The human eye is a biological marvel. Charles Darwin considered it one of the biggest challenges to his theory of evolution, famously writing : that “To suppose that the eye with all its inimitable contrivances for adjusting the focus to different distances, for admitting different amounts of light, and for the correction of spherical and chromatic aberration, could have been formed by natural selection, seems, I freely confess, absurd in the highest degree.” Of course he did go on to explain how natural selection could account for the eye, but we can see why he wrote these words under the heading of “Organs of Extreme Perfection and Complication.” [More]

The sun strikes every square meter of our planet with more than 1,360 watts of power. Half of that energy is absorbed by the atmosphere or reflected back into space. 700 watts of power, on average, reaches Earth’s surface. Summed across the half of the Earth that the sun is shining on, that is 89 petawatts of power. By comparison, all of human civilization uses around 15 terrawatts of power, or one six-thousandth as much. In 14 and a half seconds, the sun provides as much energy to Earth as humanity uses in a day.

The numbers are staggering and surprising. In 88 minutes, the sun provides 470 exajoules of energy, as much energy as humanity consumes in a year. In 112 hours – less than five days – it provides 36 zettajoules of energy – as much energy as is contained in all proven reserves of oil, coal, and natural gas on this planet.

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Despite the enormous efforts of clinicians and researchers, our limited insight into psychiatric disease (the worldwide-leading cause of years of life lost to death or disability) hinders the search for cures and contributes to stigmatization. Clearly, we need new answers in psychiatry. But as philosopher of science Karl Popper might have said, before we can find the answers, we need the power to ask new questions. In other words, we need new technology. [More]

The psychologist Rollo May once described depression as “the inability to construct a future”. [More]

In a head-to-head competition held 10 years ago, scientists at the National Institutes of Health tested two promising new types of vaccine to see which might offer the strongest protection against one of the deadliest viruses on earth, the human immunodeficiency virus (HIV) that causes AIDS. One vaccine consisted of DNA rings called plasmids, each carrying a gene for one of five HIV proteins. Its goal was to get the recipient’s own cells to make the viral proteins in the hope they would provoke protective reactions by immune cells. Instead of plasmids, the second vaccine used another virus called an adenovirus as a carrier for a single HIV gene encoding a viral protein. The rationale for this combination was to employ a “safe” virus to catch the attention of immune cells while getting them to direct their responses against the HIV protein.

One of us (Weiner) had already been working on DNA vaccines for eight years and was hoping for a major demonstration of the plasmids’ ability to induce immunity against a dreaded pathogen. Instead the test results dealt a major blow to believers in this first generation of DNA vaccines. The DNA recipients displayed only weak immune responses to the five HIV proteins or no response at all, whereas recipients of the adenovirus-based vaccine had robust reactions. To academic and pharmaceutical company researchers, adenoviruses clearly looked like the stronger candidates to take forward in developing HIV vaccines.

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Immune system - National Institutes of Health - Vaccine - HIV - DNA

In the past researchers have observed an association between poor mitochondrial function and Parkinson's disease, a neurodegenerative disorder of the central nervous system that impairs speech and motor functions and affects five million people worldwide. A new meta-analysis suggests that low expression levels of 10 related gene sets responsible for mitochondrial machinery play an important role in this disorder--all previously unlinked to Parkinson's. The study, published online today in Science Translational Medicine , further points to a master switch for these gene sets as a potential target of future therapies. [More]

When President Richard Nixon launched the war on cancer in his January 1971 State of the Union, he called for "the same kind of concentrated effort that split the atom and took man to the moon." Yet nearly 40 years and $100 billion in federally funded cancer research later, it seems the lunar landing was a much less daunting task.

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In his magical-realist masterpiece One Hundred Years of Solitude , Colombian author Gabriel García Márquez takes the reader to the mythical jungle village of Macondo, where, in one oft-recounted scene, residents suffer from a disease that causes them to lose all memory. The malady erases “the name and notion of things and finally the identity of people.” The symptoms persist until a traveling gypsy turns up with a drink “of a gentle color” that returns them to health.

In a 21st-century parallel to the townspeople of Macondo, a few hundred residents from Medellín, Colombia, and nearby coffee-growing areas may get a chance to assist in the search for something akin to a real-life version of the gypsy’s concoction. Medellín and its environs are home to the world’s largest contingent of individuals with a hereditary form of Alzheimer’s disease. Members of 25 extended families, with 5,000 members, develop early-onset Alzheimer’s, usually before the age of 50, if they harbor an aberrant version of a particular gene.

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Alzheimer - Macondo - One Hundred Years of Solitude - Health - Conditions and Diseases

The adapted virus that immunized hundreds of millions of people against smallpox has now been enlisted in the war on cancer. Vaccinia poxvirus joins a herpesvirus and a host of other pathogens on a growing list of engineered viruses entering late-stage human testing against cancer. [More]

Cancer - Smallpox - Virus - Vaccinia - Health

In most areas of medicine, doctors have historically tried to glean something about the underlying cause of a patient’s illness before figuring out a treatment that addresses the source of the problem. When it came to mental or behavioral disorders in the past, however, no physical cause was detectable so the problem was long assumed by doctors to be solely “mental,” and psychological therapies followed suit.

Today scientific approaches based on modern biology, neuroscience and genomics are replacing nearly a century of purely psychological theories, yielding new approaches to the treatment of mental illnesses.

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NEW YORK--Will exotic orchids soon be subjected to the same genetic scrutiny as some luxury caviars? That is just one of the coding conundrums that scientists convened at the New York Botanical Garden in the Bronx to discuss on a cloudy mid-April afternoon. [More]

Summary

gene therapy, also called gene transfer therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. When a normal gene is inserted into the nucleus of a mutant cell, the gene most likely will integrate into a chromosomal site different from the defective allele; although that may repair the mutation, a new mutation may result if the normal gene integrates into another functional gene. If the normal gene replaces the mutant allele, there is a chance that the transformed cells will proliferate and produce enough normal gene product for the entire body to be restored to the undiseased phenotype.

Human gene therapy has been attempted on somatic (body) cells for diseases such as cystic fibrosis, adenosine deaminase deficiency, familial hypercholesterolemia, cancer, and severe combined immunodeficiency (SCID) syndrome. Somatic cells cured by gene therapy may reverse the symptoms of disease in the treated individual, but the modification is not passed on to the next generation. Germline gene therapy aims to place corrected cells inside the germ line (e.g., cells of the ovary or testis). If that is achieved, those cells will undergo meiosis and provide a normal gametic contribution to the next generation. Germline gene therapy has been achieved experimentally in animals but not in humans.

Scientists have also explored the possibility of combining gene therapy with stem cell therapy. In a preliminary test of that approach, scientists collected skin cells from a patient with alpha-1 antitrypsin deficiency (an inherited disorder associated with certain types of lung and liver disease), reprogrammed the cells into stem cells, corrected the causative gene mutation, and then stimulated the cells to mature into liver cells. The reprogrammed, genetically corrected cells functioned normally.

Prerequisites for gene therapy include finding the best delivery system (often a virus, typically referred to as a viral vector) for the gene, demonstrating that the transferred gene can express itself in the host cell, and establishing that the procedure is safe. Few clinical trials of gene therapy in humans have satisfied all those conditions, often because the delivery system fails to reach cells or the genes are not expressed by cells. Improved gene therapy systems are being developed by using nanotechnology. A promising application of that research involves packaging genes into nanoparticles that are targeted to cancer cells, thereby killing cancer cells specifically and leaving healthy cells unharmed.

Some aspects of gene therapy, including genetic manipulation and selection, research on embryonic tissue, and experimentation on human subjects, have aroused ethical controversy and safety concerns. Some objections to gene therapy are based on the view that humans should not play God and interfere in the natural order. On the other hand, others have argued that genetic engineering may be justified where it is consistent with the purposes of God as creator. Some critics are particularly concerned about the safety of germline gene therapy, because any harm caused by such treatment could be passed to successive generations. Benefits, however, would also be passed on indefinitely. There also has been concern that the use of somatic gene therapy may affect germ cells.

Although the successful use of somatic gene therapy has been reported, clinical trials have revealed risks. In 1999 American teenager Jesse Gelsinger died after having taken part in a gene therapy trial. In 2000 researchers in France announced that they had successfully used gene therapy to treat infants who suffered from X-linked SCID (XSCID; an inherited disorder that affects males). The researchers treated 11 patients, two of whom later developed a leukemia-like illness. Those outcomes highlight the difficulties foreseen in the use of viral vectors in somatic gene therapy. Although the viruses that are used as vectors are disabled so that they cannot replicate, patients may suffer an immune response.

Another concern associated with gene therapy is that it represents a form of eugenics, which aims to improve future generations through the selection of desired traits. While some have argued that gene therapy is eugenic, others claim that it is a treatment that can be adopted to avoid disability. To others, such a view of gene therapy legitimates the so-called medical model of disability (in which disability is seen as an individual problem to be fixed with medicine) and raises peoples hopes for new treatments that may never materialize.

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Gene therapy | Description, Uses, Examples, & Safety Issues

References

1. Wirth T, Parker N, Yl-Hertuala. History of gene therapy. Gene. 2013;252(2):62-169.2. Food and Drug Administration. FDA continues strong support of innovation in development of gene therapy products. Press release. Accessed July 1, 2021. https://www.fda.gov/news-events/press-announcements/fda-continues-strong-support-innovation-development-gene-therapy-products3. Science History Institute. James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin. Accessed July 1, 2021. https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin4. Nirenberg M. Historical review: Deciphering the genetic codea personal account. Trends Biochem Sci. 2004;29(1):46-54.5. Science History Institute. Herbert W Boyer and Stanley N Cohen. Accessed July 1, 2021. https://www.sciencehistory.org/historical-profile/herbert-w-boyer-and-stanley-n-cohen6. Sun M. Cline loses two NIH grants. Science. 1981;214(4525):1220.7. Blaese RM, Culver KW, Miller D, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270(5235):475-480.8. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A. 1996;93(3):1156-1160.9. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263-267.10. Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001;164(11):1612.11. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2018;118(9):3132-3142.12. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007;117(6):1456-1465.13. Humeau L. From the bench to the clinic: story and lessons from VRX496, the first lentivector ever tested in a phase 1 clinical trial. Presented at: Beilstein Bozen Symposium; May 15-May 19, 2006; Bozen, Italy.14. Pearson S, Jia H, Kandachi K. China approves first gene therapy. Nat Biotechnol. 2004;22(1):3-4. 15. Daley J. Gene therapy arrives. Nature. 2019;576:S12-S13.16. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597-1605.17. Luxturna (voretigene neparvovec-ryzl) [prescribing information]. Philadelphia, PA: Spark Therapeutics, Inc.; 2017.18. Christian M, Cermak T, Doyle EL, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186(2):757-761.19. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human -thalassaemia. Nature. 2010;467(7313):318-322.20. Flemming A. Regulatory watch: Pioneering gene therapy on brink of approval. Nat Rev Drug Discov. 2012 ;11(9):664.21. Pharmaphorum. Glybera, the most expensive drug in the world, to be withdrawn after commercial flop. Accessed April 29, 2021. https://pharmaphorum.com/news/glybera-expensive-drug-world-withdrawn-commercial-flop/22. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819-823.23. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9(6):737-740.24. Strimvelis Summary of Product Characteristics, GlaxoSmithKline (GSK); 2016.25. Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Accessed April 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma26. European Medicines Agency. Yescarta. Accessed April 29, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/yescarta27. Cross R. CRISPR is coming to the clinic this year. Chem Eng News. 2018;96(2):18-19.28. Food and Drug Administration. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. Accessed April 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease29. European Medicines Agency. Zolgensma. Accessed May 26, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma30. European Medicines Agency. Zynteglo. Accessed April 29, 2021. https://www.ema.europa.eu/en/medicines/human/referrals/zynteglo31. 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History of Gene Therapy | Discovery and Evolution

Many people whove recently received a diagnosis of type 1 diabetes (T1D) immediately think, When will there be a cure?

While the potential for a cure has been dangling in front of people with T1D for what seems like forever, more researchers currently believe that gene therapy could finally one day soon, even be the so-called cure thats been so elusive.

This article will explain what gene therapy is, how its similar to gene editing, and how gene therapy could potentially be the cure for T1D, helping millions of people around the world.

Gene therapy is a medical field of study that focuses on the genetic modification of human cells to treat or sometimes even cure a particular disease. This happens by reconstructing or repairing defective or damaged genetic material in your body.

This advanced technology is only in the early research phases of clinical trials for treating diabetes in the United States. Yet, it has the potential to treat and cure a wide range of other conditions beyond just T1D, including AIDS, cancer, cystic fibrosis (a disorder that damages your lungs, digestive tract, and other organs), heart disease, and hemophilia (a disorder in which your blood has trouble clotting).

For T1D, gene therapy could look like the reprogramming of alternative cells, making those reprogrammed cells perform the functions your original insulin-producing beta cells would otherwise perform. If you have with diabetes, that includes producing insulin.

But the reprogrammed cells would be different enough from beta cells so that your own immune system wouldnt recognize them as new cells and attack them, which is what happens in the development of T1D.

While gene therapy is still in its infancy and available only in clinical trials, the evidence so far is becoming clearer about the potential benefits of this treatment.

In a 2018 study, researchers engineered alpha cells to function just like beta cells. They created an adeno-associated viral (AAV) vector to deliver two proteins, pancreatic and duodenal homeobox 1 and MAF basic leucine zipper transcription factor A, to a mouses pancreas. These two proteins help with beta cell proliferation, maturation, and function.

Alpha cells are the ideal type of cell to transform into beta-like cells because not only are they also located within the pancreas, but theyre abundant in your body and similar enough to beta cells that the transformation is possible. Beta cells produce insulin to lower your blood sugar levels while alpha cells produce glucagon, which increases your blood sugar levels.

In the study, mouse blood sugar levels were normal for 4 months with gene therapy, all without immunosuppressant drugs, which inhibit or prevent the activity of your immune system. The newly created alpha cells, performing just like beta cells, were resistant to the bodys immune attacks.

But the normal glucose levels observed in the mice werent permanent. This could potentially translate into several years of normal glucose levels in humans rather than a longtime cure.

In this Wisconsin study from 2013 (updated as of 2017), researchers found that when a small sequence of DNA was injected into the veins of rats with diabetes, it created insulin-producing cells that normalized blood glucose levels for up to 6 weeks. That was all from a single injection.

This is a landmark clinical trial, as it was the first research study to validate a DNA-based insulin gene therapy that could potentially one day treat T1D in humans.

This was how the study worked:

The researchers are now working on increasing the time interval between therapy DNA injections from 6 weeks to 6 months to provide more relief for people with T1D in the future.

While this is all very exciting, more research is needed to determine how practical the therapy is for people. Eventually, the hope is that the AAV vectors could eventually be delivered to the pancreas through a nonsurgical, endoscopic procedure, in which a doctor uses a medical device with a light attached to look inside your body.

These kinds of gene therapy wouldnt be a one-and-done cure. But it would provide a lot of relief to people with diabetes to perhaps enjoy several years of nondiabetes glucose numbers without taking insulin.

If subsequent trials in other nonhuman primates are successful, human trials may soon begin for the T1D treatment.

Does that count as a cure?

It all depends on who you ask because the definition of a cure for T1D varies.

Some people believe that a cure is a one-and-done endeavor. They see a cure as meaning youd never have to think about taking insulin, checking blood sugars, or the highs and lows of diabetes ever again. This even means you wouldnt have to ever go back to a hospital for a gene therapy follow-up treatment.

Other people think that a once-in-a-few-years treatment of gene editing may be enough of a therapy plan to count as a cure.

Many others believe that you need to fix the underlying autoimmune response to truly be cured, and some people dont really care one way or another, as long as their blood sugars are normal, and the mental tax of diabetes is relieved.

One potential one-and-done therapy could be gene editing, which is slightly different from gene therapy.

The idea behind gene editing is to reprogram your bodys DNA, and if you have type 1 diabetes, the idea is to get at the underlying cause of the autoimmune attack that destroyed your beta cells and caused T1D to begin with.

Two well-known companies, CRISPR Therapeutics and regenerative med-tech company ViaCyte, have been collaborating for a few years to use gene editing to create islet cells, encapsulate them, and then implant them into your body. These protected, transplanted islet cells would be safe from an immune system attack, which would otherwise be the typical response if you have T1D.

The focus of gene editing is to simply cut out the bad parts of our DNA in order to avoid conditions such as diabetes altogether and to stop the continuous immune response (beta cell attack) that people who already have diabetes experience daily (without their conscious awareness).

The gene editing done by CRISPR in their partnership with ViaCyte is creating insulin-producing islet cells that can evade an autoimmune response. These technology and research are ever evolving and hold a lot of promise.

Additionally, a 2017 study shows that a T1Dcure may one day be possible by using gene-editing technology.

Both gene therapy and gene editing hold a lot of promise for people living with T1D who are hoping for an eventual future without needing to take insulin or immunosuppressant therapy.

Gene therapy research continues, looking at how certain cells in the body could be reprogrammed to start making insulin and not experience an immune system response, such as those who develop T1D.

While gene therapy and gene-editing therapy are still in their early stages (and much has been held up by the coronavirus disease 19 [COVID-19] pandemic), theres a lot of hope for a T1D cure in our near future.

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Gene therapy: The Potential for Treating Type 1 Diabetes - Healthline

The potential importance of cell and gene therapy (CGT) to healthcare and the biopharma industry seems clear. CGT accounts for just 1 percent of launched products in major markets, with treatment of the vast majority of diseases still using small-molecule drugs. Yet those productswhich include cell therapies, such as chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell lymphomas, and gene therapiesto treat a range of monogenic rare diseaseshave proved transformative for patients. And there are many more in development. As of February 2020, CGT products account for 12 percent of the industrys clinical pipeline and at least 16 percent of the preclinical pipeline, but as most manufacturers do not disclose their preclinical assets, the true figure may be considerably higher (Exhibit 1).

Exhibit 1

New CGT products will surely emerge from this pipeline upon the continuing discovery of indications that CGT can address and the growing industry understanding of the genetic drivers and determinants of more complex, multifactorial diseases. Indeed, the pace of CGT-asset development is similar to that of monoclonal-antibody (mAb) assets in that modalitys early years, and mAb therapy went on to transform the biopharma market (see sidebar, Cell and gene therapy: Mirroring monoclonal-antibody therapy).

Exciting clinical results are helping to propel this pace. Success rates for CGT products are higher than those for small-molecule products, probably because CGT tends to target specific disease drivers rather than the broad targets (with potential for off-target effects) of small-molecule therapy. The sample size of launched CGTs is small, so comparisons may change as the market evolves. Nevertheless, there is a marked difference thus far. Between 2008 and 2018, the R&D success rate from Phase I to launch for small-molecule products was 8.2 percent; for CGT products, it was 11 percent.

Recognizing CGTs potential, 16 of the worlds largest (by revenue) 20 biopharmacos now have CGT assets in their product portfolios. Yet most companies are moving cautiouslyonly two of the top 20 have CGT assets making up more than 20 percent of their pipelines. They are still considering whether, when, and how to reposition their portfolios. In the meantime, biotech companies remain leaders in CGT innovation.

As of February 2020, only a small percentage of launched CGT assets either originated from or are owned by a top 20 biopharmacoin both cases, only 15 percent of launched assetsindicating how much opportunity there is for such companies to increase their exposure to CGT assets (Exhibit 2).

Exhibit 2

The figures are not altogether surprising, given that biopharmacos expertise often lies in disease areas, not in the development of the technology platforms that generate CGT products. More often than not, the original research behind new platforms is conducted by academics (who go on to set up their own biotech companies) and investors (whose models include company origination because of the potential financial gains and the concentrated technical risk that platform investments carry). Venture-capital firms are more comfortable than established biopharmacos with such risks.

Nevertheless, given the growth potential of CGT and the promise it holds for patients, most large biopharmacos are considering increasing their presence in the market. This article is intended to help guide their decisions, describing the key considerations when assessing investment opportunities and the various entry strategiesas well as the trade-offs to be made when choosing among them.

There are many technology platforms in development that seek to address different challengesassociated with CGT. In cell therapy, work is afoot to improve the manufacture of autologous therapies to reduce the cost of goods sold or vein-to-vein time, enable breakthrough efficacy in solid tumors, and improve the patient or customer experience. In gene therapy, there are investment opportunities in platforms that aim to overcome the limitations of current vectors (such as the size of the transgene, suboptimal tropism, or the triggering of an immune response) that enable nonviral delivery methods, reduce manufacturing costs, and expand manufacturing capacity.

The decision, therefore, is about not only whether to increase investment in CGT but also which technology platforms or assets to back. Companies should thus assess each investment opportunity by both strategic fit and technology attractiveness. Strategic considerations on a CGT platform or asset include whether it complements a companys disease areas of focus, the internal pipeline would benefit from diversification with new modalities, and the company has the required capabilities, capital, and conviction.

A host of questions need to be asked to gauge the attractiveness of the technology. Has it demonstrated proof of concept? What risks remain? Does the company have enough understanding of the underlying mechanisms? Does the technology enable first-mover advantage? What are the intellectual-property considerations? Is the platform differentiated from competing platforms? And given the rapid pace of innovation in CGT, what is the risk that the technology platform quickly becomes obsolete?

CAR T-cell therapy, whereby a patients T cells are genetically engineered to express a chimeric antigen receptor that targets a specific tumor antigen, illustrates the potential risk. In a relatively short time, the field has progressed from an initial set of constructs to a second generation that has given rise to two FDA-approved products, YESCARTA and KYMRIAH, even as third- and fourth-generation products are in development.

Investment opportunities that have a strong strategic fit and high-potential technologythose that fall into the top-right quadrant shown in Exhibit 3will be attractive. For example, a CAR T-cell or T-cell-receptor platform would fall in the top right for many oncology-focused companies. In the absence of such opportunities, those in the top-left or bottom-right quadrants may still be worthwhile as a means of gaining exposure to CGT, perhaps through an early-stage investment. For example, next-generation, unproven gene-editing technologies may fall in the bottom-right quadrant for companies focused on rare diseases with known genetic drivers. Companies would have to be prepared to tolerate the associated risks, however, and not all will conclude that now is the time to make a move.

Exhibit 3

Once a manufacturer has decided that it makes strategic sense to invest in CGT and has identified an attractive technology, it must choose an entry strategy. There are three main options: build a proprietary platform, buy an existing platform or one or more of its assets, or form a partnership to gain access to assets on platforms developed by others (Exhibit 4). The three options have different profiles in the capital required, changes to the operational model needed, and risk (as measured by the degree of diversification offered across different technologies).

Exhibit 4

Companies that build a platform or platforms from scratch enjoy full control over development efforts and retain all the financial rewards of successful assets. They also get the chance to build their own CGT capabilitiesscientific, clinical, and commercialand have the freedom to adapt as the technology evolves. In return, they have to commit significant resources to internal R&D and will, in effect, be placing big, early bets on a single or very limited number of platforms. Additionally, they may need to make significant changes to operating models designed for traditional modalities.

Buying a developed platform or late-stage asset carries less technical risk (assuming robust early data), though invariably a price premium too. This means that few, if any, companies will be able to acquire a large number of them, so companies continue to bet on a single or limited number of platforms.

The third optionforming a partnership to gain access to assets on platforms that others have developedlies between these two extremes in investment cost and risk. Because partnerships in the still-nascent CGT sector are relatively cheap, biopharmacos can afford to spread their bets on where future success might lie through establishing several partnerships.

Accordingly, most biopharmacos to date have followed the partnership route when placing a stake in CGT. Between 2010 and 2014, there were a total of 16 M&A deals in the CGT space. That rose to more than 60 between 2015 and 2019. However, even in 2019, when M&A activity was strongest, partnerships accounted for more than 80 percent of total transaction activity (Exhibit 5).

Exhibit 5

Nearly all of the top 20 biopharmacos have formed at least one partnership, while ten have made an acquisition. Just one has built its own platform. Exhibit 6 details this, along with the impact that the deals have had on the composition of company pipelines.

Exhibit 6

Partnerships come in three main varieties: those that give a biopharmaco access to a single asset, those that give it access to all assets in selected therapeutic areas that might emerge from a platform, and those that give it access to all platform assets, regardless of the therapeutic area or indication.

Partnerships structured to give a biopharmaco access to a single asset are the simplest way to enter the CGT market and are often chosen by companies that have a strong focus on certain indications and believe that their competitive advantage lies in owning multiple therapies across modalities in that space. A single-asset partnership also minimizes the investment required. However, this kind of partnership may leave a biopharmaco having to introduce a new operating model for a single asset.

Partnerships structured to give a biopharmaco access to all assets from a platform in certain therapeutic areas can help companies with a strong strategic focus on a given therapeutic area strengthen their portfolios and build more expertise in that area. In addition, more assets in a new modality means more opportunity to build the relevant development and commercial expertise.

The third option, partnering to win access to all the assets in a particular modality generated by a platform, tends to be the partnership of choice for biopharmacos that believe future competitive advantage lies in access to the best technology, no matter what may be the associated indication or therapeutic area. Through such a partnership, a company can follow the science, developing the technology for the indications in which it can provide the most clinical benefit. Such a strategy requires more investment than other forms of partnership, however, and so carries more concentrated technology risk. Companies may also find themselves developing products for therapeutic areas in which they have no expertise and thus are at a competitive disadvantage.

In addition to these three kinds of partnerships with biotech companies, some biopharmacos are considering more innovative ways to allocate their limited resources across multiple CGT technologies in a manner that also boosts their chances of keeping pace with rapid innovation. By partnering with venture-capital firms or biotech originators to launch new assets, new platforms, or even new companies or by collaborating with large academic institutions to license multiple new technologies, they are making much earlier-stage bets on where future success might lie.

The CGT era is an exciting one for healthcare, and all biopharmacos will want to reassess their portfolio strategies to decide whether and to what extent to diversify their pipelines. Most big biopharmacos have chosen partnerships to explore CGT initially, though the likelihood is that many will use a combination of strategies to increase their exposure and access to several technologies as the market evolves. Yet whether a company is still testing the water or is ready to commit, it will need to think carefully about how it builds its exposure to the CGT market and be fully aware of how to assess each investment opportunity, the range of possible entry strategies, and the different advantages and risks that each carries.

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Cell and gene therapy: Biopharma portfolio strategy | McKinsey

Key Difference Ex Vivo vs In Vivo Gene Therapy

Gene therapy is an important technique which is used to treat or prevent genetic diseases by introducing genes for missing or defective genes. Certain diseases can be cured by inserting the healthy genes in place of mutated or missing genes responsible for the disease. Gene therapy is mostly applied for somatic cells than germline cells, and it can be categorized into two major types named Ex vivo gene therapy and In vivo gene therapy. The key difference between Ex vivo and In vivo gene therapy is that therapeutic genes are transferred to in vitro cell cultures and reintroduced into a patient in ex vivo gene therapy while genes are delivered directly to patients tissues or cells without culturing the cells in vitro in in vivo gene therapy.

CONTENTS1. Overview and Key Difference2. What is Ex Vivo Gene Therapy3. What is In Vivo Gene Therapy4. Side by Side Comparison Ex Vivo vs In Vivo Gene Therapy5. Summary

Ex vivo gene therapy is a type of gene therapy which involves exterior modification of a patients cell and reintroduction of it to the patient. The cells are cultured in the labs (outside the patients body), and genes are inserted. Then the stable transformants are selected and reintroduced into the patient to treat the disease. Ex vivo gene therapy can be applied only to certain cell types or selected tissues. Bone marrow cells are the cells frequently used for ex vivo gene therapy.

There are several major steps involved in Ex vivo gene therapy as follows;

In ex vivo gene therapy, carriers or vectors are used to deliver genes into target cells. Successful gene delivery is dependent on the carrier system, and the important vectors used in ex vivo gene therapy are viruses, bone marrow cells, human artificial chromosome, etc. Compared to the in vivo gene therapy, ex vivo gene therapy does not involve adverse immunological reactions in the patients body since the genetic correction is done in vitro. However, the success depends on stable incorporation and expression of the remedial gene within the patient body.

Figure 01: Ex vivo gene therapy

In vivo gene therapy is a technique which involves direct delivery of genes into the cells of a particular tissue inside the patients body to treat genetic diseases. It can be applied to many tissues of the human body including liver, muscle, skin, lung, spleen, brain, blood cells, etc. The therapeutic genes are introduced by the viral or nonviral-based vectors into the patient. However, the success depends on several factors such as efficient uptake of the therapeutic gene carrying vectors by the target cells, intracellular degradation of the genes within the target cells and gene uptake by the nucleus, expression ability of the gene, etc.

Figure 02: In vivo gene therapy

Therapeutic genes are introduced into patients body as a treatment for certain diseases. It is known as gene therapy and can be done in two ways namely ex vivo gene therapy and in vivo gene therapy. The difference between ex vivo and in vivo gene therapy is that gene insertion in ex vivo gene therapy is done in the cell cultures exterior to patients body and the corrected cells are reintroduced to the patient while in in vivo gene therapy genes are introduced directly into the interior target tissues without isolating the cells. The success of the both processes depends on the stable insertion and transformation of the therapeutic genes into the patient cells.

Reference:1.What is gene therapy? Genetics Home Reference. U.S. National Library of Medicine. National Institutes of Health, n.d. Web. 24 Apr. 2017.2.Evaluation of the Clinical Success of Ex Vivo and In Vivo Gene Therapy | JYI The Undergraduate Research Journal. JYI The Undergraduate Research Journal. N.p., n.d. Web. 24 Apr. 20173. Crystal, Ronald G. In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene transfer vectors. SpringerLink. Springer-Verlag, n.d. Web. 24 Apr. 2017

Image Courtesy:1. ExVivoGeneTherapy plBy Pisum na podstawie pracy Lizanne Koch Own work (CC BY-SA 3.0) via Commons Wikimedia2. In vivo gene therapy pl By Pisum na podstawie pracy Lizanne Koch Own work (CC BY-SA 3.0) via Commons Wikimedia

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Difference Between Ex Vivo and In Vivo Gene Therapy

THURSDAY, Dec. 15, 2022 (HealthDay News) -- An experimental gene therapy that's applied as a skin gel appears to heal wounds caused by a rare and severe genetic skin disease.

Experts called the findings "remarkable," and said they bring hope of a better quality of life to children and young adults living with the condition, called dystrophic epidermolysis bullosa (DEB).

The disease affects about 3 out of every 1 million people. It's caused by a flawed gene that renders the body unable to produce a particular collagen -- a "glue" between the skin layers that is essential to its strength and integrity.

Kids born with DEB are sometimes called "butterfly children" because their skin is so fragile, even an ordinary bump or friction can cause blistering that progresses to painful open wounds.

In the most severe cases, infants have blisters or missing skin at birth, or soon after. Those children typically develop widespread scarring over their bodies and can have eye inflammation that impairs their vision. Blisters and scarring also arise along the lining of the mouth, throat and digestive tract -- which can interfere with eating and cause malnutrition.

As young adults, people with DEB face a high risk of squamous cell carcinoma, a form of skin cancer that is normally highly curable, but in a person with DEB often proves deadly.

There has never been any specific treatment for DEB. Managing it is all about wound care, preventing infections, trying to relieve pain and other "supportive" therapies, said Dr. Peter Marinkovich, the senior researcher on the new study.

"We're helplessly watching blisters and wounds form, without any way to stop them," said Marinkovich, who directs Stanford University's Blistering Disease Clinic.

The new gene therapy, delivered by a skin gel applied directly to wounds, could become the first treatment for the rare disease. Krystal Biotech, the product's developer, has submitted an application for approval to the U.S. Food and Drug Administration, and said the agency granted it "priority review" designation.

The therapy does not correct the genetic flaw causing DEB, or cure the disease.

Instead, the gel contains a modified herpes virus that delivers two functioning copies of the gene, called COL7A1, to patients' skin cells. The cells are then able to produce the missing collagen protein -- with the goal of healing wounds.

In the new trial, published Dec. 15 in the New England Journal of Medicine, Marinkovich and his team found the approach did just that.

The study involved 31 children and adults with DEB. Each patient had one wound treated with the gene therapy gel, and a second, similar wound treated with a placebo (inactive) gel. In all cases, it was applied during weekly bandage changes.

After six months, 67% of wounds treated with the gene therapy were completely closed, versus 22% of those treated with the placebo gel. That included healing of longstanding -- even 10-year-old -- wounds, according to Marinkovich.

Other experts called the trial "pivotal," and said that if the therapy continues to have such benefits over the long term, it could have a "transformational" impact on patients' quality of life.

"This is a devastating disease," said Dr. Aimee Payne, a professor of dermatology at the University of Pennsylvania.

Payne, who wrote an editorial published with the study, said that various high-tech treatments for DEB have been attempted -- including stem cell therapies and skin grafts.

"And now this comes along, and it's a salve that you put on the skin," Payne said. "It almost seems magical."

The notion of topical treatments is new to the gene therapy field, said David Schaffer, a professor of chemical and biomolecular engineering at the University of California, Berkeley.

A limitation of the approach is that it's transient, explained Schaffer, who wrote a separate editorial published with the study. As skin cells naturally die, the functioning COL7A1 gene is lost, too.

So the topical therapy will likely need to be repeated indefinitely. In addition, it does not penetrate the skin, Schaffer said. That means while it can be applied as needed to new wounds, it cannot prevent them.

That said, a gel capable of closing wounds could transform patients' lives, according to Schaffer. And if that healing is ultimately shown to prevent squamous cell carcinoma, he said, "that would be huge."

As for safety, the trial found no serious side effects. A theoretical concern, the experts said, is that the immune system could react against the herpes simplex virus used in the gel, or the newly produced collagen protein.

The herpes virus is genetically modified so that it cannot replicate or spread in the body. But because the virus is naturally adept at evading the immune system, Marinkovich explained, it's a good vehicle for delivering the COL7A1 gene to cells without sparking an immune response.

The skin gel does not address the internal lesions that DEB causes. But, Marinkovich said, it's possible the same gene therapy could be delivered to those areas of the body by other means -- drops for the eyes, an oral "swish" for the mouth, or suppositories for anal lesions.

Among the ongoing research steps, he said, is to treat skin lesions in younger children, as early as 6 months of age, to see if that can prevent extensive skin scarring.

Schaffer pointed to the bigger picture. Gene therapy, he said, has long been "held back" by a lack of good delivery systems. But that's changing. Just last month, Schaffer noted, the first gene therapy for hemophilia B -- delivered by a single IV infusion -- was approved by the FDA.

"Gene therapy is beginning to work," he said.

More information

The nonprofit DEBRA has more on the different forms of epidermolysis bullosa.

SOURCES: M. Peter Marinkovich, MD, associate professor, dermatology, and director, Blistering Disease Clinic, Stanford University School of Medicine; Aimee S. Payne, MD, PhD, professor, dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia; David V. Schaffer, PhD, professor, chemical and biomolecular engineering, bioengineering, molecular and cell biology, University of California, Berkeley; New England Journal of Medicine, Dec. 15, 2022

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Gene Therapy Gel Offers New Hope Against Rare Blistering Disease

Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use 1.

Gene therapy is a technique that modifies a persons genes to treat or cure disease. Gene therapies can work by several mechanisms:

Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases.

There are a variety of types of gene therapy products, including:

Gene therapy products are biological products regulated by the FDAs Center for Biologics Evaluation and Research (CBER). Clinical studies in humans require the submission of an investigational new drug application (IND) prior to initiating clinical studies in the United States. Marketing a gene therapy product requires submission and approval of a biologics license application (BLA).

Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry, January 2020

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What is Gene Therapy? | FDA - U.S. Food and Drug Administration

Hope may be on the horizon for people with retinitis pigmentosa, a rare inherited eye disease with no cure. Existing treatments only help a fraction of the estimated 100,000 Americans with this condition. But advances in gene therapy may soon help restore vision to a greater number of people.

Retinitis pigmentosa causes light-detecting cells in the retina to break down over time, destroying vision. Mutations in more than 60 different genes can contribute to this condition.

If you are diagnosed with retinitis pigmentosa, its vital to undergo genetic testing to identify your underlying mutation," says Ninel Gregori, M.D., an Academy member and a professor of clinical ophthalmology at Bascom Palmer Eye Institute.

That's because people with certain genetic mutations may qualify to participate in a clinical trial of a new treatment before it's widely available.

"Knowing which gene causes your disease and asking your ophthalmologist about options to join a clinical trial may help save your vision, Gregori says.

Two treatments are currently available for patients with retinitis pigmentosa.

The gene therapy Luxturna is only for patients with a mutation in both copies of the RPE65 gene. Because of this mutation, the retina doesn't respond properly to light. A single injection of Luxturna delivers a healthy copy of the RPE65 gene directly to the retina. This restores the retina's ability to respond to light.

If patients receive the treatment early enough after diagnosis, Luxturna can improve night vision and help patients better navigate in low-light conditions.

Luxturna was developed by Spark Therapeutics and approved in 2017 by the U.S. Food and Drug Administration. It costs $850,000 for both eyes, which may be covered by insurance.

Patients with advanced retinitis pigmentosa may experience some minor improvements in vision using the Argus II bionic eye. Patients who benefit from this treatment often have very low visual acuity, and may only be able to perceive light. A surgery is required to place a small electronic device on the retina. Patients must also wear a special pair of glasses mounted with a video processing technology. The glasses send images to the device, which stimulates light-sensing cells in the retina and transmits these images to the brain.

Earlier this year, Second Sight Medical Products announced a redesigned set of glasses for use with previously implanted Argus II systems, but the glasses are not yet commercially available. Although new Argus II implants are no longer available, a different implant is in early development in Australia.

Several new treatments on the horizon aim to benefit people with retinitis pigmentosa. Many of these therapies are still being tested, and it will likely be several years before they become available to patients. But the results so far are promising. Ask your ophthalmologist whether you qualify for a clinical trial.

GenSight Therapeutics is testing a treatment that has the potential to help people with retinitis pigmentosa regardless of their genetic mutation. Treatments that use light as a tool to control cells are known as optogenetic therapies.

The optogenetic therapy from GenSight combines an eye injection with the use of high-tech goggles. The injection delivers a gene that helps retinal cells respond to light. The goggles allow these cells to send electrical signals to the brain. Together, the injection and goggles attempt to replicate the work of light-sensing cells called photoreceptors, which don't work well in people with retinitis pigmentosa.

Patients must train for several months to learn how to use the goggles. So far, five patients have had the treatment. Some have gained the ability to distinguish high-contrast objects on a table and identify crosswalk lines on the street. They are still not able to read, recognize faces or drive. Other companies pursuing optogenetic therapies include Retrosense Therapeutics (Allergan), Nanoscope Therapeutics, and Vedere Bio, Inc. (Novartis).

People with an aggressive form called X-linked retinitis pigmentosa may benefit from experimental gene therapies in development by three companies: Meira GTX, Applied Genetic Technologies and BioGen. This condition is caused by a mutation in the RPGR gene and typically affects men.

All three treatments involve a procedure called vitrectomy and an eye injection that delivers healthy copies of the RPGR gene to a part of the retina called the macula. Some patients in the clinical trials who received treatment in one eye experienced improvements in their field of vision, light sensitivity and ability to navigate in a dark room. A company called 4D Molecular Therapeutics is testing another type of gene therapy that does not require a vitrectomy.

ProQR Therapeutics is developing a gene therapy that could stop vision loss in people with retinitis pigmentosa and Usher syndrome caused by a mutation in the USH2Agene. This mutation prevents patients from making the USH2A protein, which is essential for vision. The therapy, called QR-421a, is injected into the retina and allows cells to produce a healthier version of the USH2A protein. So far, patients with both advanced and early-moderate disease experienced improvements in both visual acuity and field of vision. ProQR Therapeutics expects to test the therapy in a phase 2-3 clinical trial in the fall of 2021.

Another study by ProQR Therapeutics is testing a treatment for people who have retinitis pigmentosa due to a mutation in the RHOgene. This is also known as RP4. This mutation causes patients to produce a faulty version of the rhodopsin protein, which normally converts light into an electrical signal. The faulty protein becomes toxic to the retina over time. The new treatment, QR-1123, is delivered by an eye injection and prevents the faulty protein from being made. This allows the normal version of the protein to rule the retina again. This therapy is currently being studied in a phase 1-2 clinical trial.

Leber congenital amaurosis is a form of retinitis pigmentosa that affects infants. This disease destroys light-sensing cells in the retina. Type 10 disease is caused by a defect in the CEP290 gene that leads to progressive vision loss and, in many cases, legal blindness.

There are two promising treatments in development for this treatment.

Scientists have developed a gene-editing tool called CRISPR to try to remove the genetic defect. The treatment is delivered to the retina during an eye injection. Researchers hope the tool will help the retina produce a protein that keeps cells from dying and also revives some dead cells. This could help patients regain some vision. Allergan and Editas Medicine are leading the phase 1-2 BRILLIANCE clinical trial with 18 patients to test this treatment.

ProQR Therapeutics is testing a type of gene therapy known as RNA antisense oligonucleotide therapy. This treatment is delivered via an eye injection, and it allows production of a protein needed for vision. Patients in an ongoing phase 2-3 clinical trial are experiencing significant improvements in vision and retinal structure several months after injection.

These treatments could help patients avoid debilitating vision loss due to retinitis pigmentosa.

Gene therapy for some forms of retinitis pigmentosa offer the potential of halting the otherwise relentless progressive loss of vision and visual field. In some patients, it may actually improve vision, light sensitivity, and ability to see and navigate in the dark, says Christine Kay, MD, director of retinal genetics at Vitreoretinal Associates in Gainesville, FL.

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Vaccines that use mRNA technology are not gene therapy because they do not alter your genes, experts have told Reuters after contrary claims were posted online.

Thousands of social media users have shared such posts since the rollout of COVID-19 vaccines began (here) and have continued to do so through August.

Its not a vaccine. Its gene therapy! wrote one Facebook user on Aug. 9, noting that gene therapy manipulates genetic code (here and here).

Pfizer/BioNTech and Moderna have both developed shots that use a piece of genetic code from SARS-CoV-2, the coronavirus that causes COVID-19, to prompt an immune response in recipients (here). However, experts told Reuters that this is not the same as gene therapy.

As mRNA is genetic material, mRNA vaccines can be looked at as a genetic-based therapy, but they are classified as vaccines and are not designed to alter your genes, said Dr Adam Taylor, a virologist and research fellow at the Menzies Health Institute, Queensland, Griffith University.

Gene therapy, in the classical sense, involves making deliberate changes to a patients DNA in order to treat or cure them. mRNA vaccines will not enter a cells nucleus that houses your DNA genome. There is zero risk of these vaccines integrating into our own genome or altering our genetic makeup.

Taylor explained that mRNA enters cells shortly after vaccination and instructs them to create a SARS-CoV-2 spike protein, prompting the immune response.

He added that unlike gene therapy, mRNA vaccines are then rapidly degraded by the body.

In fact, because mRNA is degraded so quickly chemical modifications can be made to mRNA vaccines to make them a little more stable than regular mRNA.

Gene therapy, on the other hand, involves a process whereby an individuals genetic makeup is deliberately modified to cure or treat a specific genetic condition (here).

It can be done in several ways, such as replacing a disease-causing gene with a healthy alternative, disabling a disease-causing gene or introducing a new gene to help treat a disease, according to the U.S. Food and Drug Administration (FDA) (here).

If we suffer from an inherited blood disease then the defect in our genes can be corrected in blood cells and then we can be cured, said David Schaffer, professor of Chemical and Biomolecular Engineering and Director of the Berkeley Stem Cell Center at the University of California, Berkeley, in an email to Reuters.

In most cases, the DNA is therapeutic because it encodes a mRNA, which encodes a protein that has a beneficial effect on a patient. So, if someone has a disease where the gene encoding an important protein is mutated - such as hemophilia, cystic fibrosis, retinitis pigments - then it can be possible to deliver the DNA encoding the correct copy of that protein in order to treat the disease.

He added: Because DNA has the potential to persist in the cells of a patient for years, this raises the possibility of a single gene therapy treatment resulting in years of therapeutic benefit.

Moderna, which has developed one of the mRNA COVID-19 vaccines used across the world, explained in a fact sheet that mRNA and gene therapy take fundamentally different approaches.

Gene therapy and gene editing alter the original genetic information each cell carries, the company writes. The goal is to produce a permanent fix to the underlying genetic problem by changing the defective gene. Moderna is taking a different approach to address the underlying cause of MMA and other diseases. mRNA transfers the instructions stored in DNA to make the proteins required in every living cell. Our approach aims to help the body make its own missing or defective protein (www.modernatx.com/about-mrna).

Reuters has in the past debunked claims that COVID-19 vaccines can genetically modify humans here and here .

Missing context. Scientists told Reuters that while mRNA vaccines can be considered genetic-based therapy because they use genetic code from COVID-19, they are not technically gene therapy. This is because the mRNA does not change the bodys genetic makeup.

This article was produced by the Reuters Fact Check team. Read more about our work to fact-check social media postshere .

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Fact Check-mRNA vaccines are distinct from gene therapy ... - Reuters