Gene therapy is a medical therapeutic process involving the delivery of the gene into cells to treat diseases. It is an application of recombinant DNA technology in the field of medicine. The main aim of gene therapy is to cure a disease by providing the patient with a correct copy of the defective gene. The technique can be applied to target specific affected tissues in the body. Although gene therapy was used to treat inherited disease in earlier attempts, the application has now been extended to cure any disease by the introduction of a cloned gene into the patients cells or tissues instead of drugs. One of the potential benefits of gene therapy is that it can be used to treat diseases with single or few administrations rather than frequent dosing.

The possibility of gene therapy began in the 1960s and 1970s when scientists discovered the first evidence for uptake and expression of exogenous DNA in mammalian cells. However, due to the lack of gene transfer methods and the inefficiency of the techniques available, then, the concept could not be materialized. In the early 1970s, the development of genetically marked cell lines and the clarification of mechanisms of cell transformation by the papovaviruses polyoma and SV40 suggested the use of transforming viruses for therapeutic gene transfer. The first attempt to the gene transfer in a human was carried out by Martin Cline and his colleagues at UCLA in 1980. They conducted an rDNA transfer into the bone marrow cells of two thalassemia patients.

There are two basic approaches to gene therapy Germline Therapy and Somatic Cell Therapy.

In germline therapy, germ cells (sperms or eggs) are modified. A fertilized egg is provided with a copy of the correct version of the relevant gene and re-implanted into the mother. If successful, the gene is present and expressed in all cells of the resulting individual. Germline therapy is usually carried out by microinjection of a somatic cell followed by nuclear transfer into an oocyte and theoretically could be used to treat any inherited disease. Germline gene therapy, however, raises various ethical and technical concerns and is prohibited in many countries, including Australia, Canada, Germany, Switzerland, and Israel.

Somatic cell therapy involves the manipulation of cells, which either can be removed from the organism, transfected, or then placed back in the body, or transfected in situ without removal. The technique has the most promise for inherited blood diseases such as hemophilia and thalassemia, with genes being introduced into stem cells from the bone marrow, which give rise to all the specialized cell types in the blood. The strategy is to prepare a bone marrow extract containing several billion cells, transfect these with a retrovirus-based vector, and then re-implant the cells. Subsequent replication and differentiation of transfectants lead to the added gene being present in all the mature blood cells. Thus, in somatic cell therapy, the effects caused by the foreign gene is restricted to the individual patient only and is not inherited to the offspring.

The gene therapy can be carried out ex vivo or in vivo. In the ex vivo approach, the intended genes are transferred into the cells grown in culture. Transformed cells are selected and then re-introduced into the patient. The in vivo approach involves the transfer of cloned genes directly into the tissues of the patient.

The process of gene therapy starts with the selection of a suitable vector, a carrier that will transfer the intended gene to the cells. Two types of vectors used in gene therapy are viral vectorsrecombinant viruses, and non-viral vectorsnaked DNA or DNA complexes. The viral vectors introduce their genetic material into the host cell and use the host cells machinery to produce proteins encoded by the viral DNA. Viruses used in gene therapy are retroviruses, adenoviruses, adeno-associated virus, herpes simplex, and vaccinia. Retroviruses are most commonly used because they can incorporate their genetic material into the host cells DNA, thus changing the genetic component of that cell. And they have an extremely high transfection frequency, enabling a large proportion of the stem cells in a bone marrow extract to receive the new gene.

As the vector binds and enters inside the target cell, its genetic material enters the cells nucleus. Then, the viral vector either tricks the host cells machinery to replicate its genetic material or integrate its genetic material into the host genome and cause it to replicate and produce proteins encoded by the viral genetic material. Thus, the therapeutic gene previously recombined with the viral genetic material can be expressed in the host cell.

Gene therapy techniques are applied with various strategies based on the need for function. Gene augmentation therapy is used to add a functioning gene into a cell with a non-functioning copy of that gene. It is suitable to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein. Similarly, Gene inhibition therapy is suitable for the treatment of cancer, infectious, and inherited diseases caused by improper gene activity. This does so by blocking the expression of a gene or interfering with the activity of the product of another gene. The third strategy is targeted killing of specific cells such as cancers by inserting suicide genes or genes encoding antigenic proteins. The fourth strategy is correcting a defective or mutant gene to restore its function.

Scientists and researchers have been working on gene therapy for a few decades, and hundreds of trials are in the clinical phase, most in the first-in-human phase. The number of patients who have received effective gene-based therapy is few, but the future of gene therapy is promising. The diseases and disorders that have been successfully treated by gene therapy so far include immune deficienciesSevere Combined Immune Deficiency (SCID) and Adenosine deaminase (ADA) deficiency, Hereditary blindness, Hemophilia, beta-Thalassemia, Fat metabolism disorder, several types of cancermelanoma, leukemia, and Parkinsons disease. Gene therapy is, therefore, becoming the game changer of modern therapeutic medicine.

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Gene Therapy How Does It Work and Its Examples

Boston Children's Hospital researchers used an investigational gene therapy to treat heart failure in a mouse model of Barth syndrome. Barth syndrome is a rare genetic disorder in boys that results in life-threatening heart failure. It also causes weakness of the skeletal muscles and the immune system. The disease is caused by a mutation of a gene known as tafazzin or TAZ.

In 2014, William Pu and researchers at Boston Childrens Hospital collaborated with the Wyss Institute to develop a beating heart on a chip model of Barth syndrome. It used heart-muscle cells with the TAZ mutation that came from patients own skin cells. This was able to prove that TAZ was the cause of the cardiac problems. The heart muscle cells did not organize normally and the mitochondria, the cells energy engines, were disorganized, resulting in the heart muscle contracting weakly. By adding healthy TAZ genes, the cells behaved more normally.

The next step was an animal model. The results of the research were published in the journal Circulation Research.

The animal model was a hurdle in the field for a long time, Pu said. Pu is director of Basic and Translational Cardiovascular Research at Boston Childrens and a member of the Harvard Stem Cell Institute. Efforts to make a mouse model using traditional methods had been unsuccessful.

Douglas Strathdees research team at the Beatson Institute for Cancer Research in the UK recently developed animal models of Barth syndrome. Pu, research fellow Suya Wang, and colleagues characterized the knockout mice into two types. One had the TAZ gene deleted throughout the body; the other had the TAZ gene deleted just in the heart.

Most of the mice that had TAZ deleted throughout their whole bodies died before birth, likely from skeletal muscle weakness. Of those that survived, they developed progressive cardiomyopathy, where the heart muscle enlarges and is less able to pump blood. The heart also showed signs of scarring similar to humans with dilated cardiomyopathy, where the hearts left ventricle is dilated and thin-walled.

The mice that lacked TAZ only in their heart tissue that survived to birth had the same features. Electron microscopy indicated that the heart muscle cells and mitochondria were poorly organized.

Pu and Wang and their team then used gene therapy to replace TAZ in the newborn mice and in older mice, using slightly different techniques. In the newborn mice the engineered virus was injected under the skin; in the older mice it was injected intravenously. The mice who had no TAZ in their bodies and received the gene therapy survived to adulthood.

In the newborn mice receiving the gene therapy, the therapy prevented cardiac dysfunction and scarring. In the older mice receiving the therapy, it reversed the cardiac dysfunction.

The study also showed that TAZ gene therapy offered durable treatment of the cardiomyocytes and skeletal muscle cells, but only when at least 70% of the heart muscle cells had taken up the gene via the therapy. Which the researchers point out that when the therapy is developed for humans, that will be the most challenging problem. You cant just scale up the dose because of inflammatory immune responses, and multiple doses wont work either because the body develops an immune response. Maintaining the gene-corrected cell is also a problem. In the heart muscles of the treated mice, the corrected TAZ gene stayed relatively stable, but slowly dropped in skeletal muscles.

The biggest takeaway was that the gene therapy was highly effective, Pu said. We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle.

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Gene Therapy Reverses Heart Failure in Animal Model of Barth Syndrome - BioSpace

The Center for Gene Therapy at Nationwide Childrens Hospital is working to develop childrens gene therapy treatments. Officials say the gene therapy research and clinical trials there are starting to attract companies to central Ohio.

Nationwide Childrens Hospital is in the forefront of curing several genetic childhood diseases, transforming Columbus into a major medical hub, several gene therapy experts say.

The hospital's Center for Gene Therapy at the Abigail Wexner Research Institute is working to develop treatments for children, which is attracting patients and companies to Ohio, according to officials at Nationwide Childrens and JobsOhio, the state's economic development organization.

The illnesses that were making use of in gene therapy are devastating illnesses, said Dr. Kevin Flanigan, the director of Nationwide Childrens Center for Gene Therapy. These are ones we know that children would be significantly impaired for life or die because of the disease.

Gene therapy involves altering the genes inside the patient's cells in an effort to treat or stop disease. It gives doctors the chance to treat many previously untreatable rare and genetic diseases.

Gene therapy is currently available primarily in a research setting, with only four gene therapy products approved by the U.S. Food and Drug Administration for sale in the United States. One of the four, Zolgensma, started as a clinical trial for spinal muscular atrophy at Nationwide Childrens in 2014.

The hospital is working on a handful of gene therapy treatments for various childhood diseases that affect muscle, motor or mental functions, Flanigan said.

Gene therapy presents a tremendous opportunity for our medical system, and Columbus has been a huge part of that growth thanks to the work being done at Nationwide Childrens Hospital, Edith Pfister, chairwoman of the American Society of Gene & Cell Therapys communications committee, said in an email.

The FDA approved Zolgensma, a one-time treatment that intravenously delivers the gene that is missing in children with spinal muscular atrophy, on May 24.

SMA is a progressive childhood neuromuscular disease that is caused by a mutation in a single gene that attacks nerve cells. It causes major physical limitations including the inability to breathe, swallow, talk or sit up. Children born with SMA typically die or need permanent breathing assistance by the time they turn 2 years old.

Donovan Weisgarber was diagnosed with SMA type 1 at Nationwide Childrens in November 2015 when he was 5 weeks old. His parents, Matt and Laura Weisgarber, decided to participate in a clinical trial at the hospital and Donovan received Zolgensma.

Before the treatment, Donovan was unable to swallow and had difficulty breathing. Today, the 4-year-old has doubled his life expectancy and is able to talk, sit up, roll over and hold his head up on his own. He also attends the Early Childhood Education and Family Center on Johnstown Road on the East Side, which offers services from the Franklin County Board of Developmental Disabilities.

(Gene therapy) has given us an opportunity that we otherwise wouldnt have to love Donovan and experience him, said Matt Weisgarber, 33, of northeast Columbus.

A lot of people hear Ohio and think flyover state, but now Columbus is going to be a hub of the most groundbreaking science known to mankind and thats a really cool thing, he said.

Boston Childrens Hospital and Childrens Hospital of Philadelphia also have impressive gene therapy centers, but Columbus sets itself apart from those East Coast cities, said Severina Kraner, JobsOhios health care director.

The cost to operate, manufacture and live in Ohio is cheaper than Boston and Philadelphia, putting Ohio in a position to win cell and gene therapy companies, she said.

People are being priced out of these coastal cities, Kraner said.

One of the companies who has committed to building in Columbus is Sarepta Therapeutics, a Massachusetts-based biopharmaceutical company. Sarepta signed an agreement with Nationwide Childrens in May 2019, giving the company the licensing to a gene therapy treatment that came out of hospital research for limb-girdle muscular dystrophies, a group of diseases that cause weakness and wasting of the muscles in the arms and legs.

Sarepta is scheduled to open an 85,000-square-foot Gene Therapy Center of Excellence near Nationwide Childrens Hospital in the fall to do early research for all the companys gene therapy programs. A team of about 30 employees from Sarepta is currently working at a facility at Easton Town Center.

The region has every ingredient needed for a thriving gene therapy cluster: a strong academic foundation, world-renowned research hospitals, and, now, industry investment, Louise Rodino-Klapac, Sareptas senior vice president of gene therapy, said in an email. All of these contribute to creating a pipeline of talented people who will accelerate scientific advances that help patients.

Nationwide Childrens recently also announced it will be expanding its gene therapy research by creating Andelyn BioSciences, a new for-profit subsidiary that will manufacture gene therapy products for the biotechnology and pharmaceutical industries.

Were hoping, and we have a vision, that Andelyn can help capitalize a biotechnology hub in central Ohio focused on developing and advancing gene therapies, said Dr. Dennis Durbin, Nationwide Childrens chief science officer.

Andelyn BioSciences will launch this summer and operate out of the Abigail Wexner Research Institute, 575 Children's Crossroad. Nationwide Children's is trying to secure a permanent location for Andelyn and is looking at land on Ohio State Universitys West Campus.

Gene therapy treatment, however, comes at a high price.

The manufacturer set the price of Zolgensma at more than $2.1 million. Insurers can pay $425,000 a year for five years for one treatment.

Insurance companies are used to regular installment payments, but the single-dose nature of gene therapies are adding a level of uncertainty to health insurance structures, Pfister said in an email. A one-time administration gene therapy costs less overall, but it occurs in one upfront payment.

Pfister said she is hopeful the cost of gene therapy will go down.

Currently, most of the FDA-approved gene and cell therapies are tailored for the specific patient, but theres an incredible amount of research going into standardizing the components and delivery mechanisms behind gene therapy, Pfister said in an email.

Dr. Jerry Mendell helped usher in the era of gene therapy at Nationwide Childrens when he came to the hospital in 2004.

Nationwide Childrens first gene therapy trial was in 2006 for duchenne muscular dystrophy, a rare, inherited, degenerative muscle disorder that almost exclusively affects boys.

Things have really changed significantly in the gene therapy world because of the contributions weve made here, and its been a very gratifying experience, said Mendell, the principal investigator in Nationwide Childrens Center for Gene Therapy.

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Nationwide Childrens among hospitals leading the way in gene therapy - Massillon Independent

New research has found that there are 362 cell and gene therapies in clinical pipelines in the US, an increase from 2018.

A new report from Americas Biopharmaceutical Companies has revealed that there are 362 cell and gene therapies in development in the US. Roughly a third of the therapies, 132, are potential treatments for rare diseases.

The research also highlights that the rate of R&D in this field is growing, as in 2018, a Pharmaceutical Research and Manufacturers of America (PhRMA) report on the cell and gene therapy pipeline found 289 therapies in clinical development in the US.

There are currently nine cell or gene therapy products approved by the US Food and Drug Administration (FDA).

Cell and gene therapies represent two overlapping fields of biomedical research with similar aims, which target DNA or RNA inside or outside the body. Gene therapies use genetic material, or DNA, to alter a patients cells and treat an inherited or acquired disease, whereas cell therapy is the infusion or transplantation of whole cells into a patient for the treatment of an inherited or acquired disease.

According to the report, the novel cell and gene therapies range from early to late stages of clinical development and are focused on a variety of diseases and conditions from cancer, genetic disorders and neurologic conditions.

Some of the cell and gene therapies in the pipeline include:

Another finding highlighted by the report is the 60 RNA therapeutics in development. Whilst not a kind of cell or gene therapy,RNA interference (RNAi) and antisense RNA use a genes DNA sequence to turn it off or modify the gene expression. So, these treatments can potentially inhibit the mechanism of disease-causing proteins.

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Almost 400 cell and gene therapies in US pipeline, finds report - European Pharmaceutical Review

Barth syndromeis a rare metabolic disease caused by mutation of a gene calledtafazzinorTAZ. It can cause life-threatening heart failure and also weakens the skeletal muscles, undercuts the immune response, and impairs overall growth. Because Barth syndrome is X-linked, it almost always occurs in boys. There is no cure or specific treatment.

In 2014, to get a better understanding of the disease,William Pu, MD, and colleagues at Boston Childrens Hospital collaborated with the Wyss Institute to create a beatingheart on a chip model of Barth syndrome. The model used heart-muscle cells with theTAZmutation, derived from patients own skin cells.It showedthatTAZis truly at the heart of cardiac dysfunction: the heart muscle cells did not assemble normally, mitochondria inside the cells were disorganized, and heart tissue contracted weakly. Adding a healthyTAZgene normalized these features, suggesting that gene replacement therapy could be a viable treatment.

But to fully capture Barth syndrome and its whole-body effects, Pu and colleagues needed an animal model. The animal model was a hurdle in the field for a long time, says Pu, director of Basic and Translational Cardiovascular Research at Boston Childrens and a member of the Harvard Stem Cell Institute. Efforts to make a mouse model using traditional methods had been unsuccessful.

As described in the journalCirculation Research, most mice with the whole-bodyTAZdeletion died before birth, apparently because of skeletal muscle weakness. But some survived, and these mice developed progressive cardiomyopathy, in which the heart muscle enlarges and loses pumping capacity. Their hearts also showed scarring, and, similar to human patients with dilatedcardiomyopathy, the hearts left ventricle was dilated and thin-walled.

Mice lackingTAZjust in their cardiac tissue, which all survived to birth, showed the same features. Electron microscopy showed heart muscle tissue to be poorly organized, as were the mitochondria within the cells.

Pu, Wang, and colleagues then used gene therapy to replaceTAZ, injecting an engineered virus under the skin (in newborn mice) or intravenously (in older mice). Treated mice with whole-bodyTAZdeletions were able to survive to adulthood.TAZgene therapy also prevented cardiac dysfunction and scarring when given to newborn mice, and reversed established cardiac dysfunction in older mice whether the mice had whole-body or heart-onlyTAZdeletions.

Thats where the challenge will lie in translating the results to humans. Simply scaling up the dose of gene therapy wont work: In large animals like us, large doses risk a dangerous inflammatory immune response. Giving multiple doses of gene therapy wont work either.

The problem is that neutralizing antibodies to the virus develop after the first dose, says Pu. Getting enough of the muscle cells corrected in humans may be a challenge.

Another challenge is maintaining populations of gene-corrected cells. While levels of the correctedTAZgene remained fairly stable in the hearts of the treated mice, they gradually declined in skeletal muscles.

The biggest takeaway was that the gene therapy was highly effective, says Pu. We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle."

Reference: Wang et al. (2020).AAV Gene Therapy Prevents and Reverses Heart Failure in A Murine Knockout Model of Barth Syndrome.Circulation Research.https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.119.315956.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Gene Therapy Reverses Heart Failure in Mouse Model - Technology Networks

Tim Kelly, PhD

Tim Kelly joins AskBio to lead manufacturing of clinical- and commercial-scale AAV vectors to be used in gene therapy.

RESEARCH TRIANGLE PARK, N.C., March 12, 2020 (GLOBE NEWSWIRE) -- Asklepios BioPharmaceutical, Inc. (AskBio), a leading, clinical-stage adeno-associated virus (AAV) gene therapy company, today announced the appointment of Tim Kelly, PhD, as President of Manufacturing. He will oversee all manufacturing functions at AskBio and its Viralgen affiliate for the production of clinical- and commercial-scale AAV vectors. Prior to joining AskBio, Dr. Kelly was the President and Chief Executive Officer at KBI Biopharma, a contract services organization that provides drug development and biomanufacturing services to pharmaceutical and biotechnology companies globally.

AskBio currently has clinical studies underway in late-onset Pompe disease and congestive heart failure. To meet the growing demand for AAV gene therapies, the company is investing in manufacturing innovation, talent and capacity that will allow it to effectively and efficiently serve patient populations.

Our goal at AskBio is to continue advancing production technology to drive down costs to make gene therapies accessible to all patients who may benefit from treatment. I am delighted that Tim has joined the company to help us shape the future of manufacturing, said Sheila Mikhail, JD, MBA, Chief Executive Officer and co-founder at AskBio. He brings a wealth of experience successfully leading therapeutic development and manufacturing and fostering the entrepreneurial, patient-focused culture that drives us at AskBio.

In January, Viralgen broke ground on a 300,000 square foot commercial facility in San Sebastin, Spain, with production expected to start in the spring of 2022, complementing the clinical-scale production currently carried out at its existing cGMP facility.

AskBios technology is truly transforming human health, and I am incredibly excited to help translate our innovations into reliable delivery of AAV gene therapy products to patients in need, said Dr. Kelly.

More about Tim KellyDr. Kelly has more than 20 years of experience in the development and manufacture of therapeutic proteins. He has overseen biopharmaceutical services for over 320 molecules at all stages of development and commercialization and supported numerous successful FDA and international regulatory inspections throughout his career. He began his tenure at KBI Biopharma in 2005, initially acting as Vice President of Biopharmaceutical Development, where he led the establishment and growth of KBIs analytical development, formulation development and cGMP laboratory services business. He subsequently served as Executive Vice President of Operations with responsibility for KBIs development and manufacturing functions in North Carolina and Colorado before becoming President and Chief Executive Officer. Prior to KBI, he directed the quality control function for Diosynth Biotechnology, where he supported clinical and commercial biopharmaceutical products. Dr. Kelly earned his PhD in molecular genetics and biochemistry from Georgia State University.

About AskBioFounded in 2001, Asklepios BioPharmaceutical, Inc. (AskBio) is a privately held, clinical-stage gene therapy company dedicated to improving the lives of children and adults with genetic disorders. AskBios gene therapy platform includes an industry-leading proprietary cell line manufacturing process called Pro10 and an extensive AAV capsid and promoter library. Based in Research Triangle Park, North Carolina, the company has generated hundreds of proprietary third-generation AAV capsids and promoters, several of which have entered clinical testing. An early innovator in the space, the company holds more than 500 patents in areas such as AAV production and chimeric and self-complementary capsids. AskBio maintains a portfolio of clinical programs across a range of neurodegenerative and neuromuscular indications with a current clinical pipeline that includes therapeutics for Pompe disease, limb-girdle muscular dystrophy 2i/R9 and congestive heart failure, as well as out-licensed clinical indications for hemophilia (Chatham Therapeutics acquired by Takeda) and Duchenne muscular dystrophy (Bamboo Therapeutics acquired by Pfizer). Learn more at https://www.askbio.com or follow us on LinkedIn.

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/512b3baa-aaff-4a92-8539-152021f4527d

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Tim Kelly Joins AskBio as President of Manufacturing to Lead AAV Vector Production for Gene Therapy - GlobeNewswire

Mar 12th 2020

BEING ABLE to see all the details of the genome at once necessarily makes medicine personal. It can also make it precise. Examining illness molecule by molecule allows pharmaceutical researchers to understand the pathways through which cells act according to the dictates of genes and environment, thus seeing deep into the mechanisms by which diseases cause harm, and finding new workings to target. The flip side of this deeper understanding is that precision brings complexity. This is seen most clearly in cancer. Once, cancers were identified by cell and tissue type. Now they are increasingly distinguished by their specific genotype that reveals which of the panoply of genes that can make a cell cancerous have gone wrong in this one. As drugs targeted against those different mutations have multiplied, so have the options for oncologists to combine them to fit their patients needs.

Cancer treatment has been the most obvious beneficiary of the genomic revolution but other diseases, including many in neurology, are set to benefit, too. Some scientists now think there are five different types of diabetes rather than two. There is an active debate about whether Parkinsons is one disease that varies a lot, or four. Understanding this molecular variation is vital when developing treatments. A drug that works well on one subtype of a disease might fail in a trial that includes patients with another subtype against which it does not work at all.

Thus how a doctor treats a disease depends increasingly on which version of the disease the patient has. The Personalised Medicine Coalition, a non-profit advocacy group, examines new drugs approved in America to see whether they require such insights in order to be used. In 2014, it found that so-called personalised medicines made up 21% of the drugs newly approved for use by Americas Food and Drug Administration (FDA). In 2018 the proportion was twice that.

Two of those cited were particularly interesting: Vitrakvi (larotrectinib), developed by Loxo Oncology, a biotech firm, and Onpattro (patisiran), developed by Alnylam Pharmaceuticals. Vitrakvi is the first to be approved from the start as tumour agnostic: it can be used against any cancer that displays the mutant protein it targets. Onpattro, which is used to treat peripheral-nerve damage, is the first of a new class of drugssmall interfering RNAs, or siRNAsto be approved. Like antisense oligonucleotides (ASOs), siRNAs are little stretches of nucleic acid that stop proteins from being made, though they use a different mechanism.

Again like ASOs, siRNAs allow you to target aspects of a disease that are beyond the reach of customary drugs. Until recently, drugs were either small molecules made with industrial chemistry or bigger ones made with biologynormally with genetically engineered cells. If they had any high level of specificity, it was against the actions of a particular protein, or class of proteins. Like other new techniques, including gene therapies and anti-sense drugs, siRNAs allow the problem to be tackled further upstream, before there is any protein to cause a problem.

Take the drugs that target the liver enzyme PCSK9. This has a role in maintaining levels of bad cholesterol in the blood; it is the protein that was discovered through studies of families in which congenitally high cholesterol levels led to lots of heart attacks. The first generation of such drugs were antibodies that stuck to the enzyme and stopped it working. However, the Medicines Company, a biotech firm recently acquired by Novartis, won approval last year for an siRNA called inclisiran that interferes with the expression of the gene PCSK9thus stopping the pesky protein from being made in the first place. Inclisiran needs to be injected only twice a year, rather than once a month, as antibodies do.

New biological insights, new ways of analysing patients and their disease and new forms of drug are thus opening up a wide range of therapeutic possibilities. Unfortunately, that does not equate to a range of new profitable opportunities.

Thanks in part to ever better diagnosis, there are now 7,000 conditions recognised as rare diseases in America, meaning that the number of potential patients is less than 200,000. More than 90% of these diseases have no approved treatment. These are the diseases that personalised, precision medicine most often goes after. Nearly 60% of the personalised medicines approved by the FDA in 2018 were for rare diseases.

Zolgensma is the most expensive drug ever brought to market.

That might be fine, were the number of diseases stable. But precision in diagnosis is increasingly turning what used to be single diseases into sets of similar-looking ones brought about by distinctly different mechanisms, and thus needing different treatment. And new diseases are still being discovered. Medical progress could, in short, produce more new diseases than new drugs, increasing unmet need.

Some of it will, eventually, be met. For one thing, there are government incentives in America and Europe for the development of drugs for rare diseases. And, especially in America, drugs for rare diseases have long been able to command premium prices. Were this not the case, Novartis would not have paid $8.7bn last year to buy AveXis, a small biotech firm, thereby acquiring Zolgensma, a gene therapy for spinal muscular atrophy (SMA). Most people with SMA lack a working copy of a gene, SMN1, which the nerve cells that control the bodys muscles need to survive. Zolgensma uses an empty virus-like particle that recognises nerve cells to deliver working copies of the gene to where it is needed. Priced at $2.1m per patient, it is the most expensive drug ever brought to market. That dubious accolade might not last long. BioMarin, another biotech firm, is considering charging as much as $3m for a forthcoming gene therapy for haemophilia.

Drug firms say such treatments are economically worthwhile over the lifetime of the patient. Four-fifths of children with the worst form of SMA die before they are four. If, as is hoped, Zolgensma is a lasting cure, then its high cost should be set against a half-century or more of life. About 200 patients had been treated in America by the end of 2019.

But if some treatments for rare diseases may turn a profit, not all will. There are some 6,000 children with SMA in America. There are fewer than ten with Jansens disease. When Dr Nizar asked companies to help develop a treatment for it, she says she was told your disease is not impactful. She wrote down the negative responses to motivate herself: Every day I need to remind myself that this is bullshit.

A world in which markets shrink, drug development gets costlier and new unmet needs are ceaselessly discovered is a long way from the utopian future envisaged by the governments and charities that paid for the sequencing of all those genomes and the establishment of the worlds biobanks. As Peter Bach, director of the Centre for Health Policy and Outcomes, an academic centre in New York, puts it with a degree of understatement: if the world needs to spend as much to develop a drug for 2,000 people as it used to spend developing one for 100,000, the population-level returns from medical research are sharply diminishing.

And it is not as if the costs of drug development have been constant. They have gone up. What Jack Scannell, a consultant and former pharmaceutical analyst at UBS, a bank, has dubbed Erooms lawEroom being Moore, backwardsshows the number of drugs developed for a given amount of R&D spending has fallen inexorably, even as the amount of biological research skyrocketed. Each generation assumes that advances in science will make drugs easier to discover; each generation duly advances science; each generation learns it was wrong.

For evidence, look at the way the arrival of genomics in the 1990s lowered productivity in drug discovery. A paper in Nature Reviews Drug Discovery by Sarah Duggers from Columbia University and colleagues argues that it brought a wealth of new leads that were difficult to prioritise. Spending rose to accommodate this boom; attrition rates for drugs in development subsequently rose because the candidates were not, in general, all that good.

Today, enthused by their big-science experience with the genome and enabled by new tools, biomedical researchers are working on exhaustive studies of all sorts of other omes, including proteomesall the proteins in a cell or body; microbiomesthe non-pathogenic bacteria living in the mouth, gut, skin and such; metabolomessnapshots of all the small molecules being built up and broken down in the body; and connectomes, which list all the links in a nervous system. The patterns they find will doubtless produce new discoveries. But they will not necessarily, in the short term, produce the sort of clear mechanistic understanding which helps create great new drugs. As Dr Scannell puts it: We have treated the diseases with good experimental models. Whats left are diseases where experiments dont replicate people. Data alone canot solve the problem.

Daphne Koller, boss of Insitro, a biotech company based in San Francisco, shares Dr Scannells scepticism about the way drug discovery has been done. A lot of candidate drugs fail, she says, because they aim for targets that are not actually relevant to the biology of the condition involved. Instead researchers make decisions based on accepted rules of thumb, gut instincts or a ridiculous mouse model that has nothing to do with what is actually going on in the relevant human diseaseeven if it makes a mouse look poorly in a similar sort of way.

But she also thinks that is changing. Among the things precision biology has improved over the past five to 10 years have been the scientists own tools. Gene-editing technologies allow genes to be changed in various ways, including letter by letter; single-cell analysis allows the results to be looked at as they unfold. These edited cells may be much more predictive of the effects of drugs than previous surrogates. Organoidsself-organised, three-dimensional tissue cultures grown from human stem cellsoffer simplified but replicable versions of the brain, pancreas, lung and other parts of the body in which to model diseases and their cures.

Insitro is editing changes into stem cellswhich can grow into any other tissueand tracking the tissues they grow into. By measuring differences in the development of very well characterised cells which differ in precisely known ways the company hopes to build more accurate models of disease in living cells. All this work is automated, and carried out on such a large scale that Dr Koller anticipates collecting many petabytes of data before using machine learning to make sense of it. She hopes to create what Dr Scannell complains biology lacks and what drug designers need: predictive models of how genetic changes drive functional changes.

There are also reasons to hope that the new upstream drugsASOs, siRNAs, perhaps even some gene therapiesmight have advantages over todays therapies when it comes to small-batch manufacture. It may also prove possible to streamline much of the testing that such drugs go through. Virus-based gene-therapy vectors and antisense drugs are basically platforms from which to deliver little bits of sequence data. Within some constraints, a platform already approved for carrying one message might be fast-tracked through various safety tests when it carries another.

One more reason for optimism is that drugs developed around a known molecule that marks out a diseasea molecular markerappear to be more successful in trials. The approval process for cancer therapies aimed at the markers of specific mutations is often much shorter now than it used to be. Tagrisso (osimertinib), an incredibly specialised drug, targets a mutation known to occur only in patients already treated for lung cancer with an older drug. Being able to specify the patients who stand to benefit with this degree of accuracy allows trials to be smaller and quicker. Tagrisso was approved less than two years and nine months after the first dose was given to a patient.

With efforts to improve the validity of models of disease and validate drug targets accurately gaining ground, Dr Scannell says he is sympathetic to the proposal that, this time, scientific innovation might improve productivity. Recent years have seen hints that Erooms law is being bent, if not yet broken.

If pharmaceutical companies do not make good on the promise of these new approaches then charities are likely to step in, as they have with various ASO treatments for inherited diseases. And they will not be shackled to business models that see the purpose of medicine as making drugs. The Gates Foundation and Americas National Institutes of Health are investing $200m towards developing treatments based on rewriting genes that could be used to tackle sickle-cell disease and HIVtreatments that have to meet the proviso of being useful in poor-country clinics. Therapies in which cells are taken out of the body, treated in some way and returned might be the basis of a new sort of business, one based around the ability to make small machines that treat individuals by the bedside rather than factories which produce drugs in bulk.

There is room in all this for individuals with vision; there is also room for luck: Dr Nizar has both. Her problem lies in PTH1R, a hormone receptor; her PTH1R gene makes a form of it which is jammed in the on position. This means her cells are constantly doing what they would normally do only if told to by the relevant hormone. A few years ago she learned that a drug which might turn the mutant receptor off (or at least down a bit) had already been characterisedbut had not seemed worth developing.

The rabbit, it is said, outruns the fox because the fox is merely running for its dinner, while the rabbit is running for its life. Dr Nizars incentives outstrip those of drug companies in a similar way. By working with the FDA, the NIH and Massachusetts General Hospital, Dr Nizar helped get a grant to make enough of the drug for toxicology studies. She will take it herself, in the first human trial, in about a years time. After that, if things go well, her childrens pain may finally be eased.

This article appeared in the Technology Quarterly section of the print edition under the headline "Kill or cure?"

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New drugs are costly and unmet need is growing - The Economist