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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

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Vision 2020: what could come about in the next decade for biotech?

2020 Vision

Michael Yee

  More than 2,000 years ago, around 400 BC, Hippocrates revolutionized medicine by describing diseases for the first time in history. In fact, he is credited as the first to believe disease was caused naturally, not by the Gods. Beyond characterizing diseases, he is also credited with establishing the earliest forms of diagnosing diseases, including […]

DOI: 10.18609/cgti.2019.129
Citation: Cell & Gene Therapy Insights 2019; 5(12), 1473-1481.
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More than 2,000 years ago, around 400 BC, Hippocrates revolutionized medicine by describing diseases for the first time in history. In fact, he is credited as the first to believe disease was caused naturally, not by the Gods. Beyond characterizing diseases, he is also credited with establishing the earliest forms of diagnosing diseases, including acute and chronic conditions. While he is often considered the Father of Medicine due to his contributions to the field, the Hippocratic Corpus was a collection of medical works from ancient Greece.

Figure 1: Over 180 gene therapy programs in development. Source: Jefferies research (sourced each individual company’s websites).

Through another long 1,000 years man practiced various forms of plant, herbal, and other cultural medicines to attempt to treat and cure disease – mostly through trial and error.

In 1798, around another 1,000 years later, Edward Jenner used a vaccine against smallpox. Yet, it was not for another 150 years that Jonas Salk, in 1955, discovered and developed the polio vaccine, saving millions of lives against one of the most frightening public health epidemics.

While DNA was first isolated in 1869, it took 70 years for Watson and Crick to describe the double-helix molecular structure. In fact, it was on February 28, 1953 that Crick entered a noisy pub and declared to all “We have discovered the secret of life.”

What he didn’t realize was that while it took 1,000 years to understand and describe various diseases and another 500-700 years just to understand and develop vaccines against global epidemics, the rate of achievement and potentially the cure of many diseases would exponentially improve in the next century. It was only 60 years ago that we first understood the molecular structure of DNA. 20 years ago, we sequenced the whole human genome. Within one decade this led to a breakthrough in understanding genetic function and underlying cause for many diseases. In fact, we now know that approximately half of all genetic diseases are caused by only one nucleotide base pair error.

Figure 2: Biotech fund size by year. Source: PitchBook Data.

The recent era of innovation is moving quickly. While it took scientists centuries to understand the basics of disease and to develop vaccines and medicines to ‘treat’ them, it now only takes decades or less to have major medical breakthroughs. Based on the recent breakthroughs in science–along with the efforts of the pharmaceutical industry, the critical capital from investors, and important support and oversight of the FDA–in the last 5 years alone we have gone from ‘treating’ diseases with toxic chemotherapy or merely adding a few months of survival to a colorectal cancer patient (Avastin), to giving CAR-T therapy and one’s own engineered T cells as a treatment to wipe out DLBCL in 35% of patients. As of a few years ago, we have immunotherapy to induce metastatic melanoma patients to achieve durable remission. Now, there are over 50 different CAR-T programs in development.

And now we have the first gene therapy approved drugs that target the genetic underlying cause of disease. These include the first FDA-approved one-time administration gene therapy drug to cure a rare blindness (Luxturna) and a gene therapy to treat babies with a fatal spinal muscular atrophy (Zolgensma). Previously, these were both diseases with no approved treatment. Now, over 100 other gene therapy drugs are in the industry pipeline (Figure 1).

Figure 3: Total Biotech IPO proceeds by year.
Source: Jefferies research (FactSet, Bloomberg, Company reports, Nasdaq:

Given our vision of where we see the scientific breakthroughs occurring, the FDA’s willingness and motivation, and importantly, the record levels of VC and investor capital in 2018 and 2019 being deployed to fund all these projects (Figures 2 & 3), we foresee a new pace of innovation in the next 10 years, particularly in the way drugs could cure diseases. The science is moving quickly, the FDA is approving these breakthroughs, and the capital continues to come in. Over the next 10 years, this will be exciting news for doctors, scientists, investors, and most importantly, patients. We believe this rapid pace of innovation is just beginning.

Three areas of medicine we predict will see tremendous innovation for patients in the next 10 years:

Gene therapy & gene editing

In 10 years (a very short period of time of development based on the historical timelines of medicine previously described) we could be curing and treating 100 more diseases that have a genetic root cause with a one-time administration of gene therapy to the patient. As evidence that the regulatory framework is evolved to help accelerate these critical breakthrough innovations, former FDA Commissioner Scott Gottlieb recently said “I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses…we’re at a turning point when it comes to this novel form of therapy and at the FDA, we’re focused on establishing the right policy framework to capitalize on this scientific opening…”

Figure 4: Mechanism of CRISPR Cas9 gene editing.

We believe the primary use of gene therapy will be to address and target thousands of (often hereditary or genetic) diseases based on a dysfunctional or missing protein. Over the next couple of years, more gene therapy drugs in late stage development have the potential to be approved, including ones for hemophilia and DMD. Importantly, over the next 10 years many more are likely to be approved as there are more than 100 programs in development for rare genetic diseases and other diseases.

Further, the development of gene editing drugs, CRISPR/Cas9-based gene and single-base pair therapies, could take this concept to another level of breakthrough.While earlier in development (the candidates are just now entering the first human studies and have only presented preliminary results versus gene therapy drugs already approved) gene editing could be more powerful because the CRISPR/Cas9 ‘editing’ construct could ‘cure’ a patient by just editing the existing genes (Figure 4), opposed to delivering the corrected gene sequence that needs to be transcribed and translated in a robust manner to produce enough protein.

At least three companies are working with CRISPR Cas9 and are in or near the clinic. This technology has the ability to potentially: (1) disrupt a mutated (disease causing) gene, (2) edit the mutated gene to be replaced with a correct copy into the genome. In addition, with ‘single base pair’ editing (which has broad applicability as almost half of all genetically defined diseases are caused by only one base pair error) a deaminase protein combined with a CRISPR construct can change a single base pair to introduce a stop codon, correct the erroneous nucleotide to the correct one, with possibly greater accuracy and precision. This could potentially address an even wider field of diseases than gene therapy and/or CRISPR/Cas9 editing. These types of drugs are around two years from the clinic and hence could be approved in the coming decade.

Allogeneic cell therapy

Figure 5: iPSC differentiation overview.

In 10 years, we predict there will be treatments for non-genetic diseases using off-the-shelf engineered cells as a therapeutic approach for patients. The idea to deliver ‘healthy cells’ such as tissues or organs isn’t necessarily a novel approach, but the ability to do it in an allogeneic and robust wide-scale approach has always been a limitation to the idea. Currently, numerous companies have been able to address two primary historical issues: GMP manufacturing of these cells and immunogenicity. For the most part, this stems from processes that have been refined on a robust GMP scale to selectively differentiate CD34+ stem cells from a donor or use induced pluripotent stem cells (iPSC) to make a specific cell of interest (neuron, cardiomyocyte, islet beta cells, etc.) as shown in Figures 5 & 6.

Although still early and just going into the first clinical trials, we predict that in the next decade we will be delivering fully functional cells of interest as a treatment for a disease (Figures 7 & 8). For example, in development are iPSC-derived dopamine-producing neurons to treat Parkinson’s disease, cardiomyocyte cells harvested and engrafted to treat heart failure, and insulin-producing islet beta cells to treat Type I diabetes. Additional companies are working on delivering iPSC-derived cells in micro-encapsulated spheres that can be implanted into the gut. One company is using engineered allogeneic red blood cells as a platform to deliver proteins of interest inside the cell, or to deliver an antigen of interest on the surface of the red blood cell to treat autoimmune diseases. And in oncology, there is a company now testing the ability to deliver iPSC-derived NK cells to fight various cancers.

Figure 6: iPSC differentiation possibilities.

We may no longer need to deliver a small molecule or antibody drug to help the body fight disease. Rather, for a disease caused by a dysfunctional protein we will actually be making new healthy cells to get at the root of the disease, such as enabling diabetes patients to have insulin producing cells again. This could possibly offer a functional cure to the disease.

In oncology the same concept of delivering engineered donor T cells to fight cancer is now well into clinical trials. Only five years ago it was unclear if we could safely and effectively deliver a patient’s own engineered lymphocytes to fight DLBCL (CAR-T therapy). But in those five years it has been proven to be possible and now multiple autologous CAR-T therapies are FDA-approved (Kymriah, Yescarta) and several others are advancing through clinical trials. The key limitation of CAR-T has been finding antigens present on cancerous tissue only, not on healthy tissue. This has led to a massive investment in TCR-based therapies going after intracellular targets in cancer cells and a tremendous amount of capital is being invested in this area.

In the next decade we believe there will be a potential long-term shift away from autologous CAR-T therapy to allogeneic CAR-T therapy as companies have been able to engineer T cells using gene editing and other similar approaches to produce a CAR-T that can be derived from healthy donor cells. One donor could provide allogeneic CAR-T to 50 patients rather than a 1 for 1 self-approach with current autologous CAR-T. Many companies are working on this and are in or soon to enter the clinic.

Innovation in technology could transform drug discovery efforts in the next decade

Figure 7: Over 75 cell therapy programs in development. Jefferies research (sourced each individual company’s websites).

On a different note, the critical developments in computing power and AI technology could quickly find its way into benefitting drug development in this coming decade. While the traditional drug development path starts with thousands and thousands of molecules in a screening library, new drug development software that use complex algorithms and massive computing power to calculate complex physics and interactions involved with small molecules will likely lead to significantly faster and more efficient discovery of small molecule drugs, particularly against difficult targets of interest. Bill Gates has been a major proponent of these efforts and has made significant investments in these areas in order to enable these efforts to come up with better and smarter engineered drugs in a shorter timeframe. Combined with computing power at a scale that was not even possible a decade ago, this is likely to accelerate the drug discovery process

Separately, we are reluctant to predict too much about the potential applications of Big Data and the efforts of AI. Presumably if technology and AI can create self-driving cars it would seem to certainly be able to make the old school efforts of 96-well titers and drug screening exponentially more efficient along the lines of Moore’s Law. We are aware of efforts by Big Pharma and Big Biotech in figuring out ways to utilize Big Data to mine clinical trial data to figure out why patients respond or do not respond to therapy, but issues such as HIPAA and privacy concerns, and inability and disinterest in sharing of clinical trial data between sponsors, are clearly gating factors.

The risks to this amazing upcoming decade include

Continued capital investment. Mark Zuckerberg’s widely touted $3 billion investment to ‘cure all disease’ is certainly a generous effort that is worthy of applause. However, that’s just a start – it will help fund developments, but it’s not enough. To put it into perspective, the biotech industry spent $55 billion in R&D in 2018 alone and will have spent over $350 billion in the last 10 years, and they aren’t saying we will cure all diseases (to be fair, the Zuckerberg initiative is built to focus on developing tools that are geared toward eradicating diseases rather than simply treating them). The VC chart shows $35 billion in funding for biopharma investments in 2018 and investment into these innovative companies has doubled in just the last few years. The good news is we think evidence suggests ROI on R&D is improving due to the scientific breakthroughs and the significant leaps in clinical benefit for patients based on the aforementioned three areas of technology. It is these scientific breakthroughs that we (and Mark) could be relying on to move the needle from treating disease to ‘curing’ all diseases.

A willing and able FDA that regulates and serves as the gate-keeper to any drug development in the USA. The recent Zolgensma uncoverings has led to fear about elevated levels of scrutiny and extra caution by regulatory agencies that could slow or hamper development, or become much more restrictive, which would decelerate the tremendous momentum we have.

Figure 8: Over 30 iPSC programs in development. Jefferies research (sourced each individual company’s websites)

And lastly, no discussion of this amazing innovation can be had without a reasonable consensus on how society will pay for these therapies. If there’s one thing that’s certain to occur over the next 10 years, it will be an ongoing political and societal debate on how to pay for drugs while not slowing the pace of innovation that got us to this critical juncture in the first place – a point in time where, as we have just explained, innovation is about to significantly accelerate to create an enormous number of life-saving medicines. How will we pay? Will society accept the relative high price of drugs while understanding the high cost of R&D, or that the $350 billion in drugs in the USA is only 10% of the cost of the total healthcare spend annually in the USA? Will they understand that numerous breakthroughs have come in part as a result of investors and entrepreneurs (VC’s, etc.) plowing $7 billion in IPO proceeds in 2018 and over $30 billion in capital raising for biotech in 2018 overall? These investments are not to be overlooked – they have resulted in the significantly improved benefit to patients unheard of decades ago, a time when gene therapy was a scary concept.

Our generation and the next generation will expect even more. Ten years ago, we didn’t have gene therapy and cell therapy drugs approved by the FDA. We look forward to the exciting innovation on the horizon of the next decade. What genes will we have discovered? What cures will be developed? As we embark on a vision of 2020, we can only hope that the pace of innovation in biotech over the next 10 years would make Hippocrates, Dr Watson, and Dr Crick proud.

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Acknowledgements: None.
Disclosure and potential conflicts of interest: The author declares that they have no conflicts of interest.
Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.

Article & copyright information

Copyright: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2019 Michael Yee. Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.
Article source: Invited
Revised manuscript received: Sep 12 2019; Publication date: Nov 29 2019.


Michael Yee
Jefferies, 520 Madison Ave, New York, NY 10022, USA

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