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Tuesday, April 2, 2019

New approach to repairing damaged peripheral nervous system

A new University of Virginia study proves that a damaged peripheral nervous system is capable of repairing itself—when healthy cells are recruited there from the central nervous system. The finding has implications for the future treatment of debilitating and life-threatening nervous system disorders affecting children, such as muscular dystrophy, Guillain-Barre Syndrome and Charcot-Marie-Tooth Disease.

The study will be published in the April 2 issue of the journal Cell Reports.

Researchers found that when they chemically disrupt specific mechanisms of neural activity in the central nervous system, they can, in effect, open a border wall to allow a critical nerve-repairing cell to migrate into the peripheral nervous system—a region those cells generally don’t enter. The cells, a subset of non-neuronal cells called oligodendrocytes, ultimately come to function in their new environment, the muscles, in the same way they operate in their original home in the central nervous system—they make repairs to damaged neuronal cells.

Oligodendrocytes are a type of cell called glia. They are the glue that hold together brain matter, and are key components in the development of the central nervous system. These cells also are important to the regeneration or repair of these systems in response to disease or injury.

They make myelin, a layer of protein and fatty material that acts like electrical tape to insulate axons, a threadlike part of nerve cells on which electrical signals transmit in a line from one cell to the next. When that sheathing degenerates, such as happens to diseased nerve cells in multiple sclerosis, critical messages from the brain are disrupted along the path to other areas of the body, resulting in severe impairment.

Study identifies new approach to repairing damaged peripheral nervous system — Sarah Kucenas, a UVA professor of biology, cell biology and neuroscience, and member of the UVA Brain Institute, led the study. Credit: University of Virginia

“Oligodendrocytes are highly migratory, but they always end up in the same locations of the central nervous system, even though they actually have the capability to go anywhere,” said study leader Sarah Kucenas, a UVA professor of biology, cell biology and neuroscience, and member of the UVA Brain Institute. “We set out to find the mechanism that might keep them restricted, and we found it.”

Using zebrafish as a study model (about 80 percent of a zebrafish’s nervous-system genes are the same as in humans), Kucenas and postdoctoral fellow Laura Fontenas discovered that oligodendrocytes are actively segregated to the central nervous system through tight control of neural activity. But they don’t necessarily have to be.

“When we disrupt specific mechanisms of neural activity, we find that we can actually get these oligodendrocytes to migrate to portions of the nervous system where they technically shouldn’t go—to the periphery—and we wanted to know if they can conduct repairs there,” Kucenas said.

She and Fontenas identified a compound that perturbs the oligodendrocytes into migration and used zebrafish that were genetically mutated to model such diseases as muscular dystrophy, Guillain-Barre syndrome and Charcot-Marie-Tooth disease. They disrupted the mechanism of neuronal activity to recruit oligodendrocytes to the peripheral nervous system, and found that they indeed replace defective myelin that is lost in those disorders.

In ongoing studies in the lab using models of these diseases, Kucenas and Fontenas are finding that adult fish with oligodendrocytes in the peripheral nervous system swim better than mutant adult fish with no oligodendrocytes. This suggests that a new class of drugs could be developed to coax oligodendrocytes to migrate to the peripheral nervous systemand help it repair itself.

“This finding has a very real potential to change how we think about approaching the treatment of neurodegenerative diseases,” Kucenas said. “My hope is that someday our discoveries will help children with impairing neurological diseases to be able to get out of their wheelchairs and live an enhanced quality of life.”

Explore further

Multiple sclerosis – helping cells to help themselves

More information: Cell Reports (2019). DOI: 10.1016/j.celrep.2019.03.013

https://medicalxpress.com/news/2019-04-approach-peripheral-nervous.html

Transplanted marrow endothelial progenitor cells delay ALS progression

Transplantation of human bone marrow-derived endothelial progenitor cells (EPCs) into mice mimicking symptoms of amyotrophic lateral sclerosis (ALS) helped more motor neurons survive and slowed disease progression by repairing damage to the blood-spinal cord barrier (BSCB), University of South Florida researchers report.

The new study, published March 27 in Scientific Reports, contributes to a growing body of work exploring cell therapy approaches to barrier repair in ALS and other neurodegenerative diseases.

The progressive degeneration of nerve cells that control muscle movement (motor neurons) eventually leads to total paralysis and death from ALS. Each day, an average of 15 Americans are diagnosed with the disease, according to the ALS Association.

Damage to the barrier between the blood circulatory system and the central nervous system has been recognized as a key factor in the development of ALS. A breach in this protective wall opens the brain and spinal cord to immune/inflammatory cells and other potentially harmful substances circulating in peripheral blood. The cascade of biochemical events leading to ALS includes alterations of endothelial cells lining the inner surface of tiny blood vessels near damaged spinal cord motor neurons.

This latest study by lead author Svitlana Garbuzova-Davis, Ph.D., and colleagues at the USF Health Morsani College of Medicine’s Center of Excellence for Aging & Brain Repair, builds upon a previous study showing that human bone marrow-derived stem cells improved motor functions and nervous system conditions in symptomatic ALS mice by advancing barrier repair. However, in that earlier USF study the beneficial effect was delayed until several weeks after cell transplant and some severely damaged capillaries were detected even after a high-dose treatment. So in this study, the researchers tested whether human EPCs—cells harvested from bone marrow but more genetically similar to vascular endothelial cells than undifferentiated stem cells—would provide even better BSCB restoration.

ALS mice were intravenously administered a dose of human bone-marrow derived EPCs. Four weeks after transplant, the results of the active cell treatment was compared against findings from two other groups of mice: ALS mice receiving a media (saline) treatment and untreated healthy mice.

The symptomatic ALS mice receiving EPC treatments demonstrated significantly improved motor function, increased motor neuron survival and slower disease progression than their symptomatic counterparts injected with media. The researchers suggest that these benefits leading to BSCB repair may have been promoted by widespread attachment of EPCs to capillaries in the spinal cord. To support this proposal, they point to evidence of substantially restored capillaries, less capillary leakage, and re-establishment of structural support cells (perivascular astrocytes) that play a role in helping form a protective barrier in the spinal cord and brain.

Further research is needed to clearly define the mechanisms of EPC barrier repair. But, the study authors conclude: “From a translational viewpoint, the initiation of cell treatment at the symptomatic disease stage offered robust restoration of BSCB integrity and shows promise as a future clinical therapy for ALS.”

Explore further

Stem cell transplants may advance ALS treatment by repair of blood-spinal cord barrier

More information: Svitlana Garbuzova-Davis et al, Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier, Scientific Reports (2019). DOI: 10.1038/s41598-019-41747-4

https://medicalxpress.com/news/2019-04-transplanted-bone-marrow-endothelial-progenitor.html

HHS website now lists ceiling prices for 340B drugs

A 340B facility can now determine whether it’s being bilked by a drug manufacturer for covered drugs thanks to an update to an HHS website.

The Health Resources and Services Administration on Monday updated the Office of Pharmacy Affairs 340B Information System, which facilities use to register for the program. It now allows 340B providers to verify the accuracy of ceiling prices drugmakers are charging.

The lobbying group 340B Health, which represents more than 1,300 hospitals, said the new information can also help increase accountability for drug manufacturers.

“When this information is combined with the civil monetary penalty authority that Congress granted HRSA, manufacturers that knowingly and intentionally charge safety-net providers too much will be subject to financial penalties,” 340B Health CEO Maureen Testoni said in a statement.

HRSA spokesman Martin Kramer told Modern Healthcare that the agency was required to update the website as a result of a long-delayed and controversial rule that went into effect in January.

HHS was originally supposed to finalize the rule in July 2018 and had wanted to delay the rule’s implementation until July 2019 because it was concerned whether the rule originally proposed by the Obama administration was legal.

However, the American Hospital Association and other hospital trade groups sued the agency last fall to get them to finalize the regulations. HHS eventually agreed to implement the rule and settled the lawsuit.

The lawsuit over the rule’s implementation has been one front in a war between hospital groups and the Trump administration on 340B.

The administration tried to make a roughly 30% cut to 340B reimbursements to facilities, but a federal judge struck down those cuts in December 2018, saying the agency didn’t have the authority to implement them.

https://www.modernhealthcare.com/government/hhs-website-now-lists-ceiling-prices-340b-drugs

Single-dose antidote may help prevent fentanyl overdoses

Synthetic opioids outlast current antidotes. A nanoparticle-based alternative could fix that.

A newly developed single-dose opioid antidote lasts several days, a study in mice shows. If the results can be duplicated in humans, the treatment may one day help prevent overdoses from deadly drugs like fentanyl.

Normally, a dose of the opioid antidote naloxone passes through a person’s body in about 30 minutes — far too quickly to fully counteract the effects of such synthetic opioids as fentanyl and carfentanil (SN Online: 5/1/18). These drugs, tens to thousands of times stronger than morphine, can linger in a person’s system for hours or even days (SN: 6/10/17, p. 22). That requires multiple doses of an antidote to prevent someone from overdosing.

So researchers developed a new naloxone-based antidote to outlast synthetic opioids by creating nanoparticles in which naloxone molecules are tangled up with a biodegradable polymer called polylactic acid. Water and enzymes in the body slowly break down these nanosized tangles, gradually releasing naloxone.

In mice, the new nanoparticle delivery system counteracted the pain-relieving effects of morphine for up to 96 hours after administering a single dose of the antidote, according to research being presented March 31 at the American Chemical Society meeting in Orlando, Fla.

“We’re now going to start moving onto fentanyl and carfentanil” and ramping up opioid doses to test whether the antidote can prevent a mouse from overdosing, says Saadyah Averick, a biomaterials researcher at the Allegheny Health Network Research Institute in Pittsburgh.

In 2017, synthetic narcotics like fentanyl far outstripped prescription opioids and heroin as the most common drugs involved in overdose deaths, according to the U.S. Centers for Disease Control and Prevention. Drugs specifically designed to counteract these synthetic opioids could play a key role in curbing these deaths.

Citations

S. Averick. Next-generation opioid antidotes: Covalent nanoparticles for the delivery of Mu opioid antagonists. American Chemical Society meeting, Orlando, Fla., March 31, 2019.

Inovio Presents Cancer Killing Data of DNA-Encoded Bi-specific T Cell Engagers

Data demonstrates tumor-clearing ability of Inovio’s dBiTE technology in preclinical cancer model

Inovio Pharmaceuticals, Inc. (INO) announced today the company’s novel DNA-Encoded Bi-specific T Cell Engagers (dBiTEs^™) generated potent anti-tumor activities in a preclinical study. Results were presented as a poster at the American Association for Cancer Research (AACR) Annual Meeting in Atlanta. For this study, Inovio, with its collaborators at The Wistar Institute, developed a novel dBiTE targeting the HER2 molecule which was tested in therapeutic models for the treatment of ovarian and breast cancers. Importantly, just a single dose of Inovio’s HER2 dBiTE resulted in high levels of corresponding BiTE in mice for four months, far exceeding what is typically displayed with conventional BiTE’s short half-life of only a few hours. The HER2 dBiTE effectively generated T cell cytotoxicity against HER2-expressing tumor cells resulting in a near-complete tumor clearance. Also presented was Inovio’s CD19 dBiTE which can kill B cell cancers by targeting B cell specific marker CD19.

Dr. J. Joseph Kim, Inovio’s President and CEO, said, “In layman’s terms, dBiTEs are like a double-sided tape that binds to a tumor and to a cancer-killing T cell. By allowing the products be expressed directly and efficiently in the patient, our dBiTEs could finally fulfill the therapeutic promise of BiTEs. Based on these promising preclinical results, we are rapidly preparing for the clinical development of our dBiTE candidates, as well as constructing more cancer tumor targeting dBiTE candidates using our transformative dBiTE platform.”

Dr. Kim added, “Leveraging Inovio’s in vivo synthetic nucleic expression platform, we have shown that just one dose of Inovio’s dBiTE could generate corresponding BiTEs at high levels in mice for several months, demonstrating a dramatic advantage over conventional BiTEs. Our CD19 dBiTE has the potential to treat multiple B cell cancers and to compete favorably with CD19 CAR-T products with potentially improved tolerability and safety profiles. Similarly, the HER2 dBiTE could be used to treat multiple solid tumors which express HER2 such as breast, ovarian, and gastric cancers.”

BiTEs are a class of artificial bi-specific monoclonal antibodies that has the potential to transform the immunotherapy landscape for cancer. They direct a host’s immune system, more specifically the T cells’ cytotoxic activity, against cancer cells. BiTEs have two binding domains. One domain binds to the targeted tumor (like HER2 or CD19 expressing cells) while the other engages the immune system by binding directly to CD3 molecules on T cells. This double-binding activity drives T cell activation directly at the tumor resulting in a killing function and tumor destruction.

The biggest drawback of conventional protein-based BiTEs is the delivery and expression. The BiTEs have a half-life of only about two hours, which requires patients to undergo continuous intravenous infusion for several weeks to maintain therapeutic levels, making treatment adherence more difficult and resulting in high levels of infusion-associated adverse events. In addition, just like other traditional monoclonal antibodies, conventional BiTEs are also manufactured in bioreactors, typically requiring costly large-scale manufacturing facility development and laborious production as well as having to deal with improper product folding and stability. They must also be kept and distributed frozen at all times. These difficulties collectively have limited the development and commercialization of conventional BiTEs as only one licensed product is currently on the market (BLINCYTO^® (blinatumomab)).

Inovio’s dBiTE is a new transformative application of Inovio’s dMAb™ platform. The dBiTEs share many advantages of Inovio’s dMAbs as they both are composed of engineered DNA sequences which encode two antibody fragments. When administered by Inovio’s CELLECTRA^® delivery device, the patient’s own cells become the factory to manufacture functional BiTES encoded by the delivered dBiTE sequences.

Inovio’s dBiTEs provide major potential advantages over a conventional protein-based BiTE therapy because of dBiTEs’ better product expression and availability as well as simplicity in administration and manufacturing. Inovio has demonstrated that a single dose of dBiTE construct delivered with CELLECTRA^® expressed the product at high levels in mice for four months. Inovio’s dBiTEs are developed with simplified design using novel plasmid vectors and unique formulations allowing for rapidity of development, long-term product stability at refrigeration, ease of validated and scalable manufacturing and deployability.

https://finance.yahoo.com/news/inovio-presents-cancer-killing-data-114500102.html

How Much Does Medicare Spend on Insulin?

The rising cost of prescription drugs is currently a major focus for policymakers. One medication that has come under increasing scrutiny over its price increases is insulin, used by people with both Type 1 and Type 2 diabetes to control blood glucose levels. Among people with Medicare, one third (33%) had diabetes in 2016, up from 18% in 2000. The rate of diabetes is higher among certain groups, including more than 40% of black and Hispanic beneficiaries. Although not all people with diabetes take insulin, for many it is a life-saving medication and essential to maintaining good health. Three companies—Eli Lilly, Novo Nordisk, and Sanofi—manufacture most insulin products, and there are no generic insulin products currently available, despite the fact that insulin was discovered in the 1920s. Committees in both the House and the Senaterecently convened hearings on prescription drug costs that focused on rising insulin prices and affordability concerns for patients, and congressional investigations are underway.

This data note examines spending on insulin by Medicare and beneficiaries enrolled in private Part D drug plans, based on data from the Centers for Medicare & Medicaid Services (see Data and Methods). Because drug-specific rebate data for Medicare are proprietary, the analysis examines Medicare spending without rebates, but also uses average Part D rebates reported by Medicare’s actuaries to illustrate the potential effects on total Part D insulin spending. While rebates may help to lower Part D premiums, they do not lower enrollees’ out-of-pocket drug costs, which are based on list prices.

Key Findings

Total Medicare Part D spending on insulin increased by 840% between 2007 and 2017, from $1.4 billion to $13.3 billion (Figure 1)—including what Medicare, plans, and beneficiaries paid.

With rising prices and the introduction of more costly insulin products over time, average total Medicare Part D spending per user on insulin products increased by 358% between 2007 and 2016, from $862 to $3,949.
Aggregate out-of-pocket spending by Part D enrollees on insulin quadrupled between 2007 and 2016, from $236 million to $968 million, reflecting both an increase in the number of users and price increases for insulin. Among enrollees without low-income subsidies, average per capita out-of-pocket spending on insulin nearly doubled between 2007 and 2016 (from $324 to $588; an increase of 81%).
Among all insulin products, Lantus Solostar, a long-acting insulin manufactured by Sanofi, accounted for the largest share of both total Part D spending and out-of-pocket spending by enrollees who used insulin. Spending on Lantus Solostar, which was used by 1.1 million Part D enrollees in 2017, accounted for 20% of total Part D spending on insulin therapies in 2017 and 25% of out-of-pocket spending on insulin by non-low income subsidy enrollees in 2016.

Total Medicare Part D Spending on Insulin

According to our analysis, total Medicare Part D spending on insulin increased by 840% between 2007 and 2017, from $1.4 billion to $13.3 billion—including what Medicare, plans, and beneficiaries paid. In light of rising prices for existing insulin products and the introduction of more costly insulin therapies over time, average annual total Part D spending on insulin products per user increased by 358% between 2007 and 2016—from $862 to $3,949—while average total Medicare Part D spending per insulin prescription increased by 280% over these years—from $96 to $363 (Figure 2).

The total number of Part D enrollees using any insulin therapy nearly doubled between 2007 and 2016, from 1.6 million enrollees to 3.1 million—a much smaller increase in percentage terms (86%) than the percent increase in total Part D spending on insulin over the 2007-2016 period (753%) (Table 1). The total number of insulin prescriptions covered by Part D also increased over these years (from 14.8 million in 2007 to 33.3 million in 2016), but the percentage increase (125%) was also substantially lower than the percent increase in total insulin spending.

Total Part D spending on top insulin therapies. In 2017, the top five insulin therapies covered under Part D accounted for 62% of total Part D spending on insulin, or $8.2 billion out of the $13.3 billion total spending on insulin (Figure 3). Among all insulin products, Part D spending was highest for Lantus Solostar, a long-acting insulin manufactured by Sanofi, with $2.6 billion in Part D spending in 2017. This one drug alone, used by 1.1 million Part D enrollees in 2017, accounted for 20% of total Part D spending on insulin that year. Lantus Solostar was also among the top five drugs overall in terms of total Part D spending in 2017.

Average total Part D per capita costs for insulin therapy in 2017 ranged from $693 for Humulin R, a short-acting regular insulin manufactured by Eli Lilly—used by 102,000 Part D enrollees in 2017—to $10,014 for Humulin R U-500, a concentrated regular insulin for people who need large doses of insulin, also manufactured by Eli Lilly—used by 14,500 beneficiaries in 2017.

Total Part D spending by insulin manufacturer. In 2017, total Part D spending on all of the different insulin products from the three main manufacturers was $5.5 billion for Novo Nordisk, $4.8 billion for Sanofi, and $3.0 billion for Eli Lilly (Figure 4). Between 2007 and 2017, spending on insulin therapies from all three manufacturers increased dramatically. Over this time period, cumulative total Part D spending was $27.0 billion for insulin products from Novo Nordisk, another $27.0 billion for Sanofi, and $15.0 billion for Eli Lilly.

Trends in insulin spending per dosage unit. Of the 22 insulin therapies listed in the CMS Part D drug spending dashboard in both 2013 (the first year of dashboard data) and 2017 (the most recent year), 19 products had increases of more than 10% in annual Part D spending per dosage unit between 2013 and 2017, according to CMS estimates (Table 2). Six insulin products had increases of more than 10% in average spending per dosage unit between 2016 and 2017 alone (Figure 5).

These percentage increases in average spending per dosage unit for insulin products represent price increases that can translate to large increases in total spending per claim over time—even if the change in average spending per dosage unit measured in dollars may be relatively low—since there are typically multiple dosage units associated with each claim. For example, while Afrezza has the lowest average spending per dosage unit in 2017 of all the insulin products in the CMS dashboard data ($3.54), the 2016-2017 change of 21.6% was the largest in percent terms—and it translates into a large difference in spending per claim for Afrezza between 2016 and 2017—from $566 per claim in 2016 to $690 per claim in 2017, a $124 increase (Table 2).

Out-of-Pocket Spending on Insulin by Medicare Part D Enrollees

Part D enrollees’ total annual out-of-pocket costs for insulin. Since Medicare Part D plans cover a portion of enrollees’ total drug costs, enrollees pay less than the retail price of drugs covered by their plan, and those who receive Part D low-income subsidies (LIS) face relatively low out-of-pocket costs. Still, in the aggregate, out-of-pocket spending among all Part D enrollees on insulin quadrupled between 2007 and 2016, from $236 million to $968 million, reflecting both an increase in the number of users and price increases for insulin (Figure 6). Between 2007 and 2016, Part D enrollees spent a combined $5.5 billion out of pocket on insulin therapy.

Part D enrollees’ average per capita out-of-pocket costs for insulin. Among Part D enrollees who did not receive LIS, average per capita out-of-pocket spending for insulin alone was $588 in 2016, but including costs for all other prescriptions, total per capita out-of-pocket spending among those who used insulin was $1,334. Non-LIS enrollees’ average per capita out-of-pocket spending on insulin in 2016 was nearly double the amount in 2007 ($324; an increase of 81%).

For several insulin products, average per capita out-of-pocket spending by non-LIS enrollees increased by more than 100% between 2007 and 2016; for example, average per capita out-of-pocket spending on Lantus Solostar increased by 291% from $106 to $413 (Figure 7).

In 2016, average annual per capita out-of-pocket spending by non-LIS enrollees who used insulin therapies ranged from $110 for Levemir Flexpen, a long-acting insulin manufactured by Novo Nordisk, to $822 for Humulin R U-500 (Table 3).

Part D enrollees’ out-of-pocket spending on top insulin therapies. In 2016, the top five insulin therapies accounted for 67% of aggregate out-of-pocket spending on insulin by non-LIS enrollees that year, or $0.6 billion out of the $0.9 billion in out-of-pocket spending on insulin by non-LIS enrollees (Figure 8). Aggregate out-of-pocket spending was highest for Lantus Solostar, accounting for 25% ($230 million) of non-LIS enrollees’ total out-of-pocket spending on insulin therapy in 2016.

Illustrating the Potential Effect of Rebates on Total Insulin Spending

Our analysis is based on retail claims data and aggregated spending data that do not take into account manufacturer rebates and discounts to plans, which are considered proprietary and therefore not publicly available. There is data suggesting that insulin manufacturers have provided large rebates and discounts to payers that have produced net prices that are significantly lower than the high list prices that have attracted public scrutiny. Regardless of the magnitude of rebates for insulin products, however, rebates do not help to lower enrollees’ out-of-pocket costs for insulin. This is because the amount that enrollees pay out of pocket is either a flat dollar copayment (depending on their plan’s cost-sharing design) or, if they are paying full cost in the deductible phase or a coinsurance amount, their cost is based on pre-rebate list prices rather than post-rebate net prices.

Because CMS does not disclose drug-specific rebates, we are unable to know exactly the degree to which our estimates of total Part D spending on insulin therapy might overstate actual costs to Medicare and plans. We can approximate the potential effect of rebates on total Part D spending by assuming that all Part D plans had received for all insulin products the average rebate reported by Medicare’s actuaries each year between 2007 and 2017. Based on this assumption, insulin spending would have increased from $1.3 billion in 2007 (applying the 9.6% average rebate in 2007) to $10.3 billion in 2017 (applying the 22.8% estimated average rebate in 2017). This amounts to a 702% increase in total Part D spending on insulin between 2007 and 2017, compared to an 840% increase based on the pre-rebate total spending amounts ($1.4 billion and $13.3 billion, respectively). If actual rebates for insulin products were larger than these averages, total spending would be lower than these estimates.

Implications

Rising prices for insulin have attracted increasing scrutiny from policymakers in recent months. Our analysis demonstrates that rising insulin prices since 2007 have translated into significantly higher out-of-pocket spending for beneficiaries in Medicare Part D plans and higher spending for the program overall (not taking into account rebates). The number of people Medicare covers for insulin therapy has increased as the number of Medicare beneficiaries with diabetes has risen. Average annual total Part D spending per insulin user increased by 358% between 2007 and 2016, while average out-of-pocket costs for insulin by non-low income subsidy Part D enrollees nearly doubled.

Members of Congress and the Trump Administration have introduced several proposals that could help to address concerns about rising prices for insulin products and affordability concerns for patients, including banning rebates from drug manufacturers unless they are shared directly with patients at the point of sale, taking steps to increase the availability of generic products, allowing Medicare to negotiate drug prices, and allowing patients to import drugs from other countries. Rising prices for insulin therapy in recent years and the resulting increases in Medicare Part D and beneficiary out-of-pocket spending illustrate why the cost of prescription drugs is an ongoing concern for patients and public and private payers, and a pressing issue for policymakers.

https://www.kff.org/medicare/issue-brief/how-much-does-medicare-spend-on-insulin/

Nobel Prize winner argues banning CRISPR babies won’t work

Scientists are vigorously debating how, and if, they can put the human gene-editing genie back in the bottle.

There is widespread agreement that it’s currently “irresponsible” to make heritable changes in human cells. Gene editors, even the much lauded CRISPR/Cas9 molecular scissors, have not yet been proven safe and effective enough to use to alter genes in the human germline; embryos, eggs, sperm or the cells that give rise to eggs and sperm. But that didn’t stop Chinese scientist Jiankui He from announcing in 2018 the births of two gene-edited babies.

Now in the wake of almost universal outrage over He’s actions, efforts are under way to prevent others from doing the same thing.

Some scientists have recently proposed a temporary moratorium on editing that would result in babies that carry heritable changes. Such a ban would last for perhaps five years to buy enough time to improve the technology and to allow for public debate (SN Online: 3/13/19) .

An advisory committee to the World Health Organization has alternatively proposed a global registry of work on human gene editing. Such a database would provide transparency and a better understanding of the state of gene-editing science, committee representatives said in a news conference March 19.

Science News talked with Nobel laureate David Baltimore, who is president emeritus of Caltech, about the ongoing debate. Baltimore, a virologist and immunologist, chaired two international summits on human gene editing. The interview has been edited for brevity and clarity.

SN: You’ve come out in the past as not being in favor of a moratorium. Why?

Baltimore: It’s largely a semantic issue. Statements made after the first summit and the second summit have avoided using the term moratorium. Consciously. Because that word has been associated with very firm rules about what you can do and what you can’t do.

I fully agree — and the whole group of us involved in the summits agree — that we’re not ready to be doing germline modification of humans, if we ever are. You might say, “Well, that’s a moratorium,” and, in a sense, it is. I don’t have a big argument about that.

But the important point is to be flexible going forward. That’s what’s wrong with a moratorium. It’s that the idea gets fixed in people’s minds that we’re making firm statements about what we don’t want to do and for how long we don’t want to do it.

With a science that’s moving forward as rapidly as this science is, you want to be able to adapt to new discoveries.

— David Baltimore

With a science that’s moving forward as rapidly as this science is, you want to be able to adapt to new discoveries, new opportunities and new understandings. To make rules is probably not a good idea.

What’s a good idea is to be on top of a changing environment and to adjust to it as time goes by. And that’s both an ethical environment and a practical environment of the mechanics of gene editing.

SN: Would a global registry of all gene-editing experiments help?

Baltimore: A gene-editing event in which a human being’s genes have been modified, or in which a child’s genes have been modified, is something that will be passed on through the rest of time. It is now part of the heredity of the human species. If we don’t know it’s happened, we don’t know that [edited] gene is there, so we can’t identify the effect of having that [altered] gene.

So I think it is important that there be a registry of all gene-editing events, so that we can follow, over time, the consequences of those modified genes.… It is important [to] follow these children as they get older. You just want to make sure there is not some sort of untoward medical aspect to it, and second of all, to know what genes have been modified.

A registry would be very important for germline modifications. For somatic modifications [non-heritable edits in DNA of children’s and adults’ body cells], it’s not important, any more than for any other medical procedure, because it really isn’t any different from any other medical procedure.

SN: Are there similar registries for other types of research?

Baltimore: There is a global registry of clinical trials. I don’t know of another global registry that focuses on a particular therapeutic activity. On the other hand, there is nothing quite similar to gene editing that has ever been done before, so it would be reasonable to create it.

a photo of Jiankui He at the Second International Summit on Human Genome Editing

GOING ROGUE Despite widespread agreement that human gene editing isn’t safe, Jiankui He secretly altered genes in human embryos, which resulted in the birth of two babies last year. The incident has scientists debating how to stop other researchers from mimicking He’s actions.

IRIS TONG/VOA

SN: Can rogue activity, such as He’s creation of gene-edited babies, be prevented?

Baltimore: We want to create an environment where it’s very clear that we shouldn’t be moving ahead right now. [But] we can’t absolutely prevent that. You can’t prevent murder by having a law against murder. It still happens. Laws aren’t ways of preventing something; they are ways of indicating society’s opinion, and to take a person who has done it out of circulation if they’re a danger, but you don’t prevent the actual event from happening.

SN: What is the potential impact of individual governments or an international treaty restricting gene editing?

Baltimore: It could hold back the science. Right now there are many countries that have outlawed [germline editing] and the way they have phrased it prevents certain kinds of experimental work from being done. That is unfortunate, because I think we want to move forward with experimentation.

In the United States, you can’t do anything that modifies an embryo [paid for] with federal funds. But you can with private funds, so we are moving forward in the United States, using nonfederal money.

[In the moratorium proposal], they talk about individual countries making their own decisions, and I think that’s how it has to happen. It’s very hard to imagine a treaty with all of them and all the complications surrounding this issue. It would take so long, it would be out-of-date before it was passed.

I don’t see how we could prevent a country from saying it’s their position that germline editing should be allowed. There would be a lot of debate about that and such a country would find itself in the position of being an international outlier, and [might] not want to be that, so there would be a lot of pressure to conform. But we just don’t have the mechanism for international law beyond treaties.

SN: Do you envision a day when gene editing will be safe and effective enough to use for germline modifications?

Baltimore: I do.

SN: When?

Baltimore: You never know, because it depends on new technological innovations. They could happen tomorrow or they could not happen for years. It probably isn’t a matter of more than a few years.

SN: Has there been enough public education and debate that society will be ready for germline modification?

Baltimore: There are couples today who would like to have a child that inherits their genes, but among their genes, there is one [mutated gene] they would not like their offspring to inherit. If we could guarantee that the offspring would not inherit a mutated gene, they would then be able to have the child they want to have. They would be able to say to a physician, “Is there a procedure that could safely give us the child we want?” I think when the answer to that question is “yes,” there will be tremendous pressure on the medical community to carry out gene modification.

At that point, we’ll have to balance the desires of couples to have children without mutated genes with the fact that this is a new kind of procedure that we don’t have a lot of experience with, and that some people may think is inappropriate. In general, people are responsive to the desires and needs of these couples. I think they will say this is something we should do.

a photo of a cell being removed from an early embryo

ONE FOR ALL Doctors can test whether an embryo carries harmful genetic variants by removing one or more cells from an early embryo (shown) and testing the DNA of those cells. The process, called preimplantation genetic diagnosis, allows doctors to weed out embryos that carry genetic diseases.

JUAN GAERTNER/SCIENCE SOURCE

SN: Some people argue that it’s already possible to have a baby without a genetic disease through preimplantation genetic screening. So would germline gene editing be restricted to very specific cases?

Baltimore: It depends on what’s safest and most effective. If embryo selection can give us a very high percentage elimination of the gene, then we can do it by embryo selection. Today, the probability of getting a good implanted embryo that comes to term is about 25 percent. So 75 percent of couples that have a procedure don’t get an offspring, so it’s not very effective. Some people say, “Why don’t you just concentrate on making it more effective?” That would be a good thing, but we don’t know that you can. It really comes down to what works and what solves the problem.

SN: Are there any issues that need to be talked about more?

Baltimore: I think the biggest impediment to actually using the technology is the danger of mosaicism: embryos in which some cells are modified and some cells are not, and we don’t know which is which. We have not yet solved that problem.

There’s nothing like actually moving ahead [with research] to teach us what the actual pitfalls are.

— David Baltimore

There was a paper a year or more ago in Nature that claimed to have minimized mosaicism, but many people are doubtful that that paper is exactly right (SN Online: 8/8/18). So until we get that ambiguity solved, I don’t see how we can go forward. There are ways on the drawing boards to solve that problem, but they’re not in actual practice.

SN: Are there any other pitfalls we should be aware of?

Baltimore: There’s nothing like actually moving ahead [with research] to teach us what the actual pitfalls are.

Citations

WHO Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. WHO-RUSH Human genome editing 1st advisory committee VPC. News conference, March 19, 2019.

E. Lander et al. Adopt a moratorium on heritable genome editing. Nature. Vol. 567, March 14, 2019, p. 165. doi: 10.1038/d41586-019-00726-5

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Tuesday, April 2, 2019

Total Medicare Part D Spending on Insulin

Out-of-Pocket Spending on Insulin by Medicare Part D Enrollees

Illustrating the Potential Effect of Rebates on Total Insulin Spending

Implications