Category Archives: Genetic Medicine

In a new trial funded through UABs urgent COVID-19 research program, investigators are comparing the widely available steroid methylprednisolone with dexamethasone, which lowered risk of dying by one-third in a U.K. trial this summer.

Early results from the United Kingdom's RECOVERY trial this summer were a welcome piece of good news in the midst of the COVID-19 pandemic. Critically ill patients on ventilators who received dexamethasone, a corticosteroid drug, were at a one-third lower risk of dying than those who did not receive the drug. Patients receiving oxygen therapy, but not on ventilators, had a 20% lower risk of dying. Nature, the scientific journal, called it a"coronavirus breakthrough."

Better yet, as Nature noted, dexamethasone is both cheap and commonly used. The trouble is, "dexamethasone is already in short supply," said Randy Cron, M.D., Ph.D., professor of pediatrics and medicine at UAB. So Cron and Winn Chatham, M.D., professor of medicine at UAB, are conducting a pilot study of another corticosteroid, methylprednisolone. Outside of COVID-19, oncologists often use dexamethasone to treat hemophagocytic lymphohistiocytosis, a cytokine storm syndrome seen in patients with blood cancers such as leukemias and lymphomas. Rheumatologists such as Cron treat cytokine storm syndrome (where it is commonly called macrophage activation syndrome) in patients with lupus and rheumatoid arthritis using methylprednisolone.

"Methylprednisolone is more readily available than dexamethasone," Cron said. "The thought is if both are equally effective, then physicians can use what is available to them to treat COVID-19 cytokine storm syndrome." And, "by implication, other glucocorticoids will likely be equally effective at the glucocorticoid equivalent dosing."

UAB urgent research grants against COVID-19

This study is one of10 pilot projectsrecently funded by $402,000 in donations as part of the second round of UAB's urgent, high-impact COVID-19 grant initiative. This follows 14 projects funded in the first round of urgent, high-impact COVID-19 grants.

Cron is a leading expert on cytokine storm syndrome, a potentially life-threatening overreaction by inflammatory immune proteins known as cytokines. (In 2019, he published thefirst textbook on cytokine storm syndrome.) "Cytokines are there to fight off infections and ward off cancers," Cron said. "But when they are out of control, they can make you very ill."

Anyone battling a serious infection, regardless of cause, may experience a cytokine storm, Cron said. In addition to blood cancers and rheumatic diseases, cytokine storm syndrome is seen in herpes virus family member infections, and case reports have noted nearly 100 different infectious agents that can cause cytokine storms. In patients with COVID-19, clinicians increasingly see cytokine storm syndrome as a major factor in poor outcomes. Cytokine storm syndrome develops in a large percentage of COVID-19 patients who are ill enough to require hospitalization, Cron said.

Glucocorticoids, such as dexamethasone and methylprednisolone, are both "used to calm the cytokine storm," Cron said. "They have very broad-ranging effects on the immune system," including decreasing production of pro-inflammatory proteins and "decreasing function of multiple immune cell types."

In a pilot project that was one of10 recently fundedby UAB's urgent, high-impact COVID-19 grant initiative, Cron and Chatham, plan to enroll at least 30 patients hospitalized with COVID-19 pneumonia who have features of cytokine storm syndrome.

The World Health Organization initially recommended against use of glucocorticoids in treating COVID-19 because studies of their effectiveness when used against coronaviruses in SARS and MERS outbreaks had varying results, and glucocorticoids increase the risk of secondary infection in patients. "Nevertheless, out of desperation, many overwhelmed centers have resorted to glucocorticoids in treating COVID-19 cytokine storm syndrome," Cron and Chatham wrote in their project proposal, and early reports "have shown promising results." These drugs' effectiveness at calming cytokine storms means the benefits of short-term use outweigh concerns about secondary infections, Cron said. "They can be tapered over time to keep the cytokine storm syndrome under control while the patient improves clinically and by lab markers of disease," he said.

Patients in the study will be randomized to receive either 6mg daily of dexamethasone or 32mg daily of methylprednisolone. The goal is to reduce the need for invasive mechanical ventilation and ICU care. "We believe methylprednisolone will minimize ICU admissions and enhance survival," wrote Cron and Chatham in their project proposal.

Methylprednisolone and dexamethasone have similar side-effect profiles, "but are often used at different glucocorticoid equivalent dosing" methylprednisolone tends to be used at higher doses "and they have different pharmacokinetics, which has implications for tapering dosing when patients are recovering," Cron said.

Patients will receive the drugs at the doses listed above for seven days or until they show stable improvement in oxygen saturation and lower levels of markers of cytokine storm syndrome, including serum ferritin, D-dimer and C-reactive protein.

Genetic signatures for cytokine storm syndrome in COVID-19?

"Methylprednisolone is more readily available than dexamethasone. The thought is if both are equally effective, then physicians can use what is available to them to treat COVID-19 cytokine storm syndrome. And, by implication, other glucocorticoids will likely be equally effective at the glucocorticoid equivalent dosing."

The researchers also plan to explore genetic risk factors that may be shared by COVID-19 patients who develop cytokine storm syndrome. Cron and colleagues have identified genetic risk factors in other cytokine storm syndromes, including thosetriggered by H1N1 influenza. This earlier work suggests that as much as 15% of the general population carries genetic mutations putting them at higher risk for developing cytokine storm syndrome. Finding such risk factors in COVID-19 patients would allow clinicians to target treatments to patients with the highest potential for success on those therapies.

Cron and Chatham are co-principal investigators on the methylprednisolone study, which also includes Devin Absher, Ph.D., of the HudsonAlpha Institute of Biotechnology, where whole genome-sequencing of patients will be done.

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Studying an alternative steroid treatment to calm cytokine storms in COVID-19 - The Mix

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Gene in fruit flies, worms, zebrafish, mice and people may help explain some fertility issues

Researchers at Washington University School of Medicine in St. Louis have identified a gene that plays an important role in fertility across multiple species. Pictured is a normal fruit fly ovary (left) and a fruit fly ovary with this gene dialed down (right). Male and female animals missing this gene had substantially defective reproductive organs. The study could have implications for understanding human infertility and early menopause.

A new study from Washington University School of Medicine in St. Louis identifies a specific genes previously unknown role in fertility. When the gene is missing in fruit flies, roundworms, zebrafish and mice, the animals are infertile or lose their fertility unusually early but appear otherwise healthy. Analyzing genetic data in people, the researchers found an association between mutations in this gene and early menopause.

The study appears Aug. 28 in the journal Science Advances.

The human gene called nuclear envelope membrane protein 1 (NEMP1) is not widely studied. In animals, mutations in the equivalent gene had been linked to impaired eye development in frogs.

The researchers who made the new discovery were not trying to study fertility at all. Rather, they were using genetic techniques to find genes involved with eye development in the early embryos of fruit flies.

We blocked some gene expression in fruit flies but found that their eyes were fine, said senior author Helen McNeill, PhD, the Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor and a BJC Investigator at the School of Medicine. So, we started trying to figure out what other problems these animals might have. They appeared healthy, but to our surprise, it turned out they were completely sterile. We found they had substantially defective reproductive organs.

Though it varied a bit by species, males and females both had fertility problems when missing this gene. And in females, the researchers found that the envelope that contains the eggs nucleus the vital compartment that holds half of an organisms chromosomes looked like a floppy balloon.

This gene is expressed throughout the body, but we didnt see this floppy balloon structure in the nuclei of any other cells, said McNeill, also a professor of developmental biology. That was a hint wed stumbled across a gene that has a specific role in fertility. We saw the impact first in flies, but we knew the proteins are shared across species. With a group of wonderful collaborators, we also knocked this gene out in worms, zebrafish and mice. Its so exciting to see that this protein that is present in many cells throughout the body has such a specific role in fertility. Its not a huge leap to suspect it has a role in people as well.

To study this floppy balloon-like nuclear envelope, the researchers used a technique called atomic force microscopy to poke a needle into the cells, first penetrating the outer membrane and then the nucleuss membrane. The amount of force required to penetrate the membranes gives scientists a measure of their stiffness. While the outer membrane was of normal stiffness, the nucleuss membrane was much softer.

Its interesting to ask whether stiffness of the nuclear envelope of the egg is also important for fertility in people, McNeill said. We know there are variants in this gene associated with early menopause. And when we studied this defect in mice, we see that their ovaries have lost the pool of egg cells that theyre born with, which determines fertility over the lifespan. So, this finding provides a potential explanation for why women with mutations in this gene might have early menopause. When you lose your stock of eggs, you go into menopause.

On the left is a normal fruit fly ovary with hundreds of developing eggs. On the right is a fruit fly ovary that is totally missing the NEMP gene. It is poorly developed and no eggs are visible.

McNeill and her colleagues suspect that the nuclear envelope has to find a balance between being pliant enough to allow the chromosomes to align as they should for reproductive purposes but stiff enough to protect them from the ovarys stressful environment. With age, ovaries develop strands of collagen with potential to create mechanical stress not present in embryonic ovaries.

If you have a softer nucleus, maybe it cant handle that environment, McNeill said. This could be the cue that triggers the death of eggs. We dont know yet, but were planning studies to address this question.

Over the course of these studies, McNeill said they found only one other problem with the mice missing this specific gene: They were anemic, meaning they lacked red blood cells.

Normal adult red blood cells lack a nucleus, McNeill said. Theres a stage when the nuclear envelope has to condense and get expelled from the young red blood cell as it develops in the bone marrow. The red blood cells in these mice arent doing this properly and die at this stage. With a floppy nuclear envelope, we think young red blood cells are not surviving in another mechanically stressful situation.

The researchers would like to investigate whether women with fertility problems have mutations in NEMP1. To help establish whether such a link is causal, they have developed human embryonic stem cells that, using CRISPR gene-editing technology, were given specific mutations in NEMP1 listed in genetic databases as associated with infertility.

We can direct these stem cells to become eggs and see what effect these mutations have on the nuclear envelope, McNeill said. Its possible there are perfectly healthy women walking around who lack the NEMP protein. If this proves to cause infertility, at the very least this knowledge could offer an explanation. If it turns out that women who lack NEMP are infertile, more research must be done before we could start asking if there are ways to fix these mutations restore NEMP, for example, or find some other way to support nuclear envelope stiffness.

This work was supported by the Canadian Institutes of Health, research grant numbers 143319, MOP-42462, PJT-148658, 153128, 156081, MOP-102546, MOP-130437, 143301, and 167279. This work also was supported, in part, by the Krembil Foundation; the Canada Research Chair program; the National Institutes of Health (NIH), grant number R01 GM100756; and NSERC Discovery grant; and the Medical Research Council, unit programme MC_UU_12015/2. Financial support also was provided by the Wellcome Senior Research Fellowship, number 095209; Core funding 092076 to the Wellcome Centre for Cell Biology; a Wellcome studentship; the Ontario Research FundsResearch Excellence Program. Proteomics work was performed at the Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, a facility supported by Canada Foundation for Innovation funding, by the Ontarian Government, and by the Genome Canada and Ontario Genomics, grant numbers OGI-097 and OGI-139.

Tsatskis Y, et al. The NEMP family supports metazoan fertility and nuclear envelope stiffness. Science Advances. Aug. 28, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Genetic mutations may be linked to infertility, early menopause - Washington University School of Medicine in St. Louis

The FDA has approved Foundation Medicines liquid biopsy blood test, allowing oncologists to profile the genomic mutations found within any solid tumor without needing to remove and analyze small slices of tissue, and to help assign an individual cancer patient their most correct treatment.

The comprehensive FoundationOne Liquid CDx test returns reports on more than 300 alterations in cancer-related genes, as well as biomarkers such as tumor mutational burden and microsatellite instability to predict a persons response to certain therapies.

Many cancer patients are unable to have a tissue biopsy, said Foundation Medicine co-founder Levi Garraway, who currently serves as chief medical officer and head of global product development at Roche, its corporate parent.

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FoundationOne Liquid CDx may provide a minimally-invasive option for patients who otherwise might not have benefitted from comprehensive genomic profiling, Garraway said. The convenience of testing a blood sample may also enable more rapid treatment decisions, so that patients can feel reassured they are not losing time to fight their disease.

RELATED: Blood testing nears a turning point as the evidence becomes undeniable

The testwhich, starting today, replaces Foundation Medicines current liquid biopsy diagnostic, FoundationOne Liquidsifts through the blood to find the small pieces of floating DNA released from tumors found elsewhere in the body.

Alongside its approval as a sequencing test for understanding the genetic basis of a particular cancerbased on studies of more than 7,500 samples and over 30 tumor typesthe FDA also granted the test the ability to help oncologists directly prescribe four targeted cancer treatments.

RELATED: Foundation Medicine acquires liquid biopsy developer Lexent Bio

This includes three different tyrosine kinase inhibitor therapies for non-small cell lung cancers with certain EGFR mutations: AstraZenecas Iressa and Tagrisso, as well as Tarceva from Roches Genentech division. The liquid biopsy was also approved as a companion diagnostic for Clovis Oncologys Rubraca, for metastatic, castration-resistant prostate cancer with BRCA1 and BRCA2 alterations.

We are seeking additional companion diagnostic claims for FoundationOne Liquid CDx, which, if approved, would further enhance utility of the test in clinical practice, said Foundation Medicines chief medical officer, Brian Alexander.

Additionally, this test is an important tool for the acceleration of drug development and for understanding mechanisms of resistance, Alexander added, by providing complementary insights to tissue-based testing on the differences between cancer cells, as well as how tumors evolve over time.

The approval comes shortly after the FDAs green light earlier this month for Guardant Healths pan-tumor profiling blood test, which uses next-generation sequencing to identify mutations in 55 genes linked to multiple cancers.

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Foundation Medicine's cancer-profiling blood test approved by FDA - FierceBiotech

Modalis Therapeutics Corporation (Modalis) (TOKYO: 4883), a leading company developing innovative products for the treatment of rare genetic diseases utilizing its proprietary CRISPR-GNDM epigenetic gene modulation technology, today reported financial results for the second quarter ended June 30, 2020, as well as recent operational highlights.

Our goal is to create CRISPR based gene therapies for genetic disorders, most of which fall into the orphan disease category. There should be no disease that is ignored because of its small patient population, and our mission to develop disease modifying treatments for these diseases reflects our belief that Every Life Deserves Attention. We are proud to be a pioneer in CRISPR based gene modulation therapies and we are grateful to our investors and employees who are working to fulfill this important mission, said Haru Morita, Chief Executive Officer of Modalis.

Operational Highlights:

Second Quarter 2020 Financial Results:

About Modalis:

Modalis Therapeutics is developing precision genetic medicines through epigenetic gene modulation. Founded by Osamu Nureki and leading scientists in CRISPR gene editing from University of Tokyo, Modalis is pursuing therapies for orphan genetic diseases using its proprietary CRISPR-GNDM technology which enables the locus specific modulation of gene expression or histone modification without the need for double-stranded DNA cleavage, gene editing or base editing. Modalis is focusing initially on genetic disorders caused by loss of gene regulation resulting in excess or insufficient protein production which includes more than 660 genes that are currently estimated to cause human disease due to haploinsufficiency. Headquartered in Tokyo with laboratories and facilities in Cambridge, Massachusetts, the company had been backed by leading Japanese investors including Fast Track Initiative, SBI Investment, UTokyo-IPC, SMBC Venture Capital, and Mizuho Capital. For additional information, visit http://www.modalistx.com.

Consolidated Financial Results for the Six Months Ended June 30, 2020 [Japanese GAAP]

Company name: Modalis Therapeutics Corporation

Stock exchange listing: Tokyo Stock Exchange

Code number: 4883

URL: https://www.modalistx.com/jp/Representative: Haruhiko Morita, President and Representative Director

Contact: Naoki Kobayashi, CFO and Executive Officer

Phone: +81-3-6822-4584

Scheduled date of filing quarterly securities report: August 14, 2020

Scheduled date of commencing dividend payments:

Availability of supplementary briefing material on quarterly financial results: Available

Schedule of quarterly financial results briefing session: Scheduled (for securities analysts and institutional investors)

(Amounts of less than one million yen are rounded down.)

1.

Consolidated Financial Results for the Six Months Ended June 30, 2020 (January 1, 2020 to June 30, 2020)

(1) Consolidated Operating Results

(% indicates changes from the previous corresponding period.)

Operating revenue

Operating income

Ordinary income

Profit attributable to

owners of parent

Six months ended

Million yen

%

Million yen

%

Million yen

%

Million yen

%

June 30, 2020

337

38

29

26

June 30, 2019

(Note)

Comprehensive income:

Six months ended June 30, 2020: 26 million [-%]

Six months ended June 30, 2019: - million [-%]

Basic earnings

per share

Diluted earnings

per share

Six months ended

Yen

Yen

June 30, 2020

1.07

June 30, 2019

(Notes)

1. The Company has not prepared the consolidated financial statements for the six months ended June 2019. Accordingly, no figures are shown for the six months ended June 30, 2019 and no percentage changes are shown for the six months ended June 30, 2020.

2. Although the Company has dilutive shares, diluted earnings per share are not indicated because the Companys shares were not listed and the average share price is not available for the period under review.

(2) Consolidated Financial Position

Total assets

Net assets

Capital adequacy

ratio

Million yen

Million yen

%

As of June 30, 2020

3,961

3,868

97.7

As of December 31, 2019

3,938

3,842

97.6

(Reference)

Equity:

As of June 30, 2020: 3,868 million

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Modalis Therapeutics Reports Second Quarter 2020 Financial Results and Operational Highlights - Financialbuzz.com

DUBLIN--(BUSINESS WIRE)--The "RNA-interference (RNAi) Market - Growth, Trends, and Forecast (2020 - 2025)" report has been added to ResearchAndMarkets.com's offering.

The RNA-interference (RNAi) market is expected to witness a CAGR of 10.12% during the forecast period. Certain factors that are driving the market growth include the increasing number of applications in molecular diagnostics, particularly in cancer and improving synthetic delivery carriers and chemical modifications to RNA.

Cancer diagnosis and treatment is currently undergoing a shift with the incorporation of RNAi techniques in personalized medicine and molecular diagnostics. The availability of high throughput techniques for the identification of altered cellular molecules and metabolites allows the use of RNAi techniques in various cancer diagnosis and targeting approaches. For diagnostic purposes, small interfering RNAs (siRNA) or microRNAs (miRNA) can be utilized. The commercial availability of siRNAs to silence virtually any gene in the human genome is dramatically accelerating the pace of molecular diagnosis and biomedical research. Thus, increasing the application of RNAi in molecular diagnosis and its viability as a therapeutic technique is expected to drive the growth of the RNAi market during the forecast period.

However, in recent years, there has been a decline in FDA drug approval rates. Getting FDA approval for a new drug has become extremely challenging. It approved less than half the number of new drugs in 2016 (19 so far) when compared to 2015 (45 total) and 2014 (41 total). Hence, despite the large investments, there has been a decline in the number of innovative drugs manufactured. FDA explains manufacturing standards and other complying issues as the major reasons for this declining trend. This can impede the growth of the RNAi therapeutics, especially since the miRNAs and siRNAs fall into the relatively new field of genetic medicine, wherein they may require more intensified clinical trials. The highly extensive clinical trials effectively result in low approval rates of drugs. This would mean that the stringent guidelines will be a major restraint for the growth of the market.

Key Market Trends

Oncology is Expected to Hold Significant Market Share in the Therapeutics Type

According to the World Health Organization, cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer. The number of new cases is expected to rise by about 70% over the next two decades.

Recent advancements, such as the development of small interfering RNA (siRNA) tolerant to nucleases and the development of non-viral vectors, such as cationic liposomes and nanoparticles, can overcome this obstacle and facilitate the clinical use of RNAi-based therapeutics in the treatment of cancer.

Substantial pipeline for cancer therapies by companies and institutes such as Enzon Pharmaceuticals (Santaris Pharma), University of Texas, OncoGenex, Isarna Therapeutics, Astrazeneca (Ionis Pharmaceuticals), and INSYS Therapeutics, Inc. are expected to drive the market. In addition, many companies have invested in R&D for nanocarriers to deliver oligonucleotides for cancer treatment, which is expected to contribute to the oncology verticle.

North America Dominates the Market and Expected to do the Same in the Forecast Period

The U.S. has a number of RNAi therapeutics that are in developmental pipelines. A number of biotechnology companies have made considerably high investments for RNAi therapeutic development. Big pharmaceutical developers have entered into collaboration agreements or licensing deals with a number of smaller firms in an attempt to capitalize on the expected growth in revenue that this market can have over the forecast period. For instance, AstraZeneca's agreement with Ionis pharmaceuticals is one of the big deals that are investing heavily into RNA-interference technology

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS

4.1 Market Overview

4.2 Market Drivers

4.2.1 Increasing Number of Applications in Molecular Diagnostics, Particularly in Cancer

4.2.2 Improving Synthetic Delivery Carriers and Chemical Modifications to RNA

4.3 Market Restraints

4.3.1 Stringent FDA Regulations and Changing Reimbursement Environment

4.3.2 Unstable Potentially Immunogenic Nature of RNA

4.4 Porter's Five Forces Analysis

4.4.1 Threat of New Entrants

4.4.2 Bargaining Power of Buyers/Consumers

4.4.3 Bargaining Power of Suppliers

4.4.4 Threat of Substitute Products

4.4.5 Intensity of Competitive Rivalry

5 MARKET SEGMENTATION

5.1 Application

5.2 Geography

6 COMPETITIVE LANDSCAPE

6.1 Company Profiles

6.1.1 Alnylam Pharmaceuticals

6.1.2 Arcturus Therapeutics

6.1.3 Arrowhead

6.1.4 Dicerna Pharmaceuticals

6.1.5 Quark Pharmaceuticals Inc.

6.1.6 Ionis Pharmaceuticals Inc.

6.1.7 Merck & Co. Inc. (Sigma Aldrich)

6.1.8 Silence Therapeutics PLC

6.1.9 Qiagen NV

6.1.10 Phio Pharmaceuticals Corp.

6.1.11 Thermo Fisher Scientific Inc.

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/dff591.

About ResearchAndMarkets.com

ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

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Global RNA-interference (RNAi) Market Outlook 2020-2025: Improving Synthetic Delivery Carriers and Chemical Modifications to RNA -...

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A major breakthrough in treating a genetic disorder can be credited to our next guest. Sickle cell disease is a blood disorder that affects more than 20 million people worldwide. Theyve recently had a breakthrough. Federal News Networks Eric White spoke to one of the scientists at the National Institutes of Health conducting research on sickle cell on Federal Drive with Tom Temin. Dr. John Tisdale is a finalist in this years Service to America Medals program.

Dr. John Tisdale: I trained in internal medicine, and that was in the early 90s. I encountered patients with sickle cell disease who were experiencing extraordinary pain. And at that time, all we had was pain medication. So we would give pain medication and IV fluids because very often dehydration was what provoked the pain episode in these patients. But we had no specific treatments, nothing that were directed at the disease itself, only management of the pain. It was strange to me because I had learned about sickle cell disease in genetics classes and had known that we knew the basis for this disease longer than any other disease, yet we had no treatment, nothing. So it motivated me to think about ways that could treat the disease. The obvious thing that came to mind was a bone marrow transplant because we had a very active bone marrow transplant service at Vanderbilt. And I found that a very exciting way to approach disease and it just made sense that if you have a blood disease that causes all this difficulty in blood comes from the bone marrow well one obvious way to fix it is just to replace the bone marrow with one that doesnt have the genetics that causes the disease, like a brother or sister that we were doing for other kinds of diseases, and that could potentially cure the disease. And in fact, I learned that it had been done before in a patient who had leukemia. And that was a reason for her getting a bone marrow transplant. But she also had sickle cell disease and she was cured of both. There were some efforts during that time to bring that to the clinic, in the pediatric setting, and everything is always easier with kids because theyre tougher when it comes to medications and transplants and all the things that you can think of doing, chemotherapy. That got me motivated into studying hematology and bone marrow transplant, and trying to figure out ways to bring bone marrow transplant to patients with sickle cell disease.

Eric White: This sickle cell disease, obviously weve all heard of it. Even if you know what it is, its still a complicated disease. Can you explain what is the latest research says that sickle cell disease actually does over? As I said its a very strange disease that affects the body in many different ways. Are there any new findings as to how it does actually affect it?

Dr. John Tisdale: Well, I think weve known for a very long time exactly what happens in this disease. It arose as a way to protect from death from malaria. So just one little letter off for the gene that makes our hemoglobin, and hemoglobin is the molecule in red blood cells that carries oxygen around the blood. So one letter off in part of that molecule, and you have protection from malaria, you dont get the very severe form of malaria because the red cell is not as hospitable to the parasite. So that gets selected for in areas where theres malaria, like in Sub Saharan Africa. But if you get two copies of the gene, one from mom and one from dad, you get this disease, sickle cell disease because the hemoglobin now is different than the normal hemoglobin. Instead of carrying oxygen around and staying in solution like it does normally, you have a hemoglobin that once it does its job by dropping off oxygen out in the body, it can come out of solution and become like rock hard, distort the shape of the red cell thats normally squeezing through blood vessels to find its way back to the lungs to get more oxygen. When that happens, block the circulation. So it kind of causes a log jam and all the blood behind it gets stuck. And so wherever that happens, gets starved of its oxygen. So I mean, if it happens in the brain, for example, it causes a stroke. And so kids, eight years old can have a stroke that looks exactly like the sort that we see in the elderly who have vascular disease. If it happens in the muscle, its extremely painful or in the bone. And it happens in every organ in the body. And as a result can damage those organs over time and significantly shorten the lifespan of patients with sickle cell disease. So the lifespan currently is in the 40s. And thats much improved over the last several decades, but its still much lower than then people without the disease.

Eric White: So with your research, what has given you the most promise? What results have you all hung on to whether its bone marrow transplant or gene therapy? Is there one that you say hey, we might be on to something here?

Dr. John Tisdale: Well, I think the biggest breakthrough that weve made is figuring out just how much of the bone marrow we have to fix. So it turns out, we dont have to completely replace the bone marrow with somebody elses bone marrow to make the blood normal. So normally in a bone marrow transplant you you have to give chemotherapy to take away all of the cells that are making blood. Thats kind of like tilling the garden, right? You cant go out in the middle of a cornfield and spread a bunch of tomato seeds and expect to have tomatoes there, theyre not going to grow because the corns already growing. So the thinking is to do a bone marrow transplant, you have to harvest the corn, till the soil, plant the sees. And the same is true for bone marrow transplants. But it turns out for sickle cell disease, we dont have to do that. Weve had patients who even though we try to get rid of all their bone marrow, we failed and they had up to 80% of their own bone marrow still making blood, and presumably sickle blood. But if we had only 20% from the donor that was making normal blood, that would result in all of the blood being normal. And thats just because sickle cells live 10 or 12 days in the circulation, normal cells live 120 days in the circulation. And since the normal cells have such an advantage, you dont really have to completely eradicate the patients own bone marrow or you dont have to fix every cell. So thats important. That told us two things. One, we dont have to use toxic chemotherapy that we normally have to use to do a bone marrow transplant. And furthermore, we can start to think about gene therapy as an approach because we know we can never fix every cell. But if we could fix 20% of cells, we would predict from what weve observed in patients getting transplants from their brother or sister, that wed be able to fix the disease. And were well above the 20% mark when we transfer genes into cells. We can also correct the mutation at higher than 20%. So knowing that we only have to get to 20% has allowed us to start clinical trials, using the patients own bone marrow where we take those seeds out and try to fix them and give them back. If we can make 20%, we think we can fix the disease.

Eric White: Is there anything else that youd like to get the word out on? Is there any way people might be able to help or if if they have any family members who are suffering from this, if theres anything you would like to tell them?

Dr. John Tisdale: Well, I mean, I think the thing thats very important to understand for anyone with a genetic disease or otherwise is that clinical trials are the way that we make progress. And so participating in clinical trials is important for moving the field forward, and we partner with our patients and their family and their support structure to do these clinical trials and to make progress in the disease. So its extraordinarily important for people to understand that. Thats the way we make progress.

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NIH scientists credited with breakthrough in treating a genetic disorder - Federal News Network