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Scientists Create Human ‘Body-On-A-Chip’ Featuring Tiny Replica Organs In The Lab – IFLScience

By Adult Stem Cells

Researchers have created what they say is the world's most sophisticated lab model of the human body: a system of mini-organs made fromreal human cells and stem cells.

While it may sound like attempts to make a miniature Frankensteins monster in a petri dish, the researchers are actually hoping to create an entire lab model of miniaturized human organs that could become invaluable for drug testing and biomedical research.

Reporting in the journal Biofabrication, scientists from Wake Forest Institute for Regenerative Medicine (WFIRM) in North Carolina created a human organ tissue system that features a miniature heart-like organ that beats about 60 times a minute, a lung that breathes the air from the surrounding environment, and a liver that breaks down toxic compounds, as well as testicles and a colon.

Although just one-millionth the size of a full-sized adult human organ, these body-on-a-chip" systems are remarkably detailed, complete with their own blood vessel cells, immune system cells, and connective tissue cells. It also contains a microfluidic circuit thats able to circulate a drug throughout the system between organs, just like how a cardiovascular system pumps molecules through the human body in the blood.

Creating microscopic human organs for drug testing was a logical extension of the work we have accomplished in building human-scale organs, said study co-author Thomas Shupe of WFIRM in astatement. Many of the same technologies we have developed at the human-scale level, like including a very natural environment for the cells to live in, also produced excellent results when brought down to the microscopic level.

Don't worry, this isn't scientists creating a tiny "artificial human" the system is barely more thana load of blobs in a petri dish, not a conscious organism.

Organoids are invaluable tools for scientists looking to understand the human body. In one of the most incredible breakthroughs, researchers recently observed brain organoids that began to show signs of brain waves similar to those of preterm infants. Its hoped this kind of research could be used to understand how brain cells develop into the intensely complex organ currently sitting in your head.

They are also extremely useful for testing new pharmaceutical drugs because they react, in theory, just as a real human organ would. Plus, they are safe and relatively low-cost. The newly developed miniature organ model has already been used for a number of tests to assessthetoxicity of some drugs. In some instances, the organ model managed to show adrug might be dangerous or have some undesired effect, thereby potentially preventing harm to humans.

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Scientists Create Human 'Body-On-A-Chip' Featuring Tiny Replica Organs In The Lab - IFLScience

Why Soap Works – The New York Times

By Gene Therapy Clinics

These more resilient microbes are generally less susceptible to the chemical onslaught of ethanol and soap. But vigorous scrubbing with soap and water can still expunge these microbes from the skin, which is partly why hand-washing is more effective than sanitizer. Alcohol-based sanitizer is a good backup when soap and water are not accessible.

In an age of robotic surgery and gene therapy, it is all the more wondrous that a bit of soap in water, an ancient and fundamentally unaltered recipe, remains one of our most valuable medical interventions. Throughout the course of a day, we pick up all sorts of viruses and microorganisms from the objects and people in the environment. When we absentmindedly touch our eyes, nose and mouth a habit, one study suggests, that recurs as often as every two and a half minutes we offer potentially dangerous microbes a portal to our internal organs.

As a foundation of everyday hygiene, hand-washing was broadly adopted relatively recently. In the 1840s Dr. Ignaz Semmelweis, a Hungarian physician, discovered that if doctors washed their hands, far fewer women died after childbirth. At the time, microbes were not widely recognized as vectors of disease, and many doctors ridiculed the notion that a lack of personal cleanliness could be responsible for their patients deaths. Ostracized by his colleagues, Dr. Semmelweis was eventually committed to an asylum, where he was severely beaten by guards and died from infected wounds.

Florence Nightingale, the English nurse and statistician, also promoted hand-washing in the mid-1800s, but it was not until the 1980s that the Centers for Disease Control and Prevention issued the worlds first nationally endorsed hand hygiene guidelines.

Washing with soap and water is one of the key public health practices that can significantly slow the rate of a pandemic and limit the number of infections, preventing a disastrous overburdening of hospitals and clinics. But the technique works only if everyone washes their hands frequently and thoroughly: Work up a good lather, scrub your palms and the back of your hands, interlace your fingers, rub your fingertips against your palms, and twist a soapy fist around your thumbs.

Or as the Canadian health officer Bonnie Henry said recently, Wash your hands like youve been chopping jalapeos and you need to change your contacts. Even people who are relatively young and healthy should regularly wash their hands, especially during a pandemic, because they can spread the disease to those who are more vulnerable.

Soap is more than a personal protectant; when used properly, it becomes part of a communal safety net. At the molecular level, soap works by breaking things apart, but at the level of society, it helps hold everything together. Remember this the next time you have the impulse to bypass the sink: Other peoples lives are in your hands.

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Why Soap Works - The New York Times

Flexion Therapeutics Inc (FLXN) Q4 2019 Earnings Call Transcript – Motley Fool

By Gene Therapy Clinics

Image source: The Motley Fool.

Flexion Therapeutics Inc(NASDAQ:FLXN)Q42019 Earnings CallMar 12, 2020, 4:30 p.m. ET

Operator

Good afternoon, ladies and gentlemen. And welcome to the Flexion Therapeutics Fourth Quarter and Full Year 2019 Financial Results Conference Call. My name is Daniel and I will be your coordinator for today. At this time all participants are in listen-only mode. We will be facilitating a question-and-answer session at the end of today's call. [Operator Instructions]

I will now turn the call over to the company.

Scott Young -- Vice President, Corporate Communications & Investor Relations

Thank you, Dan. Good afternoon. This is Scott Young, Vice President for Corporate Communications and Investor Relations. Before we begin, I would call your attention to the metric slides that we will discuss in today's presentations. Those slides can be viewed directly via the webcast, in the 8-K we issued this afternoon or under the Investors tab on flexiontherapeutics.com. In addition, our Q4 earnings press release and an archive of this conference call can also be found there.

Today's call will be led by Flexion's Chief Executive Officer, Dr. Michael Clayman, and he is joined by David Arkowitz, Flexion's Chief Financial Officer and Melissa Layman, Flexion's newly appointed Chief Commercial Officer.

On today's call we will be making forward-looking statements include commercial, financial, clinical, and regulatory projections. Statements relating to future financial or business performance, conditions or strategies and other business matters, including expectations regarding net sales, operating expenses, cash utilization clinical, regulatory and commercial developments and anticipated milestones are forward-looking statements within the meaning of the Private Securities Litigation Reform Act. Flexion cautions that these forward-looking statements are subject to various assumptions, risks and uncertainties, which change over time. Additional information on the factors and risks that could affect Flexion's business, financial conditions and results of operations are contained in Flexion's Form 10-K for the year ended December 31, 2019 which was filed with the SEC and other filings which are available at http://www.sec.gov as well as Flexion's website. These forward-looking statements speak only as of the date of this call and Flexion assumes no duty to update such statements.

I will now turn the call over to Flexion's CEO, Mike Clayman.

Mike Clayman -- Chief Executive Officer & Co-Founder

Thanks, Scott, and thank you all for joining. Today, I'll recap our commercial progress in 2019, review our life cycle management activities, provide an update on our pipeline and discuss our priorities for this year. After that, I'll turn it over to David for a deeper review of our commercial metrics and a summary of our financial performance and then we will open the line and take questions.

To begin, as we reported today, we recorded full year ZILRETTA net sales of $73 million for 2019, which is fully in line with the preliminary unaudited revenue estimate we provided in early January. We are very pleased with our sales performance in 2019, which represents growth of more than 220% compared to our 2018 full year net sales of $22.5 million. Those numbers tell a very compelling story, and they speak to the outstanding work of our field based teams, the excellent coverage we have for ZILRETTA, the impact from our judicious use of volume based rebates, but most importantly, our sales performance speaks to the remarkable experience that patients and clinicians are having with ZILRETTA.

As you will see in the commercial metrics that David will review, by the end of 2019, our customers had purchased 175,000 units of ZILRETTA. While our data are limited to the account level, that number provides a reasonable surrogate for the number of patients who have been treated with ZILRETTA since it was introduced to the market in late 2017. And we know that many of those patients have received unprecedented pain relief from ZILRETTA. I say it is based on real world feedback from the countless conversation I've had with grateful ZILRETTA patients and their physicians, feedback that is wholly consistent with our compelling clinical trial data.

In fact, last year, we became aware of several professional athletes who received ZILRETTA, namely Rod Woodson, the NFL Hall of Fame Defensive back, who was named as one of the top 100 players of all time. Michael Eruzione, the captain of 1980 Gold medal winning US Olympic Hockey team and the player who scored the game winning goal against the Russians during the Miracle On Ice; and Chris Dickerson, a former outfielder who played from the New York Yankees and other major league baseball teams. From snow blowing a driveway to playing with their children and grandchildren, to jogging for the first time in years, they all have profoundly moving stories about how ZILRETTA has helped each of them manage their knee OA pain and thereby improve their ability to participate in regular everyday activities.

As part of our ongoing physician marketing initiatives, we brought all three athletes together at a major orthopedic conference last December, where they and their treating physicians, spoke to a standing room crowd of some of the country's leading sports medicine experts. They share their stories of how ZILRETTA has helped them, and the best words I can use to describe that session are inspiring and humbling. While all are elite athletes, their ZILRETTA stories echo the scores of emails and letters I've received from patients who are so grateful to reengage in things they love doing with less pain. From gardening, playing a round of golf, walking on the beach, hiking, each of these stories serves as a reminder to all of us that while we have impacted more than 175,000 patients, there are 15 million people who see their doctor every year for OA knee pain and 5 million of them receive an intra-articular injection. The opportunity for ZILRETTA inflection is truly massive, which brings me back to our performance in 2019 and our goals for 2020.

Throughout the course of 2019, we saw existing practices increase their use of ZILRETTA and more than 1,600 new accounts start using the product. Today, with the benefit of two years in the market, we have actual claims data that shows some slight changes in the payer mix versus our assumptions prior to launch. We now see that the actual payer mix is skewed slightly more toward Medicare, which accounts for roughly 55% of the market versus previous estimates of 50%. 40% is still commercial, but Medicaid, VA and 340B plans are making up roughly 5% of the mix. We view this modest increase in Medicare patients to be incrementally positive as Medicare patients can be injected the same-day they visit without any need for prior authorization.

In addition, it is important to point out that commercial coverage for ZILRETTA remains excellent. As we discussed in December, the recent approval of our sNDA result in a significantly improved label, which most importantly, removed the onerous not intended for repeat administration wording in the limitation of use statement. Within days of the approval, we developed materials to help our MBMs communicate the label update and we have anecdotal feedback from the field that tells us that the changes have been very well received. While we clearly view the label update as a tailwind, we have always said that we continue to believe that the meaningful impact will be seen over the following quarters and years.

From a commercial perspective, our progress in 2019 strengthens our belief that ZILRETTA can become the new standard of care for the intra-articular treatment for OA knee pain in the years ahead. While under normal circumstances, these factors would give us confidence that our 2020 ZILRETTA net sales guidance of $120 million to $135 million is both credible and achievable.

Like all businesses, we are acutely attuned to the potential impacts of the coronavirus global pandemic, and we are monitoring this dynamic situation very closely. To date, we have not seen any material impacts on ZILRETTA sales, our ability to access customers or to initiate our clinical trials. However, it is impossible to predict how the outbreak could evolve in the months ahead or what impacts more aggressive social distancing or other containment efforts might have on patients or practices. Regarding our supply chain, we believe we are in a very strong position. We do not source any of our key materials from China and we presently have approximately 10 months worth of finished product inventory in our warehouses in the US. Furthermore, we have an additional 12 months of API, triamcinolone acetonide at our manufacturing facility in the UK. Again, it is impossible to predict the long term impacts of the outbreak, but we feel very good about our ability to provide ZILRETTA to patients over the quarters ahead.

Shifting to our clinical development activities, our Phase 2 trial to investigate the safety and efficacy of ZILRETTA in shoulder OA and adhesive capsulitis, also known as frozen shoulder syndrome continues to advance and we anticipate data from that trial in 2020. As we've previously discussed, these two conditions combined account for roughly 800,000 injections and they present an opportunity for us to expand the use of ZILRETTA with a subset of orthopedics who primarily focus on sports medicine and commonly treat these conditions with steroid injections.

With respect to our pipeline, we've also been making progress with our two drug candidates FX201 and FX301. FX201 is our gene therapy, which holds the potential to provide OA pain relief for at least a year, improve function and potentially modify disease. As we announced last year, the IND for FX201 was accepted by the FDA and we recently treated the first two patients in our Phase 1 dose ranging study. We anticipate treating approximately 15 to 24 patients, who will be followed for 104 weeks with initial readout in 2021.

Now we'll move to FX301. Our NaV1.7 inhibitor formulated within a thermosensitive hydrogel for administration as a peripheral nerve block for control of post-operative pain. We held our pre-IND meeting with FDA and we remain on track to initiate our first FX301 clinical trial in 2021. Unlike typical local anesthetics, we believe the selective pharmacology of FX301 has the potential to deliver at least three days to five days of effective pain relief, while preserving motor function, which could enable ambulation, rapid discharge from the hospital and early rehabilitation following musculoskeletal surgery.

Finally, regarding our search for a Chief Commercial Officer. We were very excited to announce the appointment of Melissa Layman earlier this week, and I'm delighted that she is able to join us for today's call. As we've said repeatedly, in our search for a CCO, we were looking for someone who have had success leading an entire commercial enterprise, who had deep experience and expertise in each of the key commercial functional domains, who had a track record as a very strong leader and who would positively contribute to our already strong culture. Because Melissa fulfills all of these criteria and is simply a terrific person to interact with, we could not be more pleased to have her take the helm of our commercial organization.

Before David summarizes our fourth quarter financials and walks through the commercial metrics, I'd like to give Melissa the opportunity to make a few remarks. Melissa?

Melissa Layman -- Chief Commercial Officer

Thank you, Mike, and thank you for the kind words. It is such a pleasure to be here today and such an honor to join Flexion. While I've barely been in my role for a day, I can already see what an amazing group of people work here. The team has been welcoming, engaging and candid, and that was consistent throughout the entire interview process from the Executive Committee to the Board members.

The commitment to patients and passion for winning has been universal and that was one of the many reasons I wanted to join. Put simply, I can't begin to convey how excited I am about the opportunity that's ahead of us. The strong foundation that's been laid by Mike, David, Steve Meyers, and the rest of the commercial leadership team is truly impressive and I'm looking forward to working together to grow ZILRETTA's market share and help make it the leading IA treatment in this space. Over the next few months, I'll be working intensively with our commercial organization, and I look forward to representing our commercial effort on future calls.

At this point, I'll turn it over to David.

David Arkowitz -- Chief Financial Officer

Thank you, Melissa. I'll start by walking through our commercial metrics, which as Scott mentioned can be found on our website and in the 8-K we issued today.

If you look at Slide 2, you can see that we recorded ZILRETTA net sales of $23.7 million in the fourth quarter of 2019, bringing full year 2019 net sales to $73 million. As Mike mentioned, year-over-year growth topped 220%. As in previous quarters, we expanded our list of target accounts in the fourth quarter to 4,972 and by December 31, 2019 we had called on almost all of them. At the end of the fourth quarter, 3,488 accounts had purchased ZILRETTA, which is an increase of nearly 360 purchasing accounts compared to the end of the third quarter. As of the end of December, we had 2,642 accounts or 76% of all purchasing accounts placed at least one reorder for ZILRETTA. Notably, we saw our reorder rate increase in each quarter throughout 2019 and this occurred on a successively growing customer base.

Slide 3 charts our quarterly sales from launch through the fourth quarter of 2019, which provides a very compelling view of ZILRETTA's growth in the market, especially since the introduction of the permanent J Code on January 1, 2019. We do not provide quarterly guidance, but based on routine seasonality impacts, directionally we anticipate first quarter net sales to be roughly flat versus the fourth quarter of last year.

Moving to Slide 4. This slide and the remaining two slides reflect purchases of ZILRETTA by accounts, which represent physician practices, clinics and hospitals of various sizes and purchasing potential. As we look at the distribution of accounts that have purchased the ZILRETTA since launch, we stayed with the same groupings that we've used in previous quarters, accounts that have purchased one units to 10 units, purchased 11 units to 50 units or purchased more than 50 units. We continue to see a significant number of accounts with purchases of one unit to 10 units. And as of December 31, 2019, roughly 1,670 accounts had made purchases in this range, while approximately 1,030 accounts had purchased 11 units to 50 units. In addition, 794 accounts had purchased more than 50 units, which represents growth of 150% as compared to Q1 2019 when 313 accounts had purchased in this category.

Looking at Slide number 5. You can clearly see the distribution of purchases by accounts. Those 794 accounts that have each purchased more than 50 units are in total, responsible for approximately 143,000 units or roughly 81% of all units purchased since launch. As we have mentioned previously, accounts generally move along a utilization continuum from one unit to 10 units to 11 units to 50 units and then to more than 50 units. Importantly, none of our purchasing accounts has fully incorporated ZILRETTA into their practice, and this holds true for even the highest utilizers. As a result, we believe there is tremendous opportunity for us to increase utilization across each of these groups.

Before I leave this slide, I would like to point out that the total ZILRETTA purchases by accounts in the fourth quarter were approximately 37,500 units, which is lower than the 48,600 units purchased in the third quarter. We believe this quarter-over-quarter reduction was primarily the result of the broad-based rebate program that we introduced in the third quarter. There was a strong amount of enthusiasm and pent-up demand for this program and we believe that some purchases that otherwise would have occurred in the fourth quarter instead occurred in the third quarter. To a much lesser extent, we believe that the holidays in the fourth quarter had an impact on the sequential quarter reduction as well. Nevertheless, we saw total ZILRETTA purchases by accounts increased by more than 70% in the second half of 2019 versus the first half of 2019.

Moving to Slide 6. Here we break out ZILRETTA purchases by new and existing accounts and in the fourth quarter, we added about 350 new purchasing accounts. While we expect to eventually see a slowing in the number of new accounts coming on board each quarter, we continue to be pleased with the progress we are making with new accounts as they typically work their way through the ZILRETTA utilization continuum.

So at this point, I will briefly walk through the fourth quarter and full year 2019 financial results, which we included in the press release issued this afternoon and in our 10-K. We reported a net loss of $149.8 million for full year 2019 as compared to a net loss [Phonetic] of $169.7 million for full year 2018. Net sales of ZILRETTA were $23.7 million for the fourth quarter of 2019 and totaled $73 million for full year 2019. The cost of sales for full year 2019 was $10 million. The fourth quarter 2019 net sales reflect gross net reduction of 11%. A gross to net reduction is primarily comprised of distributor and service fees, return to reserve, healthcare provider rebates and mandatory government discounts and rebates such as Medicaid, 340B institutions, and Veterans Administration, Department of Defense. As we previously mentioned, in the third quarter, we started offering rebates to eligible healthcare providers that are variable based on the volume of product purchased. These provider rebates contributed 4% of the fourth quarter total gross to net reduction of 11%.

Research and development expenses were $69.6 million and $53.1 million for the years ended December 31, 2019 and 2018, respectively. The increase in research and development expenses year-over-year of $16.5 million was primarily due to an increase in salary and other related costs for additional headcount and stock based compensation expense, an increase in expenses related to portfolio expansion and other program costs, including an upfront payment to Xenon Pharmaceuticals related to FX301 and an increase in development expenses for ZILRETTA.

Selling, general and administrative expenses were $129.7 million and $121.3 million for the year ended December 31, 2019 and 2018, respectively. Selling expenses were $96.3 million and $87.3 million for the years ended December 31, 2019 and 2018, respectively. The year-over-year increase in selling expenses of $9 million was primarily due to salary and other employee related costs and external costs related to marketing and reimbursement support activities.

General and administrative expenses were $33.4 million and $34 million for the years ended December 31, 2019 and 2018, respectively, which represents a decrease of $0.6 million year-over-year.

Interest expense was $17.1 million and $15.7 million for the years ended December 31, 2019 and 2018, respectively. We expect that while our operating expenses will continue to increase in the near term, primarily driven by commercial activities in support of ZILRETTA, line extension clinical trials for ZILRETTA, continued development of FX201 and FX301 and development activities associated with future additions to the pipeline. We believe we will be able to increasingly leverage our infrastructure in support of these efforts.

As of December 31, 2019, and we had approximately $136.7 million in cash, cash equivalents and marketable securities compared with $258.8 million as of December 31, 2018. In addition, earlier this quarter, we fully drew down $20 million from our revolving credit facility, which is secured by our accounts receivables. We believe that our current cash balance with the expected future sales of ZILRETTA and the ongoing prudent management of our expenses will enable us to reach profitability. However, our projections are based on certain market assumptions, which may or may not be affected by the coronavirus pandemic. As a result, we will continue to review and reassess our assumptions in light of those factors. In addition, we will remain opportunistic as it relates to potential funding decisions, and we will do what we believe is in the best long-term interest of Flexion and our shareholders.

At this point, I would ask the operator to please open the line for questions.

Operator

Thank you. That concludes our prepared remarks. We'll now open the call for questions. [Operator Instructions] Our first question comes from Randall Stanicky with RBC Capital Markets. Your line is now open.

Dan Busby -- RBC Capital Markets -- Analyst

Good evening, this is Dan Busby on for Randall. A couple of questions. First, among the high prescribing accounts in particular, can you give us a sense of how much more room there is to grow within those practices? I think I heard you mentioned that you haven't fully penetrated any of those accounts yet. And of the physicians in those accounts who aren't using it, what's the pushback you're hearing?

David Arkowitz -- Chief Financial Officer

Yeah Dan, this is David. So as we shared in our prepared remarks and in the deck, we've got almost 800 accounts that have purchased 50 units, more than 50 units of ZILRETTA launch to date. The vast, vast majority of those accounts, ZILRETTA has not been fully adopted, incorporated into their practices and even there is a subset even within those accounts of almost 50 accounts that have purchased more than 500 of units of ZILRETTA launch to date. So there's room to run with those almost 800 accounts as well as the other accounts that are less than 50 units of ZILRETTA purchased launch to date.

And in terms of the other part of your question, in terms of why have they not fully incorporated ZILRETTA at this juncture. The way this will typically work is take a practice with five physicians or six physicians one or two of those physicians have started to use ZILRETTA and are using ZILRETTA for their patient -- appropriate patient population but there just hasn't been awareness and experience with ZILRETTA for the other three or four docs in the practice. So it's a process, it's a process for the docs that are treating the existing patients to talk to their colleagues, for our representatives to be making those physicians that are not yet using ZILRETTA aware of ZILRETTA, getting them comfortable with reimbursement. So that's really what is going on.

Dan Busby -- RBC Capital Markets -- Analyst

Okay, that's helpful. And I guess as a follow-up to that, if one practice -- if one or two physicians within a practice have secured reimbursement, is it typically the case that other doctors who aren't using it, but may in the future, they would have reimbursement set up already or is that more kind of doctor by doctor?

Mike Clayman -- Chief Executive Officer & Co-Founder

No, it's typically at the office level, at the clinical level. But the -- it's an issue of just getting familiar and comfortable with reimbursement, experiencing reimbursement and that takes those docs that have not achieved that to just go through the process.

Dan Busby -- RBC Capital Markets -- Analyst

Got it, understood. Thank you.

David Arkowitz -- Chief Financial Officer

Thanks, Dan. Sure.

Operator

Thank you. Our next question comes from Elliot Wilbur with Raymond James. Your line is now open.

Elliot Wilbur -- Raymond James and Associates -- Analyst

Thanks, good afternoon. Couple of questions. First, Mike, I believe you mentioned in your commentary that you expect 1Q 2020 ZILRETTA sales to be essentially flat versus 4Q '19. Just want to get maybe a little bit more color behind that? How much of that you think is attributable to high deductible plans, perhaps influencing utilization versus other factors such as seasonality or just sort of overall company conservatism kind of in light of potentially increased macro uncertainty here in the short term?

Mike Clayman -- Chief Executive Officer & Co-Founder

Yeah, so I think there are a few things, Elliot. So it's a good and important question. First just to recognize, historically, in this space, the hyaluronic acids are typically down 10% in the first quarter, with the driver being as you point out, deductible. That is a key driver. I think that you also have to look at an older population may be less active in the winter months. And as a result, have less need to go to their physicians. So there are a couple of reasons why there is a basis for relatively speaking the first quarter being [Indecipherable] other quarters and why we have guided to flat in the first quarter.

Elliot Wilbur -- Raymond James and Associates -- Analyst

Okay. And then with respect to your commentary around some of the data points that emerge from the claims data that you're referring to in terms of the payer mix with Medicare representing now a higher proportion. How should we think about the relative opportunity with respect to additional growth levers such as repeat administration, bilateral administration within the context of a greater Medicare book of business versus commercial?

Mike Clayman -- Chief Executive Officer & Co-Founder

Yeah, it's a good question. We -- as you know the Medicare population has the opportunity to benefit most directly in a sense from ZILRETTA and that physicians can use same day without any hesitancy and proceed with confidence that they will be reimbursed. They can repeat dose without any concern about reimbursement. They can do bilateral injections etc. So we like the Medicare population, we also like the commercial population. It's very straightforward with Medicare. And I would say directionally as a modest bump up in the representation of Medicare is wind in our sales and will improve our circumstances. As we often say this is not a light switch, but it's directionally encouraging.

Elliot Wilbur -- Raymond James and Associates -- Analyst

Okay. And then just a couple of financial questions for David as well. With respect to SG&A trends, they've held relatively flat in the $32 million, $33 million range over the last four quarters, not sure kind of directionally would expect it to increase, but obviously, you've been able to get a lot more leverage out of that line than probably what we would have expected at the beginning of the year. So how should we think about progression of that number over the course of 2020?

David Arkowitz -- Chief Financial Officer

Yeah, Elliot, great question. So to your point it has been relatively flat quarter-over-quarter in 2019, the G&A component of that. So if you just look at quarterly SG&A for fourth quarter about 20 -- about excuse me, about $32 million, about $8 million of it is G&A, that will stay flat in the ensuing quarters. $24 million of it's is commercial. And as we've talked about before, slightly more than half of that is related to headcount and support of spend and we are right sized from a headcount standpoint. So increases in that portion will be minimal, where we're going to see some increases over time are external marketing activities in support of increasing ZILRETTA sales. But because that's only less than half of the selling and marketing spend, you're not going to see SG&A go up by meaningful amounts quarter-over-quarter. And on top of all that, as you might imagine, we're very focused on leveraging as best we can, our SG&A infrastructure that we've built up over the past four quarters.

Elliot Wilbur -- Raymond James and Associates -- Analyst

Fair enough, one last question for you, David, just doing some simple back of the envelope math here, yield is a much higher net price per unit in the fourth quarter versus what we've seen during the course of the year. Wondering how much of that may be attributable to simply payer mix? Or is there some sort of Medicare true-up or other reserve adjustments that may have led to that?

David Arkowitz -- Chief Financial Officer

Yeah, so Elliot, the gross to net reductions in the third quarter that was 14%. That would have generated a net price per unit of about $490. In the fourth quarter, our gross to net, as I talked about earlier, was 11% and that generates net price per unit of about $507 per unit. And really the difference between Q4 and Q3, why the gross to net reduction is a bit less, relates to the provider rebates those were obviously less in the fourth quarter than they were in the third quarter on a per unit basis.

Elliot Wilbur -- Raymond James and Associates -- Analyst

All right, thank you.

David Arkowitz -- Chief Financial Officer

Thank you.

Operator

Thank you. Our next question comes from Gary Nachman with BMO Capital Markets. Your line is now open.

Gary Nachman -- BMO Capital Markets -- Analyst

Hi, good afternoon. Mike, first, I just want to confirm, if not for all the coronavirus uncertainty, would you be reiterating ZILRETTA guidance of $120 million to $135 million that you provided in January, based on everything that you had been seeing thus far? And David, how much flexibility do you have with expenses? If revenue ends up trailing your guidance, what sort of levers do you have -- in both SG&A and R&D?

Mike Clayman -- Chief Executive Officer & Co-Founder

Yes, good questions Gary, let me say that. We do reiterate guidance in the script. We do indicate our confidence in achieving full year revenue $120 million to $135 million. What we do is qualify that by the unknowns associated with COVID-19 and inability to predict with any sense of reality, what the situation will be in the coming weeks and months. So I think it would be imprudent for us to guide to $120 million to $135 million without that qualifier, because there are just too many unknowns. Bottom line is take COVID off the table and our confidence in the guidance continues at the highest level.

David Arkowitz -- Chief Financial Officer

And Gary, this is David. So operating expenses on a quarterly basis around $50 million. We do have a certain amount of operational flexibility to dial expenses up and dial them down. Obviously, we want to ensure that we're appropriately resourcing ZILRETTA from a commercialization standpoint from a line extension standpoint and then we're appropriately resourcing FX201 and 301 in their respective development. But with all that said, we are sitting here in Burlington, Mass in rented space that's not all that expensive and we don't have a whole lot of fixed cost. So we have a certain amount of flexibility, but we're obviously going to do what makes the most sense to the business.

Gary Nachman -- BMO Capital Markets -- Analyst

Okay, great. And then Mike, just a little bit more on what sort of impact have you been seeing or hearing so far in the label update. How have you changed your promotional materials and messaging since that label update? I know that it's pretty early, but -- and it takes some time for you to really see the impact there. But any color on the anecdotal feedback that you've been getting on that? And then just -- yes, go ahead, I'll have a follow up after.

Mike Clayman -- Chief Executive Officer & Co-Founder

Okay. I'd just say, it's a good question. We're very happy with our ability and the ability of our sales reps or MBMs to share the reprint and reprint cover that includes information about the trial, data from the trial and to be able to do that proactively.

Operator

Ladies and gentlemen, please standby your conference will resume momentarily. Once again, thank you for your patience and please continue to standby.

Mike Clayman -- Chief Executive Officer & Co-Founder

[Speech Overlap] Apologies, we had a technical snafu. So what we're hearing anecdotally is very positive, but it's too early to quantify the effect. But directionally, it is -- we're absolutely confident it will be positive.

Gary Nachman -- BMO Capital Markets -- Analyst

Okay. And then the last question is just what sort of initiatives might you have in place to try and shift an acceleration with the targeted physicians to the higher utilization buckets.

And Melissa, welcome to you, maybe it's a chance for you to comment just a little bit, based on your prior experience, where do you see the greatest opportunity to accelerate ZILRETTA? And then at what point do you think the sales force might be ready to take on some new products in the bag and then leverage that infrastructure a little bit better? Thanks. Hello?

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Flexion Therapeutics Inc (FLXN) Q4 2019 Earnings Call Transcript - Motley Fool

Scarborough brother and sister, aged 11 and 12, with the genetic cholesterol condition FH are helped by new clinic – The Scarborough News

By Gene Therapy Clinics

The clinic helps children at risk of developing heart disease in the future due to high cholesterol.

They can now attend a ground-breaking clinic run by the familial hypercholesterolemia (FH) service at York Teaching Hospital NHS Foundation Trust.

FH is an inherited condition which can lead to extremely high cholesterol levels and is passed down through families in the genes.

The FH service, led by Dr Chandrajay, Consultant in Chemical Pathology and Metabolic Medicine, and Claire Tuson, Familial Hypercholesterolaemia Specialist Nurse, has recently extended their service to include children and adolescents.

Claire explained: Research has shown that children with FH start to develop a build-up of fatty plaque in their arteries before the age of 10. Once diagnosed, FH is easy to treat so it makes sense to work with families as soon as possible.

Last year, with the support of Consultant Paediatrician Dr Dominic Smith, we extended gene testing to all children aged 10 years old and over, who have a parent affected with FH. Testing children for FH could prevent a potentially fatal heart attack or stroke.

The first six children from York and Scarborough that were identified with FH have recently attended our new Yorkshire and Humber joint paediatric clinic for children and their families, which launched at the end of January.

FH is estimated to affect 1 in 250 people in the UK, including over 56,000 children.

It is an inherited disorder of cholesterol and lipid metabolism, caused by an alteration in a single gene where people have higher levels of bad cholesterol levels from birth. If left undetected and untreated FH can lead to the early development of heart and circulatory problems.

Kiera Pickering, aged 12, and her brother Connor, aged 11, from Scarborough, were two of the first children to attend the clinic.

Claire added: Its a real breakthrough to be able to identify and treat children with FH so early. Alongside dietary and lifestyle advice to maintain a healthy body weight, children can be considered for statin therapy from as young as 10 years old.

"Statin treatment can not only prevent, but potentially reverse, the build-up of cholesterol and allow children and young people to live a perfectly healthy life.

Despite the availability of genetic testing, more than 85 percent of people with FH in the UK are undiagnosed.

The British Heart Foundation estimates that currently only around 600 children in the UK have been diagnosed with FH, meaning that thousands more are not on treatment and remain unaware of their future risk of heart disease.

For more information about the FH clinics contact claire.tuson@york.nhs.uk

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Scarborough brother and sister, aged 11 and 12, with the genetic cholesterol condition FH are helped by new clinic - The Scarborough News

Stem Cell Therapy Market: Using Stem Cell Therapy to Accelerate Cardiovascular Healing – BioSpace

By Stem Cell Treatment

Researchers are occupied with finding novel strategies to make human stem cells. This is to address the expanding interest for stem cell creation for potential examination in malady administration. This factor is absolutely anticipated that would quicken the improvement of regenerative pharmaceutical, along these lines driving mechanical development. Also, cellular treatments are perceived as the following real progressions in changing social insurance. Firms are extending their cellular therapy portfolio, understanding the future capability of this field in the treatment of Parkinsons ailment, type 1 diabetes, spinal string damage, Alzheimers sickness, and others.

One of the essential variables driving this present Stem Cell Therapy market development is the restrictions in customary organ transplantations. The developing worries with organ transplantations have driven the interest for stem cell therapy items. Traditional organ gift is related with disease hazard, immunosuppression hazard, and dismissal. Additionally, the interest for organs is expanding, and the doctors very subject to organ benefactors. To beat these issues scientists are presently investigating approaches to distinguish the use of stem cell treatments in different transplants. For example, pluripotent stem cells offer a conceivably boundless wellspring of human cells, which can determine the majority of the cells in the body. Besides, the join dismissal can be diminished with the stem cells, as these are developed utilizing a similar individual cells. These points of interest in the transplantations of organs will bring about the development of the worldwide stem cell therapy market.

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Another key variables boosting the development of this market is the constraints of customary organ transplantation, for example, the danger of disease, dismissal, and immunosuppression hazard. Another disadvantage of ordinary organ transplantation is the fact that specialists need to rely upon organ contributors totally. Every one of these problems can be killed, by the utilization of stem cell therapy. The other factor which is helping the development in this market is the developing pipeline and advancement of medications for rising applications. Expanded research thinks about meaning to extend the extent of stem cell will likewise fuel the development of the market. Researchers are continually occupied with endeavoring to discover novel strategies for making human stem cells because of the developing interest for stem cell creation to be utilized for malady administration.

The worldwide market for stem cell therapy can be fragmented into North America, Europe, Latin America, Asia Pacific, the Middle East and Africa. North America rose as the main territorial market, activated by the rising rate of government help and interminable wellbeing conditions. Europe additionally shows huge development potential, as the advantages of this therapy are progressively recognized.

Asia Pacific is known for most extreme development, on account of the monstrous patient pool, main part of interests in stem cell therapy ventures, and the expanding acknowledgment of development openings in nations, for example, Japan, China, and India by the main market players.

The worldwide stem cell therapy market is in an early stage with the nearness of couple of universal merchants. With changing directions regarding transplantations in different created and creating nations, various new players are relied upon to enter the market space. Additionally, the developing pipeline and advancement of medications for rising applications will build the opposition among merchants amid the conjecture time frame.

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Other conspicuous merchants in the stem cell therapy market incorporate VistaGen Therapeutics, AbbVie, Anterogen, Astellas Pharma, Beike Biotechnology, Cellular Dynamics International (a backup of Fujifilm), Cellular Biomedicine Group, Opsis Therapeutics, Mesoblast, Laboratorios Salvat, TWO CELLS, Pharmicell, Ivy Institute of Stem Cells, Pluristem Therapeutics, U.S. Stem Cell, Taiwan Bio Therapeutics, ReNeuron, Translational Biosciences, Nuo Therapeutics, BIOTIME, Promethera Biosciences.

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Stem Cell Therapy Market: Using Stem Cell Therapy to Accelerate Cardiovascular Healing - BioSpace

HIV patient appears to be cured after stem cell treatment – New York Post

By Stem Cell Treatment

A 40-year-old HIV patient has been declared cured after a promising treatment has left him with no active virus. The man, Adam Castillejo, was the subject of extensive research in early 2019 after doctors failed to find HIV in his body over an 18-month period after previously being diagnosed in 2003.

Castillejo, known by the nickname London Patient lived with the disease for many years, taking medicine to manage it since 2012. That same year he was diagnosed with Hodgkins Lymphoma and later endured a bone marrow transplant. That operation may have ultimately cured him of HIV and appears to have made him only the second person to ever be cured of the disease that causes AIDS.

As ScienceAlert reports, the bone marrow transplant that doctors performed on Castillejo used cells from a donor with a very special genetic quirk. The cells are thought to work against HIV in the body, but there was no guarantee that the transplant would provide any concrete benefits beyond treating the cancer.

However, it appears as though the decision to treat Castillejo with the unique stem cells worked in more ways than one and last year doctors announced they couldnt find the virus in his body after 18 months. At the time, they were hesitant to declare the London Patient cured, but after a new round of testing returned the same results, they are more confident that the active form of the virus has indeed been defeated.

This is a unique position to be in, a unique and very humbling position, Castillejo told the New York Times. I want to be an ambassador of hope.

While this sounds like incredible news and for Castillejo, it certainly is the treatment is not an option for everyone. With cancer limiting their options, doctors used the stem cell transplant as a last resort to keep him alive. Its a serious operation and one that was only performed because Castillejos condition was so dire.

Castillejo and the other HIV patient who had similar results, known as the Berlin Patient, may be uniquely fortunate. The doctors note that there are others who have had the same transplant performed but did not improve as rapidly as the others. There are obviously many factors at work here and as exciting as it is to see a second person cured of this terrible disease, theres a lot more work to be done before we can say HIV has been truly beaten.

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HIV patient appears to be cured after stem cell treatment - New York Post

Lattice Biologics to Evaluate Anti-Inflammatory Stem Cell Therapy Treatment of COVID-19 Lung Disease – BioSpace

By Stem Cell Treatment

AmnioBoost has potential for use in the treatment of ARDS, which is the principal cause of death in COVID-19 infection.1 Mortality in COVID-19 infected patients with the inflammatory lung condition (ARDS) is reported to approach 50%, and is associated with older age, co-morbidities such as diabetes, higher disease severity, and elevated markers of inflammation.1 Current therapeutic interventions do not appear to improve in-hospital survival.1

AmnioBoost is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in several diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

Major anti-inflammatory cytokines found in AmnioBoost include: interleukin (IL)-1beta, IL-1ra, TNF-alpha, IL-6, IL-8, IL-16, CCL2, CXCL7, MIF, and GRO a/b/g. Specific cytokine receptors for IL-1, and tumor necrosis factor-alpha, function as proinflammatory cytokine inhibitors.

This is supported by recently published results from an investigator-initiated clinical study conducted in China which reported that allogeneic mesenchymal stem cells (MSCs) cured or significantly improved functional outcomes in all seven treated patients with severe COVID-19 pneumonia.2

AmnioBoost

AmnioBoost was originally developed for chronic adult inflammatory conditions such as osteoarthritis, but has found multiple uses in the treatment of bone and cartilage repair, as well as soft tissue repair. It is an investigational therapy comprising concentrated allogeneic MSCs and cytokines derived from amniotic fluid.

The amniotic fluid is donated from non-related, healthy mothers and recovered by caesarian section; the baby is not harmed in any way. Additionally, AmnioBoost has been injected in over 1,000 patients with no adverse events, and appears to be well tolerated.

References

1. Liu Y et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. Medrxiv 2020; https://doi.org/10.1101/2020.02.17.20024166 2. Leng Z, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. Aging and Disease, 10.14336/AD.2020.0228

About Lattice Biologics Ltd.:

Lattice Biologics is traded on the TSX-V under the symbol: LBL. The Company is an emerging leader in the field of cellular therapies and tissue engineering, with a focus on dental indications.

Lattice Biologics develops and manufactures biologic products to domestic and international markets. The Companys products are used in a variety of surgical applications.

Lattice Biologics maintains its headquarters, laboratory and manufacturing facilities in Belgrade, Montana as well as offices in Phoenix, Arizona. The facility includes ISO Class 1000 clean rooms, and specialized equipment capable of crafting traditional allografts and precision specialty allografts for various clinical applications. The Lattice Biologics team includes highly trained tissue bank specialists, surgical technicians, certified sterile processing and distribution technicians, and CNC operators who maintain the highest standards of aseptic technique throughout each step of the manufacturing process. From donor acceptance to the final packaging and distribution of finished allografts, Lattice is committed to maintaining the highest standards of allograft quality, innovation, and customer satisfaction.

Lattice Biologics maintains all necessary licensures to process and sell its tissue engineered products within the U.S. and internationally. This includes Certificates to Foreign Governments from the U.S. Food and Drug Administration (FDA) and registrations for multiple countries, which allow the export of bone, tendon, meniscus, ligament, soft tissue, and cartilage products outside of the U.S.

Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.

Cautionary Statement on Forward-Looking Information:

Certain information contained in this news release constitutes forward-looking statements within the meaning of the safe harbour provisions of Canadian securities laws. All statements herein, other than statements of historical fact, are to be considered forward looking. Generally, forward-looking information can be identified by the use of forward-looking terminology such as planned, potential, future, expected, could, possible, goal, intends, will or similar expressions. Forward-looking statements in this news release include, without limitation: information pertaining to the Companys strategy, plans, or future financial performance, such as statements with respect to the Transaction, and other statements that express managements expectations or estimates of future performance. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of Lattice to be materially different from those expressed or implied by such forward-looking statements.

Forward-looking statements are necessarily based upon a number of factors and assumptions that, while considered reasonable by management as of the date such statements are made, are inherently subject to significant business, economic and competitive uncertainties and contingencies. The factors and assumptions that could prove to be incorrect, include, but are not limited to: that market prices will be consistent with expectations, the continued availability of capital and financing, and that general economic, market and business conditions will be consistent with expectations. The forward-looking statements are not guarantees of future performance. We disclaim any obligation to update or revise any forward-looking statements, except as required by law. Readers are cautioned not to put undue reliance on these forward-looking statements.

United States Advisory: The securities referred to herein have not been and will not be registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act"), and may not be offered, sold, or resold in the United States or to, or for the account of or benefit of, a U.S. Person (as such term is defined in Regulation S under the U.S. Securities Act) unless an exemption from the registration requirements of the U.S. Securities Act is available. This press release shall not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in the state in the United States in which such offer, solicitation or sale would be unlawful.

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Lattice Biologics to Evaluate Anti-Inflammatory Stem Cell Therapy Treatment of COVID-19 Lung Disease - BioSpace

A Second Person Has Been Cured of HIV – Nerdist

By Stem Cell Treatment

Although most of the news from the world of health and medicine has been quite bleak lately, there are still major strides being made in the sector in an effort to combat the worst illnesses that plague humankind. One such stride was just announced, and its certainly worth celebrating: A second person has been cured of HIV.

In a study published in the medical journal, The Lancet, which comes via Medical News Daily, researchers in London say theyve been able to cure a patient of HIV; meaning the patient tested negative for HIV for an extended period of time (30 months as of March, 2020) despite the lack of antiretroviral therapy.

The person whos been cured, Adam Castillejo, was formerly known only as the London patient in order to protect his identity. But Castillejo, who lives in London, came forward recently, and said that he aims to be an ambassador of hope.

The first person to be cured of HIV, Timothy Ray Brown, an American known originally as the Berlin patient, revealed his identity in 2010, saying that I wanted to do what I could to make [a cure] possible. My first step was releasing my name and image to the public. Brown lived and was treated in Berlin. Incidentally, he is technically the second Berlin patient because the results from treatment of the first one are debatable.

AIDS Policy Project with Timothy Ray Brown (third from left with sunglasses). Griffin Boyce.

Castillejo, as well as Brown, were cured of HIV not by antiretroviral medications, which are often able to drastically mitigate the effects, and transmission rate of, HIV, but rather by stem cell transplants from donor bone marrow. Both Castillejo and Brown hadand may still have, that is unclearcancer along with HIV, and were treated with the stem cell transplants primarily to tackle the former disease. (It seems in Castillejos case doctors and researchers were hoping to cure both simultaneously.)

Both Brown and Castillejo underwent a procedure known as a Hematopoietic stem cell transplantation (or HSCT), which involves injecting bone marrow stem cells from a donor, whos often times a parent or sibling, into the recipients bloodstream. Castillejos HSCT treatment was different from Browns, as well as many others, because it was performed with cells that expressed the CCR5 gene.

A video from the MD Anderson Cancer Center that gives a brief outline of how bone marrow stem cell transplants work.

In Castillejos case, stem cells with genomes that express the CCR5 gene were selected because of the fact that it allows for the production of the CCR5 protein: a protein that makes people far more resistant to HIV-1, which accounts for the vast majority of global HIV infections.

While Castillejo received stem cells that did express the CCR5 gene, Brown did notat least according to the study in The Lancet. In fact, according to a 2017 article in New Scientist (which says that Brown received cells with a mutated CCR5 gene, rather than an unexpressed CCR5 gene), some experts believe the curing of Browns HIV was actually due to a potential side effect of his procedure, known as graft-versus-host disease. According to New Scientist, these experts believe that the donor cells attacked Browns native, HIV-infected immune cells, subsequently killing off the virus.

In Castillejos case, on the other hand, it seems there was no graft-versus-host issue that could account for his diminishment of HIV infection levels beyond whats expected to be detectable. Instead, the authors of the study say that one of the implications here is that the Long-term remission of HIV-1 can be achieved utilizing these kinds of cells. The authors also say this method does not require total body irradiation, which would usually be required in cases like these to weaken a recipients immune system in order to allow them to accept donor cells.

An HIV-infected T cell. NIAID

Unfortunately, it seems the treatment that cured Castillejo of HIV is a nonstarter when it comes to mass deployment. There are fatal side effects associated with HSCT, with host-versus-graft chief among them, and doctors say that it should only be performed when there are no other options left.

Prof. Ravindra Kumar Gupta from the University of Cambridge in the U.K., the lead author of the study, told Medical News Daily that [Its] important to note that this curative treatment is high risk and only used as a last resort for patients with HIV who also have life threatening hematological [blood] malignancies.

But Gupta and the other authors of the study still appear to be optimistic that this stands as a proof-of-concept for the idea of using CCR5 gene editing to cure HIV on a larger scale. They warn in their study, however, that several barriers, including the need for increased gene editing efficiency and a lack of robust safety data, still stand in the way of something that could be used as a scalable strategy for tackling HIV.

What do you think about this method of treating HIV? Do you think gene editing will play a big role in curing HIV, or do you think there are other, more promising treatments worth pursuing instead? Let us know your thoughts in the comments.

Feature image: C. Goldsmith / Eliot Lash

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A Second Person Has Been Cured of HIV - Nerdist

Transcript: Disabled and out of money in North Korea – BBC News

By Stem Cell Treatment

This is a full transcript of Disabled and out of money in North Korea as first broadcast on 13 March and presented by Beth Rose

JITE- I got a few stares of course. I'm bald. I had a beard. I was in a wheelchair. I'm black. The first two that I went to said, "No, no, no, we probably can't do that." I didn't want to do something which was challenging for me only, rather than North Korea. Oh, well that's a tough place to go to.

[jingle: Ouch]

BETH-I've been so excited about bringing you this Ouch podcast. A few months ago I received an email. It said, "Hi Beth, a friend of mine, Jite Ugono has multiple sclerosis, or MS, and uses a wheelchair. He's just about to travel to North Korea. Would you like to talk to him?" "Yes," was my answer, "very much so."

I'm Beth Rose, and you're listening to the BBC Ouch podcast, and for a while Jite has been on my mind. From the day he flew to China to get his visa, to the five days he would spend in the country we know very little about. And finally, he's back. Also, just a quick note to say that this podcast was recorded long before the Corona virus outbreak.

[music]

BETH-Hello.

JITE-Hello, hi.

BETH-So how was the trip?

JITE-Everyone says surreal, but it was surreal. Being inside a communist country and being restricted. Also in a wheelchair, there are no provisions at all for wheelchair access and that kind of stuff. Most of the places I went to were only accessible by stairs, so they carried me, which was nice. And that's one of the good things about having a guide, because I had two guides and a driver.

BETH-So you said you were thinking about this trip a year ago. It's the kind of trip that most people won't even think you can do, so why did you suddenly decide to book your holiday to North Korea?

JITE-Well I've got MS so they said one of the treatments of MS could be stem cell therapy. So stem cell therapy involves chemo and the rest of it. I thought to myself why not do something as rare as stem cell therapy? It was almost like a redefinition of my identity. I didn't really want to be known solely because of MS or the treatment, because everyone's going to ask about the chemo. I wanted to do something else which was kind of equal and opposite.

BETH-It's quite rare, stem cell therapy for multiple sclerosis isn't it?

JITE-It is. I hadn't heard of it. Chemo for cancer, we know all about that, but as soon as she said chemo for this For me it was quite emotional because my mum died the year before of cancer and she went through chemo as well. It was a shock, but it was also some hope. It seems less bleak. What I have is Primary Progressive MS, a steady degradation of mobilities. And they have less treatment for that, so most other treatment comes for Secondary Remitting, when you have attacks and then you can recover.

BETH-So what does the chemo do?

JITE-Chemo reduces your immune system. So what they want to do is kind of knock out the immune system and then reintroduce the stem cells and then restart the immune system.

BETH-That sounds quite an intense treatment.

JITE-I was in hospital for a month. So I went in for chemo, I was in hospital for a week or so, first of all, came back out, did the injections, back into hospital for a month. It was tough going through, but easier when you do it in stages. You think, okay I'm going to do this chemo first, in ten days I'll do the injections. Bite size. So by the end of it it's like oh, I've done it. I think it taught me whatever I go through I have to be a bit more patient.

BETH-How long ago were you diagnosed with MS?

JITE-2009.

BETH-So you were quite young?

JITE-I'm 45 now, so yeah, the symptoms got worse maybe six or seven years ago in terms of difficulty walking. And that's the main thing. The first thing was the eyesight, so the eyes were playing up and I thought maybe I should go to the optician. It didn't really make a difference. So it got progressively worse. I did an MRI scan and then the consultant said, "Well, it could be MS." So I was kind of aware and I kind of knew that it was something quite serious. So when he came back and he said MS. You make a decision about how you're going to deal with it.

For me, it was you're not going to feel sorry for yourself because people go through worse. For me, it's only when I'm faced with stuff you realise you can do it. I didn't just want to survive. Because when you're diagnosed with stuff it's like getting through the day. Everyone says, "Oh, you're so brave. You went to work?" For me it's just one life, you can't spend it getting through the day, you want to do something else.

BETH-So was it when you were having your chemo when you were in hospital, the idea for North Korea?

JITE-It was actually the first consultation when she told me, "You're going to do stem cell therapy." They told me that I was going to be able to maybe walk with sticks and I thought, why waste it?

BETH-I feel like a lot of people would have had similar thoughts but maybe thought South of France would be quite nice?

JITE-It would have been challenging. If anyone said they were going to the South of France, oh okay. I didn't want to do something which was challenging for me only, rather than North Korea, oh well, that's a tough place to go to, regardless of whether you're in a wheelchair. It was important to me to do something which was challenging, not because of MS, not because of the wheelchair, but it was challenging.

BETH-So how do you go about booking a trip? Can you go to a travel agent?

JITE-I mean, that's what I did. So the first two that I went to said, "No, no, no. We can't do that, there's no access." And I was probably more determined. That's another lesson it taught me, it's more important for me that I wanted to do it. And no one was coming back to me to say, "Why don't you go?" So when the third person came back and said, "Actually, we could do that," the normal way of going to North Korea is through a group tour, with my condition anyway. You think about what the problems could be. Getting onto the coach. Holding people up.

So my tour was me on my own. I had two guides and a driver and that was it. They sorted out the visa to China and once you get to China you get the visa to North Korea from China.

BETH-Touching upon the issues of getting onto a bus, what is it like for you with MS? How does it manifest itself?

JITE-My balance is a problem. I can't really use my left leg at all. My eyesight's a problem. Maybe sometimes my memory and my vocabulary. They're difficulties which arose mainly because I did chemo. We know that the drugs are quite aggressive and concentrated, so they give you lots of water to dilute and because you're given that you're given drugs to help you relieve that stuff, so you're peeing like every ten minutes.

So it went down to probably once every hour and that became a problem and that affects your confidence, you're afraid to kind of go out, maybe there won't be toilets around, that's kind of what I was thinking about, going to North Korea.

BETH-Did you even know about that? Is there information about toilets or accessibility?

JITE-Not at all, not at all. It's only when I got there that I realised that the And sorry to go on about toilets, but it was important to me. [laughs] Okay, so in North Korea they had two types of toilets, they had the European toilets and then they had the Korean toilets, ground toilets, so you have to kind of balance, which I didn't even attempt. So everywhere we went to it was okay, "Is it a Korean toilet here or a European toilet?" Even the guides started to realise and started to know after a while.

BETH-I mean, that's such a gamble isn't it, not knowing the accessibility, not knowing what the toilet situation's going to be like. I'm guessing this was all in your mind?

JITE-Every problem has to have a solution. So before I went I'd got it up to you can pass an hour now, because I'd gone to the gym, I'd started doing core stuff, even in the plane, because it was ten and a half hours there. You think about the problems that you could face, it's personal of course, but also there are people around that can give you a hand.

And that was another thing, getting vaccinations was a problem, because when you do chemo and your immune system is low they don't advise that you have vaccinations. So I was intending to go to Korea in September but that was super close to my stem cell.

BETH-When you were flying, initially to China, what was going through our mind?

JITE-It was just getting through that first bit, hoping that someone's going to be there to meet me. The luggage I even took I had to make sure that I could carry. That's one of the solutions with a wheelchair, you're going to have to push the luggage as well so it can't be too big. Two pieces of hand luggage is what I took. That's what I was thinking about, I wasn't thinking about Pyongyang yet, I was thinking about how to get to China.

Beijing was packed, traffic everywhere. It was surprisingly western. The cars were German cars. In North Korea I had the guides, in China I didn't have guides, I had a person to take me from the airport to the hotel and that was it. So I didn't really have the confidence to kind of venture out. I got in a day before, so as soon as I landed in China I had to go and get the visa. As soon as you get the visa is when they give you a briefing, what you should and shouldn't do. The chap apparently had been doing it for 28 years, and no one had ever missed a briefing until me.

BETH-Ah! [laughs]

JITE-I mean, only because the person who picked me up said, "Oh, I can get the visa for you."

BETH-So they were being helpful, but actually

JITE-Yeah, so they went out and got the And I was appreciative, because getting in and out of the car was such a pain. And I am quite lazy naturally. If I can do without it then I won't do it, you know. So when they gave me an opportunity not to, oh okay. The travel agent contact in China was almost panicky on the phone, "No one's ever done this."

BETH-Wow, and I bet your heart was racing at that point.

JITE-To an extent, but I kind of knew what not to do. I mean, I'm not rude, and plus I'd seen stuff on YouTube and the guides tell you as well. So I was quite prepared. I flew into Pyongyang. The airport was a surprise. They only have a few planes that land for the day. They had one from Beijing, one from Shanghai and one from Moscow. There are soldiers everywhere, but the soldiers were, "Oh, look at this guy," I suppose maybe because I was a novelty in a sense. They'd never really seen someone in a wheelchair before. They were super helpful.

I'd met the guides at the airport as well. I got a few stares of course. I'm bald, and they have like five haircuts. I had a beard, I was in a wheelchair. I'm black. So all those things together.

BETH-So did you feel like you stuck out?

JITE-I didn't feel like I could relax, only because you feel like you're always on. I couldn't be anonymous, there's always someone watching, and that's tiring.

BETH-And did you feel like you were being watched by your guides?

JITE-Maybe the brief was to watch, but it is different when you have a relationship with people. So I didn't feel that way. I suppose they were constantly on about how great the leader is and after a while it got a bit tedious. Everyone walked around with badges. And it's difficult to tell because they spoke the language quite a bit. I don't know what they're saying.

BETH-They greeted you at the airport.

JITE-Yes.

BETH-Had they had disabled travellers before?

JITE-I don't think they had. What happens is that when you go on your own there is no camaraderie, I was mostly alone, but the advantage is you could probably get closer to people. There's good and there's bad about it.

BETH-What's it like, Pyongyang?

JITE-For me it was super quiet. I mean here we have adverts and stuff, people are selling you stuff all the time, there is different, you have pictures of the leaders surrounded by flowers and you have to respect that. If there's an image of a leader you can't really take a photo of it and you can't stand in front of it obscuring it. Or you can't crop it. Apparently they check people's phones to see what they've taken.

BETH-Did you take photos?

JITE-I took photos but they didn't check. But everywhere was empty. The place is set up for tourists but there are not many tourists. You go into a restaurant and there are people standing around. The restaurants are empty. It's bizarre.

BETH-So it's not really like a bustling city?

JITE-Not at all. Actually I went during King Il Sung who's the grandad of this present leader, it was his birthday, so there were two days of celebrations. I think there were more people on the street than normal, and then they had volunteers picking up stuff or gardening or I mean, because it's a communist environment they pay for everything but you have to work. They've got big roads, no cars.

BETH-Wow.

JITE-Yeah. The days were quite long. Maybe eight o'clock they'll come for me and then eight o'clock in the evening I'd finish. So there was always something to do and you were always with people. I think they had five channels, that was about it.

BETH-TV channels?

JITE-Five TV channels. On the channels they have the leader, Kim, pointing at stuff. He designed the theme park.

BETH-What's the tourist trail like?

JITE-There is an itinerary, so you would go to the war museum, flower exhibition. I went to their subway, it's the deepest subway in the world. So everything's the best in the world or the tallest in the world.

BETH-How did the subway compare to the tube?

JITE-It was more opulent. I only saw two of them and I think those are the two they show people, so maybe the others are less. There are chandeliers and stuff.

BETH-And the restaurants, you said you went into one, but they've got all the staff just waiting around?

JITE-Yeah, the restaurants seem to be for tourists, and because I was on my own, seven, ten people just standing around looking. I went to a casino, which was strange.

BETH-Oh, okay?

JITE-Yeah. But the casino was in the hotel. I think I was the only one in there. So when I went to North Korea I didn't take enough cash, and that was a problem obviously because no cards. So the guys were like, "You need some money? Go to the casino, you can change your money."

BETH-Oh, I thought you were going to say to like gamble and win.

JITE-At first I went to change money, but they didn't take sterling, they took US dollars and euros, but I didn't have either, so they allowed me to gamble, so I did.

BETH-Did you win? Did you get some money?

JITE-Yeah, I did. I don't want to get used to it. [laughs]

BETH-What game did you play?

JITE-Black Jack. I didn't know what was going on, but people around, they were almost cheering, and I was thinking by the time I won a hundred dollars I thought it's time to go, it's time to go. And everyone's around you willing you on and you don't want to disappoint them but you think okay, I'm going guys.

BETH-Is it expensive then, if you ran out of money and you're having to gamble to boost your-?

JITE-To boost. Okay, so I mean they have their own currency and they don't let you take the currency out.

BETH-I bet your guides quite enjoyed being in the casino.

JITE-The guides said, "Oh, we're not allowed in." Even when they came up to my hotel room I had to have Al Jazeera because that's the only English speaking channel, but they were almost transfixed. They were shaking their heads. Look around the world, look how happy we are type of thing. So you kind of understand why they would let Al Jazeera in, because Al Jazeera can be quite, look what's happening around the world, the protests here, the protests there.

BETH-And did you find people were willing to help you?

JITE-I think it was more because they see you as being vulnerable. "Oh, you're not comfortable, let me move your legs." So you always get somebody helping, which is not necessarily what you want all the time. Because you want to be able to be self-sufficient. Certainly in London people are a bit more patient to offer, "Okay, how can I help?" and then they stand back. In Korea it was, "Oh, we can do that for you." [laughs]

BETH-Did you see any other disabled people out and about?

JITE-No, I didn't.

BETH-No one at all?

JITE-I didn't at all. One of the guides was quite insistent on how great their society is. That's why they stay kind of thing, away from everyone else, and they obviously saw it as a good thing.

BETH-Oh, that's interesting. I was going some research, and there's a lot of reports from the UN and different charities where they say basically they send people away in an out of town community.

JITE-Yeah, they don't expect you to try. So maybe that was part of it, they were almost surprised that this person is doing something on their own.

BETH-And were they quite surprised how you just got on with everything?

JITE-Yeah, I suppose. Maybe they were. So even when I'd be going down the road people would lean over and look. They weren't rude about it. They would look, they were curious, but they weren't intrusive. And sometimes you look and they look away, except the kids, so the kids would be staring. But that's normal though, even in London you'll get kids staring. One of the guides took a video of me being lifted up the stairs, and it was quite tough to watch because you don't really see yourself as being vulnerable, except when you see it.

It's like hearing a recording of yourself and you think oh, do I sound like that? Or do I look like that? Am I really that vulnerable kind of thing? No wonder everyone helps. [laughs] It was tough to see. I didn't really see the footage until I got to the hotel and you kind of think, you know, is that how it is? They were helpful, and it sounds ungrateful almost, but it is what you think about.

It's a lack of confidence to think people only help you because you look so vulnerable. Maybe people are just nice. And that was one of the good things about going to North Korea. People say that Londoners are quite cold and I don't find that, Londoners can be helpful, and especially if you're patient enough. And MS for me does that, it allows you to be patient.

BETH-So what kinds of things is nice to have help for?

JITE-Probably getting in and out of cars. In London not so much, in London you kind of want to get strong. I know that I'm going to have to get in a car, and not everybody gives the same level of help, so you have to be self-sufficient. In North Korea there's no need. And I'm never going to be in North Korea again.

BETH-How did the access pan out? Because that was the big mystery wasn't it really? I mean, you had no idea.

JITE-It was just people lifting me. Only one place, the museum was difficult.

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Transcript: Disabled and out of money in North Korea - BBC News

Gene Therapy Reverses Heart Failure in Animal Model of Barth Syndrome – BioSpace

By Stem Cell Treatment

Boston Children's Hospital researchers used an investigational gene therapy to treat heart failure in a mouse model of Barth syndrome. Barth syndrome is a rare genetic disorder in boys that results in life-threatening heart failure. It also causes weakness of the skeletal muscles and the immune system. The disease is caused by a mutation of a gene known as tafazzin or TAZ.

In 2014, William Pu and researchers at Boston Childrens Hospital collaborated with the Wyss Institute to develop a beating heart on a chip model of Barth syndrome. It used heart-muscle cells with the TAZ mutation that came from patients own skin cells. This was able to prove that TAZ was the cause of the cardiac problems. The heart muscle cells did not organize normally and the mitochondria, the cells energy engines, were disorganized, resulting in the heart muscle contracting weakly. By adding healthy TAZ genes, the cells behaved more normally.

The next step was an animal model. The results of the research were published in the journal Circulation Research.

The animal model was a hurdle in the field for a long time, Pu said. Pu is director of Basic and Translational Cardiovascular Research at Boston Childrens and a member of the Harvard Stem Cell Institute. Efforts to make a mouse model using traditional methods had been unsuccessful.

Douglas Strathdees research team at the Beatson Institute for Cancer Research in the UK recently developed animal models of Barth syndrome. Pu, research fellow Suya Wang, and colleagues characterized the knockout mice into two types. One had the TAZ gene deleted throughout the body; the other had the TAZ gene deleted just in the heart.

Most of the mice that had TAZ deleted throughout their whole bodies died before birth, likely from skeletal muscle weakness. Of those that survived, they developed progressive cardiomyopathy, where the heart muscle enlarges and is less able to pump blood. The heart also showed signs of scarring similar to humans with dilated cardiomyopathy, where the hearts left ventricle is dilated and thin-walled.

The mice that lacked TAZ only in their heart tissue that survived to birth had the same features. Electron microscopy indicated that the heart muscle cells and mitochondria were poorly organized.

Pu and Wang and their team then used gene therapy to replace TAZ in the newborn mice and in older mice, using slightly different techniques. In the newborn mice the engineered virus was injected under the skin; in the older mice it was injected intravenously. The mice who had no TAZ in their bodies and received the gene therapy survived to adulthood.

In the newborn mice receiving the gene therapy, the therapy prevented cardiac dysfunction and scarring. In the older mice receiving the therapy, it reversed the cardiac dysfunction.

The study also showed that TAZ gene therapy offered durable treatment of the cardiomyocytes and skeletal muscle cells, but only when at least 70% of the heart muscle cells had taken up the gene via the therapy. Which the researchers point out that when the therapy is developed for humans, that will be the most challenging problem. You cant just scale up the dose because of inflammatory immune responses, and multiple doses wont work either because the body develops an immune response. Maintaining the gene-corrected cell is also a problem. In the heart muscles of the treated mice, the corrected TAZ gene stayed relatively stable, but slowly dropped in skeletal muscles.

The biggest takeaway was that the gene therapy was highly effective, Pu said. We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle.

Excerpt from:
Gene Therapy Reverses Heart Failure in Animal Model of Barth Syndrome - BioSpace

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