Daily Archives: June 3, 2022

By Tom Piombino

For the cell and gene therapy (CGT) sector, recent years have been nothing less than phenomenal. For example, according to the Alliance for Regenerative Medicine, the sector has witnessed skyrocketing investment. The $7.5 billion raised in 2017 was more than tripled by the $22.7 billion raised in 2021.

Besides creating opportunities for CGT companies, such funding is creating a crunch for both real estate and talent. For example, in San Francisco, more than half a billion square feet of manufacturing space has been acquired by CGT companies in the past year. In Philadelphia, where academia is generating intellectual property in the CGT space at a torrid pace, more than one million square feet of new laboratory space is in development.

In North Carolinas Research Triangle regionwhere vacancy rates have kept per-square-foot development in the $30s range (as opposed to downtown Bostons $100/square foot)the competition for resources has placed a premium on selection and planning, as CGT programs shift from R&D, which occurs in science clusters, to manufacturing, which occurs in attractive suburban markets.

This shift is a huge challenge for CGT companies. The transition from research and preclinical development to process development and clinical manufacturing is rough. Some stakeholders underestimate the difficulties of taking their businesses to the manufacturing phase, and they end up treading water in a sea of limited options. While the pandemic significantly impacted the office market, many of the available and proposed building conversions cannot provide the rigor or meet the cost expectations of a manufacturing facility.

Site selection in todays market goes beyond engineering and real estate. It requires bringing knowledge and talent to appreciate the perspectives of more diverse workforces and company cultures while sustaining market growth, promotion, and compliance. From an organizations project inception, unity of the resources early in a planning process offers owners the perspectives needed to make the right decisions for their businesses while focusing on the big picture of bringing groundbreaking therapies to market. All too often, these decisions are predicated on immediate needs (2 years out) or currently available resources, instead of a vision of technological progress (10 years out).

Site selection can be daunting for the most seasoned real estate professionals, and even more so for people whose expertise is outside of the field. Selecting an attractive siteone with the proper structural capacity, heights, utilities, workforce availability, access to transportation, access to parking, and amenitiescan quickly become an all-consuming task for an operating company. Additionally, predicting the needs and wants of a workforce in a transitionary state, post-pandemic, adds another dimension of complexity for peoples whose day job is attending to developing science.

Much like an engineering design process, the building out of early-stage GCT facilities requires a deliberate approach with input from experts whose knowledge in various fields benefits the project as a whole. It must start at the business case inception, utilizing a well-rounded team that can streamline the process and thoroughly explore solutions while addressing needs and challenges across the organization. While speed is incredibly important at this stage, attempts at seeing this inceptionary process as a transaction often result in a misrepresentation of the required outcome.

Using applied experience and several iterations, an experienced project team with an understanding of the business case can recognize trends, similarities, and the opportunities to quickly adapt the solutions that can be acted upon in weeks rather than months. If this approach is taken from the inception of a project, owners can realize considerable benefits and avoid distractions from their day jobs.

First, it brings into focus a clear multiyear plan addressing the operational needs of the organization: Who will need to be hired for research, quality control, manufacturing, maintenance, packaging, and shipping, among other positions? How can an organization build its culture during the growth period? What kinds of efficiencies are needed in the facility? What impact will the operational costs have on funding resources? How does residual value of the asset impact the investor appetite in a facility?

Second, it brings more value to the effort by helping owners explore costs and schedules from the outset. If owners begin months later, during conceptual design, they may belatedly discover that they could have been better positioned to seize growth opportunities.

Planning for companies in a fast-growth period can be daunting, especially in a real estate environment as competitive as the one that currently exists. Company leaders versed in other aspects of the business such as R&D may not have a sense of how much space will be needed in the long term, or of how much effort will be needed to ensure a space meets requirements such as staying up to code.

Onboarding the project team early on can be key to making a project successful because it streamlines the iterative process. By working closely with owners at the inception of the project, team members learn what works for organizations and what does not, building upon the plan as it progresses.

It also develops trust and confidencetwo elements that are especially valuable when the team needs to be flexible in the exploratory phase of project planning. Not only do these elements empower team members to present multiple options, including unconventional options, it gives them the space to learn from feedback and converge on the right solution.

When evaluating options, organizations have to focus on important factors for each element of the plan:

Site: This is about more than the location of the facility. The site plays a key role in meeting the organizations current goals and serves its future growth. With those near-term and long-term goals prioritized, the team can address details such as the need to include multi-floor manufacturing facilities or loading docks capable of accommodating particular types of vehicles.

Also, not to be overlooked in site selection is customer access. Ensuring that an organizations key audience can easily access these facilitieswhether they are in urban areas, which may present traffic and parking difficulties, or in smaller markets, which may not be as easily accessible by commercial transportationwill be a factor in the decision-making process.

Space: The rapid growth in the CGT market puts space at the forefront of planning for small companies. How big does a new facility need to be? What features will need to be included? Can the current building stock in a market serve an organizations needs, or will a greenfield development be required? Much of the real estate market is developer-driven rather than company-driven, which has both benefits and challenges.

In a developer-driven project, a facility may be fitted out to serve as a manufacturing nexus for cell therapies, gene therapies, and biologics. Alternatively, a facility may meet a particular manufacturing need, once the developer determines the appropriate scale reviews a few solutions. While there are few standard solutions that fit all CGT companies, by taking standard ideas and measuring the options to the needs, organizations can streamline the process by tailoring elements to their requirements.

Brand: More than being about aesthetics, a facilitys appearance has the ability to tell an organizations story, from its culture to its future plans. While a warehouse can serve a company like Amazon quite effectively, for growing CGT companies wanting to attract top talent and top funders, the impression that a facility presents impacts the mission of the company as well as how an organization can differentiate itself from other companies in a competitive marketplace.

Expectations: There are a lot of companies that can get derailed early on in the process, as their expectations can deviate from reality.

For owners coming out of institutions that are not well placed, moving to a central location might put them in greater proximity to talent. It also could come with significant extra costs in rent, construction, and operations. Rents within regions, not justbetween regions, can swing significantly.

However, organizations also must be honest when considering the costs. For example, is $22/square foot for rent in the suburbs more cost effective compared to $55/square foot near a city core if it means sacrificing the ability to recruit talented people who refuse to work in the suburbs?

In addition, with space at a premium, can an organization live with a real estate strategy that might require a stepped approach to growth? In the rapidly expanding CGT markets, many companies moving from research to trials to manufacturing have compromised on facilities that are too small or in the wrong location, putting growth strategies at risk.

The demands on CGT companies are different from those on other companies. Even as biopharma players have moved into the market, the competition has only increased the difficulty of coping with the markets growth.

The move from research to preclinical trials to clinical manufacturing is occurring at such a pace that it is leaving some companies waiting at a crossroads without a complete strategy on moving forward. By engaging technical and subject matter experts as part of a project team early in the process, organizational leaders can make decisions that will position their organizations for years of growth.

Tom Piombino (tpiombino@ipsdb.com) is managing director of the Americas for IPSIntegrated Project Services. For more information on the Inceptioneering process, please visit http://www.ipsdb.com/expertise/services/inceptioneering.

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Overcoming the Challenges of Cell and Gene Therapy Facilities - Genetic Engineering & Biotechnology News

Arrested Development: A brain organoid derived from the skin cells of a child with Pitt-Hopkins syndrome (right) is smaller and has fewer neurons than that derived from a child without the syndrome (left).

Tiny balls of cultured human brain cells reveal how genetic mutations linked to Pitt-Hopkins syndrome, a profound form of autism, disrupt brain development, according to a new study. These balls of cells called brain organoids also reveal how gene therapies might help lessen the mutations effects.

The data offers hope that a future clinical application with gene therapy might actually benefit certain autism spectrum disorder patients, says co-lead investigator Alysson Muotri, professor of pediatrics and of cellular and molecular medicine, and director of the stem cell program, at the University of California, San Diego. Our research is focused on profound autism spectrum disorder subtypes individuals that really need help and medical support to achieve their full potential.

Pitt-Hopkins syndrome is caused by de novo mutations in TCF4, a gene that controls when other genes are turned on or off in the embryo and is essential for brain development. Children with Pitt-Hopkins syndrome have severe cognitive and motor disabilities and typically are nonverbal.

There is a rough estimate that Pitt-Hopkins syndrome affects 1 in every 30,000 individuals, but this is an underestimate, because genetic diagnostic testing is not available in most countries, says co-lead investigator Fabio Papes, associate professor of genetics, evolution, microbiology and immunology at the University of Campinas in So Paulo, Brazil.

Papes has a relative with Pitt-Hopkins syndrome, which spurred him to study how TCF4 mutations impair brain development. He and Muotri turned to organoids because mouse models of the condition are limited: The animals display some Pitt-Hopkins syndrome-like traits, such as impairments in social interactions and memory, but fail to mimic the severe traits seen in people.

The new results highlight once more, the need for human models in order to fully understand the genetics of neurodevelopmental disorders, says Jrgen Knoblich, scientific director of the Institute of Molecular Biotechnology at the Austrian Academy of Sciences in Vienna, Austria, who did not take part in this research. It represents nice and useful progress for the field of neurodevelopmental disorders.

Muotri, Papes and their colleagues generated brain organoids using skin cells from five children with Pitt-Hopkins syndrome and five controls.

After four weeks, organoids with TCF4 mutations were significantly smaller than those without, and many of their cells had not developed into neurons from precursor cells called neural progenitors.

The neural progenitors exhibited arrested development, likely due to a disruption in a cell signaling pathway called WNT and then reduced expression of a gene called SOX, the scientists found. Compared with controls, the progenitors yielded fewer cortical neurons, which power thinking, memory, speech and other cognitive abilities. And the neurons they did produce showed impaired electrical activity and tended to cluster together instead of self-organizing into neural circuits. The findings appeared in Nature Communications in May.

It is surprising to see such significant effects on neural progenitor cells, because the obvious traits of Pitt-Hopkins syndrome, such as microcephaly, or a small head, usually develop after birth, says Ben Philpot, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who did not work on this study. This suggests that their organoid model was highly sensitive and has great value for screening potential therapeutics, he says.

The scientists also tested two different virus-based gene therapies on the organoids. One encodes molecules that boost levels of TCF4 protein, whereas the other delivers a functional copy of the gene to the cells. Both techniques resulted in organoids that resembled the controls.

We could rescue molecular, cellular and neural network alterations by just restoring the expression of the corrected gene, Muotri says.

In an unrelated study published in eLife in May, Philpot and his colleagues tested a very similar gene therapy strategy in mouse models, Papes says. Both papers complement each other very nicely, providing very solid evidence, in patient-derived human cells and in animals, that gene therapy is possible for this form of profound autism.

Muotri, Papes and their colleagues have partnered with a pharmaceutical company specializing in gene therapy to use these new findings to design a clinical trial. The clinical potential is huge, Muotri says. We will start with TCF4, but our strategy allows us to test other genes implicated in autism spectrum disorder.

The scientists caution that these findings may not translate for people with Pitt-Hopkins syndrome. A brain organoid is not a mini-brain, Muotri says. These are really small structures when compared to the human brain. Also, they are mimicking developmental stages rather than a more mature human brain.

In addition, children enrolled in a clinical trial would receive the gene therapies a few years after the prenatal stage of brain development in which the therapies were tested. Our gene therapy approach may not correct all characteristics, especially those changes that cannot be reverted once the cells and brain tissue have already been altered, Papes cautions.

Before clinical trials can ever happen, we need to be absolutely convinced that our methods will cause no harm and will be effective, Muotri says. Thus, we have a lot of work to do in the following years.

Cite this article: https://doi.org/10.53053/FQVM6681

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Organoids test gene therapies for Pitt-Hopkins syndrome - Spectrum

A new gene therapy that inhibits targeted nerve cell signaling effectively reduced neuropathic pain in mice with spinal cord or peripheral nerve injuries with no detectable side effects.

An international team of researchers led by scientists at the University of California San Diego School of Medicine reported that a gene therapy that inhibits targeted nerve cell signaling effectively reduced neuropathic pain in mice with spinal cord or peripheral nerve injuries with no detectable side effects.

The results, which were published in the online edition of Molecular Therapy on May 5, 2022, suggest a possible new treatment option for a condition that may affect more than half of individuals with spinal cord injuries. Neuropathy involves damage or dysfunction in nerves elsewhere in the body, typically resulting in chronic or debilitating numbness, tingling, muscle weakness, and pain.

There are no singularly effective remedies for neuropathy. Pharmaceutical therapy, for example, may need sophisticated, continuous medication administration and is linked with adverse side effects such as drowsiness and motor weakness. Opioids may be effective, but they can also develop tolerance and raise the risk of overuse or addiction.

Because physicians and researchers are able to pinpoint the precise location of a spinal cord injury and the origin of neuropathic pain, there has been much effort to develop treatments that selectively target impaired or damaged neurons in the affected spinal segments.

In recent years, gene therapy has proven an increasingly attractive possibility. In the latest study, researchers injected a harmless adeno-associated virus carrying a pair of transgenes that encode for gamma-aminobutyric acid or GABA into mice with sciatic nerve injuries and consequential neuropathic pain. GABA is a neurotransmitter that blocks impulses between nerve cells; in this case, pain signals.

The delivery and expression of the transgenes GAD65 and VGAT were restricted to the area of sciatic nerve injury in the mice and, as a result, there were no detectable side effects, such as motor weakness or loss of normal sensation. The production of GABA by the transgenes resulted in measurable inhibition of pain-signaling neurons in the mice, which persisted for at least 2.5 months after treatment.

Senior study author Martin Marsala, MD, is a professor in the Department of Anesthesiology at UC San Diego School of Medicine. Credit: UC San Diego Health Sciences

One of the prerequisites of a clinically acceptable antinociceptive (pain-blocking) therapy is minimal or no side effects like muscle weakness, general sedation or development of tolerance for the treatment, said senior author Martin Marsala, MD, professor in the Department of Anesthesiology in the UC San Diego School of Medicine.

A single treatment invention that provides long-lasting therapeutic effect is also highly desirable. These findings suggest a path forward on both.

Reference: Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain by Takahiro Tadokoro, Mariana Bravo-Hernandez, Kirill Agashkov, Yoshiomi Kobayashi, Oleksandr Platoshyn, Michael Navarro, Silvia Marsala, Atsushi Miyanohara, Tetsuya Yoshizumi, Michiko Shigyo, Volodymyr Krotov, Stefan Juhas, Jana Juhasova, Duong Nguyen, Helena Kupcova Skalnikova, Jan Motlik, Hana Studenovska, Vladimir Proks, Rajiv Reddy, Shawn P. Driscoll, Thomas D. Glenn, Taratorn Kemthong, Suchinda Malaivijitnond, Zoltan Tomori, Ivo Vanicky, Manabu Kakinohana, Samuel L. Pfaff, Joseph Ciacci, Pavel Belan and Martin Marsala, 5 May 2022, Molecular Therapy.DOI: 10.1016/j.ymthe.2022.04.023

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Gene Therapy Successfully Treats Spinal Cord Injuries Without Side Effects - SciTechDaily

image:In comparing the gene expression patterns of 26 species with diverse lifespans, University of Rochester biologists found that the characteristics of the different genes were controlled by circadian or pluripotency networks. view more

Credit: University of Rochester illustration / Julia Joshpe

Natural selection has produced mammals that age at dramatically different rates. Take, for example, naked mole rats and mice; the former can live up to 41 years, nearly ten times as long as similar-size rodents such as mice.

What accounts for longer lifespan? According to new research from biologists at theUniversity of Rochester, a key piece of the puzzle lies in the mechanisms that regulate gene expression.

In a paper published inCell Metabolism, the researchers, includingVera Gorbunova, the Doris Johns Cherry professor of biology and medicine;Andrei Seluanov, professor of biology and medicine; and Jinlong Lu, a postdoctoral research associate in Gorbunovas lab and the first author of the paper, investigated genes connected to lifespan. Their research uncovered specific characteristics of these genes and revealed that two regulatory systems controlling gene expressioncircadian and pluripotency networksare critical to longevity. The findings have implications both in understanding how longevity evolves and in providing new targets to combat aging and age-related diseases.

The researchers compared the gene expression patterns of 26 mammalian species with diverse maximum lifespans, from two years (shrews) to 41 years (naked mole rats). They identified thousands of genes related to a species maximum lifespan that were either positively or negatively correlated with longevity.

They found that long-lived species tend to have low expression of genes involved in energy metabolism and inflammation; and high expression of genes involved in DNA repair, RNA transport, and organization of cellular skeleton (or microtubules). Previous research by Gorbunova and Seluanov has shown that features such asmore efficient DNA repairand aweaker inflammatory responseare characteristic of mammals with long lifespans.

The opposite was true for short-lived species, which tended to have high expression of genes involved in energy metabolism and inflammation and low expression of genes involved in DNA repair, RNA transport, and microtubule organization.

When the researchers analyzed the mechanisms that regulate expression of these genes, they found two major systems at play. The negative lifespan genesthose involved in energy metabolism and inflammationare controlled by circadian networks. That is, their expression is limited to a particular time of day, which may help limit the overall expression of the genes in long-lived species.

This means we can exercise at least some control over the negative lifespan genes.

To live longer, we have to maintain healthy sleep schedules and avoid exposure to light at night as it may increase the expression of the negative lifespan genes, Gorbunova says.

On the other hand, positive lifespan genesthose involved in DNA repair, RNA transport, and microtubulesare controlled by what is called the pluripotency network. The pluripotency network is involved in reprogramming somatic cellsany cells that are not reproductive cellsinto embryonic cells, which can more readily rejuvenate and regenerate, by repackaging DNA that becomes disorganized as we age.

We discovered that evolution has activated the pluripotency network to achieve longer lifespan, Gorbunova says.

The pluripotency network and its relationship to positive lifespan genes is therefore an important finding for understanding how longevity evolves, Seluanov says. Furthermore, it can pave the way for new antiaging interventions that activate the key positive lifespan genes. We would expect that successful antiaging interventions would include increasing the expression of the positive lifespan genes and decreasing the expression of negative lifespan genes.

Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation

16-May-2022

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The secret to a longer lifespan? Gene regulation holds a clue - EurekAlert