA in May 2020.

For lung cancer patients with METex14, having the option of a non-invasive liquid biopsy expands access to this first-of-its kind therapy and helps meet a critical patient need, said Brian Alexander, M.D., M.P.H., chief executive officer at Foundation Medicine. This approval, coupled with last years simultaneous therapy and companion diagnostic approval for TABRECTA and our tissue test, FoundationOne CDx, is an important advancement and demonstrates the value of having multiple highly-validated comprehensive genomic testing options for physicians to consider for the individual needs of each patient.

Using a simple blood sample, FoundationOne Liquid CDx analyzes over 300 cancer-related genes for genomic alterations. The test is now approved as a companion diagnostic for nine targeted therapies across four cancer types. TABRECTA is the second therapy for which both of Foundation Medicines FDA-approved tests, FoundationOne CDx and FoundationOne Liquid CDx, are listed as companion diagnostics.

Additionally, as a laboratory professional service which has not been reviewed or approved by the FDA, the FoundationOne Liquid CDx report delivers information about the genomic signatures microsatellite instability (MSI) and blood tumor mutational burden (bTMB), as well as single gene alterations, including NTRK fusions, to help inform the use of other therapies including immunotherapies. Also, as a laboratory professional service, the report provides relevant clinical trial information and includes interpretive content developed in accordance with professional guidelines in oncology for patients with any solid tumor.

Foundation Medicines strategic collaboration with Novartis now includes four companion diagnostics for the Novartis portfolio of targeted oncology therapeutics.

About FoundationOne Liquid CDx

FoundationOne Liquid CDx is a qualitative next generation sequencing based in vitro diagnostic test for prescription use only that uses targeted high throughput hybridization-based capture technology to analyze 324 genes utilizing circulating cell-free DNA (cfDNA) isolated from plasma derived from anti-coagulated peripheral whole blood of advanced cancer patients. The test is FDA-approved to report short variants in over 300 genes and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies (listed in Table 1 of the Intended Use) in accordance with the approved therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Patients who are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and genomic alteration status confirmed using an FDA-approved tumor tissue test, if feasible. For the complete label, including companion diagnostic indications and complete risk information, please visit http://www.F1LCDxLabel.com.

About Foundation Medicine

Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patients cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicines molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit http://www.FoundationMedicine.com or follow Foundation Medicine on Twitter (@FoundationATCG).

Foundation Medicine and FoundationOne are registered trademarks of Foundation Medicine, Inc.

TABRECTA is a trademark of Novartis.

Source: Foundation Medicine

Original post:
Foundation Medicine Expands Indication for FoundationOneLiquid CDx to be Used as a Companion Diagnostic for TABRECTA (capmatinib) - Business Wire