National ALS Advocacy Day

  • Tuesday May 16, 2017 is National ALS Advocacy Day
  • Mark Your Calendar and Get Involved!
  • Read on to Find Out Why Involvement Matters

Lou Gehrig (1903-1941). Taken from Wikipedia.org

Amyotrophic lateral sclerosis (ALS) is more commonly referred to in North America as “Lou Gehrig disease.” Henry Louis “Lou” Gehrig was a record-setting baseball All-Star for the New York Yankees from 1923 through 1939, when he voluntarily took himself out of the lineup to stunned fans after his play was hampered by ALS. Sadly, Mr. Gehrig died only two years later, which indicates the rapidity of ALS disease progression.

ALS was first found in 1869 by French neurologist Jean-Martin Charcot, but it wasn’t until Lou Gehrig’s affliction that national and international attention was brought to the disease. ALS is now known to be a group of neurological diseases that mainly involve the degeneration of nerve cells (neurons) responsible for controlling voluntary muscle movement, like chewing, walking, breathing and talking. Motor neurons are nerve cells that extend from the brain to the spinal cord and to muscles throughout the body.

Taken from irelandms.com

The disease is relentlessly progressive, meaning the symptoms get continuously worse over time. Both the upper motor neurons in the brain and the lower motor neurons in the spine degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch, and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.

Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years.

It is generally estimated there are over 30,000 people living with ALS in the United States at any given time, and that the number worldwide is around 450,000. Someone is diagnosed with ALS every 90 minutes. The life-time incident rate for an average person is often estimated at between 1-in-400 to 1-in-600 people—an incidence rate comparable to that for multiple sclerosis.

Who Gets ALS and Why?

Following are some reliable facts that I selected from an authoritative NIH website for ALS:

  • ALS affects people of all races and ethnic backgrounds.
  • Caucasians and non-Hispanics are most likely to develop the disease.
  • Although the disease can strike at any age, symptoms most commonly develop between the ages of 55 and 75.
  • Men are slightly more likely than women to develop ALS. However, the difference between men and women disappears with aging.
  • Military veterans are about 1.5 to 2 times more likely to develop ALS, and is recognized as a service-connected disease by the U.S. Department of Veterans Affairs.
  • 90% of ALS cases are considered sporadic, i.e. the disease seems to occur at random.
  • 10% of ALS cases are familial, i.e. an individual inherits the disease from his or her parents.
  • Mutations in more than a dozen genes have been found to cause familial ALS

How is ALS treated?

Riluzole. Taken from healthtap.com

No cure has yet been found for ALS. However, there are treatments available that can help control symptoms, prevent unnecessary complications, and make living with the disease easier. In 1995, the FDA approved riluzole (Rilutek), the only disease-modifying drug to date for ALS. Riluzole has multiple neural mechanisms of action, and is believed to reduce damage to motor neurons by decreasing levels of glutamate, which transports messages between nerve cells and motor neurons. Unfortunately, clinical trials in people with ALS showed that riluzole prolongs survival by only a few months.

BrainStorm Cell Therapeutics & NurOwn®

In researching clinical trials for hopefully much more effective therapies for ALS, I came across a company in Israel named BrainStorm Cell Therapeutics Inc. (BCTI) that offers a form of stem cell therapy for ALS that appears to be quite promising. Following is a short synopsis of what I found.

Space-filling model of BDNF. Taken from Wikipedia.org

BCLI has developed a patented stem cell-based technology that delivers a growth factor that can help neurons live longer at or near the site of injury or damage. More specifically, a mesenchymal stem cell isolated from an ALS patient is grown in a cell culture under certain conditions to produce a differentiated phenotype that secretes brain-derived neurotrophic factor (BDNF) at a level at least five-times greater than normal. The term “factor” is generic in biomedical parlance, and in the case of BDNF refers to a protein pictured to the right.

After these “super secreting” cells are obtained ex vivo, they are reintroduced (aka implanted) into the same ALS patient (i.e. an autologous transplant; see schematic diagram) wherein BDNF acts on neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.

Taken from Byrne JA. Overcoming clinical hurdles for autologous pluripotent stem cell-based therapies. OA Stem Cells 2013 Sep 01;1(1):3.

Details for this cell-harvesting, ex vivo differentiation, selection, and implantation can be read in this 2014 article by BCTI in Clinical Translation Medicine. BCTI has registered these differentiated BDNF-secreting cells as NurOwn®, which I assume is intended to sound bit like “your own”—to reflect the autologous nature of the transplant—and be a linguistic blend of neuron and own. In any case, the important point is that safety and efficacy have been reported in a recently published Phase 1/2 and 2a open-label, proof-of-concept studies of patients with ALS at the Hadassah Medical Center in Jerusalem, Israel.

In the Phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT), i.e. via the spinal cord. In the Phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous BDNF-secreting cells. Interested readers can consult this publication for details, but the bottom line, if you will, was that the possible clinical benefits would be hopefully confirmed in an upcoming clinical trial.

My further research on this led to a February 2017 press release by BCTI announcing that City of Hope’s Center for Biomedicine and Genetics (CBG) in Duarte, California will produce clinical supplies of NurOwn® adult stem cells for the BCTI’s planned randomized, double-blind, multi-dose Phase 3 clinical study in patients with ALS. It added that CBG is expected to support all U.S. medical centers that will be participating in the Phase 3 trial.

A second February 2017 press release by BCTI announced an agreement with Centre for Commercialization of Regenerative Medicine (CCRM) in Toronto, Canada to support the market authorization request for NurOwn® and explore the opportunity to access Health Canada’s early access pathway for treatment of patients with ALS as early as 2018.

Other ALS Clinical Studies

My “go to” authoritative source of reliable information about clinical trials is NIH’s ClinicalTrials.gov website that has an updated database that can be searched and filtered in many ways. When I searched for ALS clinical trials that were recruiting patients, I was heartened to find over 180 studies that can be perused via this link. For each study, there is information about purpose, study design and measures, eligibility, contacts and locations.

Incidentally, as regular readers of my blog will know, modified mRNA (mod mRNA) therapeutics is a relatively new and very promising modality for treating diseases that respond to providing or supplementing proteins. Given that DNA vectors encoding BDNF mRNA are readily available, I’m hoping that a mod mRNA for BDNF will soon be investigated as yet another avenue of treatment for ALS.

Advocate for ALS!

Taken from alsa.org

The ALS Association (ALSA) has the stated mission “to discover treatments and a cure for ALS, and to serve, advocate for, and empower people affected by ALS to live their lives to the fullest.” ALSA’s website offers various ways for any individual to become an advocate for ALS, such as becoming informed and donating much needed money or time, participating in the Walk to Defeat ALS® that draws people of all ages and athletic abilities together (see picture) to honor the courageous souls who are affected by ALS, to remember those who have passed, and to show support for the cause.

One of my long-time friends has recently been diagnosed with ALS, which in part led me to research this blog to help inform him, and led me to find a Walk to Defeat ALS® in which to participate. I encourage you to do advocate for ALS in whatever way you wish and are able.

As usual, your comments are welcomed.

Nanobombs for Light-Activated MicroRNA Drug Delivery

  • Nanoparticles Designed to “Explode” Upon Irradiation with Light
  • Light Used Can Penetrate Skin and Tissue
  • Nanoparticle “Cargo” of MicroRNA Released Locally, Where Needed 

Every once in a while the title of a publication grabs my attention so much that I just have to read it, and that’s what happened when I read this one A Near-Infrared Laser-Activated “Nanobomb” for Breaking the Barriers to MicroRNA Delivery.

Taken from ajamtafireworks.com

My interest was primarily piqued by the word ‘nanobomb,’ which I had never heard of even though I consider myself quite well-read scientifically. Moreover, microRNA (miRNA) and drug delivery are both currently trending hot topics. I couldn’t find an eye catchy image of a nanobomb other than fireworks by this name sold in India, which are oddly touted as being “pollution free”! But I digress…

Delivery of miRNA and other types of nucleic acid-based drugs continues to be perhaps the biggest challenge facing successful clinical development of this broad new class of drugs. In that regard, an expert review titled Nucleic acid delivery: the missing pieces of the puzzle?, written by my good friend and long-time collaborator Prof. Frank Szoka (UCSF), is a “must read” for those of you who are interested in further details and perspectives by an expert.

Prof. Xiaoming He. Taken from bme.osu.edu

Another “hook” in the nanobomb article’s title was its use of lasers, which are also trending in biomedical or biotechnological applications. So, all of this taken together, led me to request a pdf from the corresponding coauthor, Prof. Xiaoming He at Ohio State University, who promptly complied. Since it’s a pay-to-read publication, I’ve tried my best to convey the essence of this work in what follows.

Symphony of Science

Like a symphony, which is an elaborate musical composition for full orchestra, I learned that Prof. His nanobombs for laser-induced drug delivery are also quite elaborate and composed of a full array of scientific principles. To my surprise, a Google Scholar search of the term “nanobomb” gave a large number—more than one hundred—of items that included a wide variety of ways to use nano-size, i.e. sub-micron materials and light to somehow “blow up” or otherwise kill diseased cells, and thus fall under the umbrella-term photodynamic therapy.

Carbon nanotubes (~100 nm diameter) seen through an electron microscope. Taken from item.fraunhofer.de

For example, there’s a report in 2005 coauthored by Eric Wickstrom—who coincidentally is a friend of mine from early antisense oligo days—on the first application of single-wall carbon nanotubes (SWCNT) as potent therapeutic nanobombs for killing breast cancer cells in vitro. This is accomplished by adding water molecules into SWCNTs, which then get adsorbed on target cells for 800-nm (red) laser light irradiation to vaporize the entrained water.

A more elaborate rendition of nanobomb drug delivery was published in 2013 by Lu et al., who reported that intracellular gold nanoparticles under laser irradiation generate “nanobubbles” that can kill cells. To formulate a targeting gold nanoparticle as a cancer cell-specific “nanobomb,” a 31-nt DNA aptamer was conjugated to the gold surface. While biological results from this approach have yet to be published, there’s a good tutorial on the properties and applications of gold nanoparticles that are commercially available in discrete sizes, as seen here:

Taken from simaaldrich.com

Symphonic Variations of Science

This section heading extending my musical metaphor for nanobomb drug delivery is meant to convey the fact that the study by Prof. He and his coworkers featured herein is a symphony-like variation of photodynamic therapy composed of many parts. This work stands out—in my opinion—as being a remarkably comprehensive proof-of-concept involving lots of in vitro data and, more importantly, compelling in vivo animal results. I think you’ll “tune in”—musical pun intended—on this as I now summarize the complex scientific symphony by He and coworkers pictured below.

(A) Three agents are encapsulated inside nanoparticles: microRNA-34a (miR-34a) anti-mRNA drug for gene therapy of prostate cancer stem cells, indocyanine green (ICG) for absorbing laser light, and ammonium bicarbonate for gas generation under heating. (B) Laser light causes the nanoparticles to expand, penetrating the cancer cell’s endosomal/lysosomal barrier (green circles), blowing up cancer cells (yellow), and releasing miR-34a to inhibit protein CD44, which is crucial for cancer stem cell survival. Credit: Hai Wang et al./Advanced Materials. Taken from kurzweilai.net

What’s the Nanobomb?

The top part of the above depiction labeled (A) doesn’t do justice to the elegant methodology used to prepare the water-in-oil-in-water (W-in-O-in-W) double-emulsion nanobomb, so interested readers will have to consult the publication by He and coworkers for details. However, as shown in A, the nanobomb’s active components are indocyanine green (ICG), ammonium bicarbonate (NH4HCO3) and microRNA-34a (miR-34a), the latter of which I found is a single-stranded 22-nt RNA rather than the misleading drawn double-stranded species. Chitosan’s amino groups form a polyplex with miRs like miR-34a.

I also found many references to miR-34a as an anticancer agent, and in this instance it serves to negatively regulate CD44 overexpression, which is associated with survival and growth of prostate cancer stems cells (CSCs) as previously studied by a number of other groups.

Indocyanine green (ICG). Taken from Wikipedia

Having said this, the real novelties of this nanobomb are—in my opinion—its “ignition” and “explosive” materials, namely ICG and NH4HCO3, respectively. Some among you may recognize from the name or structure of ICG that it’s a “chemical cousin,” so to speak, of cyanine-3 and cyanine-5 dyes popular for labeling, which BTW are now available from TriLink as NHS esters upon inquiry.

The ICG dye is used to absorb laser light and convert the light’s energy into heat, which then causes NH4HCO3 to very rapidly generate CO2 and NH3 gases and thus release miR-34a (as depicted in part B of the above cartoon from He and coworkers). This “release” aspect deserves the following further comments.

Why’s a Nanobomb Needed?

This rhetorical question relates to the “D-word,” i.e. delivery of miR (or other classes of oligo agents) into a cell’s cytoplasmic compartment where it is intended to block target mRNA expression after its release from the endosome/lysosome compartment, as depicted in B above. The following electron micrograph shows what these sub-compartments look like.

Electron micrograph of endosomes in human HeLa cells. Early endosomes (E), 5 minutes after internalization; late endosomes/ multivesicular bodies (M) and lysosomes (L) are visible. Bar, 500 nm. Taken from Wikipedia.com

As depicted by He and coworkers, laser light via ICG is used to “ignite” or trigger “explosive” release of miR-34a from these compartments, rather than rely on natural phenomenon or use of pH-sensitive triggering mechanisms. For those of you who are not familiar with the endosome/lysosome compartment, details can be found in the aforementioned review by Prof. Frank Szoka, which was coauthored by Juliane Nguyen.

Is the Nanobomb Effective In Vivo?

Saline (control); HLPP = formulation; miR-34a (R) unformulated plus laser light (L); HLPP with ICG (I) and NH4HCO3 (A) plus L; HLPP with A and R plus L; HLPP with I and A and R plus L. Taken from He and coworkers.

Prof. He and his coworkers carried out extensive controlled experiments in vitro and in vivo to assess efficacy (as well as biodistribution and safety) of their nanobombs, and to me the most compelling data are shown below. Briefly, mice capable of harboring tumors derived from subcutaneously placed human prostate CSCs were treated with various formulations or control, and afterwards the extent of tumor growth was accessed in various ways including by tumor weight. It’s obvious in (C), shown below, that the only statistically significant (*) effect was obtained by the nanobomb formulation.

But is This Nanobomb Practical?

Here’s what He and coworkers state with regard to the scope and practicality of their nanobomb approach:

“Although the tissue penetration of the NIR [near infrared laser] is limited to less than ~1 cm and multiple polymers are needed for preparing the nanosystem, NIR could be delivered into deep tissue using minimally invasive approaches [e.g. endoscopy] and the preparation of the nanosystem using the double-emulsion method is quite straightforward. Therefore, the present study demonstrates the great potential of the NIR laser-activated “nanobomb” for microRNA delivery to achieve augmented cancer therapy.”

Time will tell what aspects of this approach will ultimately be reduced to practice in the clinic and/or lead to an approved photodynamic therapy for cancer. However, in the meantime, I’m betting that it will also “ignite” others to explore variations on this symphony of science.

As usual, your comments are welcome.

Postscript

After this blog was written, Jalani et al. published a paper titled Photocleavable Hydrogel-Coated Upconverting Nanoparticles: A Multifunctional Theranostic Platform for NIR Imaging and On-Demand Macromolecular Delivery. This work is conceptually related—in my opinion—to the above nanobombs in that low energy red-light-absorbing nanoparticles emit higher energy UV light (i.e. photon upconversion) to simulataneously image and release drugs specially absorbed on these nanoparticles. This NIR light penetration, UV imaging, and drug release are said therein to be effective down to a depth of ~2 cm of tissue, which is twice that reported above by He and coworkers.

Chinese Scientists to Pioneer First Human CRISPR Clinical Trial

  • Chinese Team Begins First CRISPR-Based Anticancer Immunotherapy Clinical Study
  • US Consortium’s CRISPR Clinical Study OK’d by NIH Panel
  • Survey Indicates More Worry than Enthusiasm for Gene-Editing in Babies
Taken from jeantet.ch

Taken from jeantet.ch

Regular readers of my blog will recall a number of previous postings on gene editing using CRISPR-Cas9 (aka CRISPR), which has rapidly become the hottest trend in nucleic acid-based biotechnology and medical research. That opinion is partly based on the fact that this relatively new technology has already amassed thousands of publications, including 1,250 in 2015 alone! Additional evidence follows from the numerous start-up and established biopharma companies pursuing CRISPR-based therapeutics, which is “the biggest biotech discovery of the century” according to one report.

Now, even more exciting developments for CRISPR are on the horizon. Chinese researchers are poised for the first human clinical trial using CRISPR, and an analogous study in the US awaiting FDA approval. Both of these trials involve forms of cancer immunotherapy, which is a very hot field in itself, and is briefly introduced in the next section.

Cancer Immunotherapy

Cancer immunotherapy is the use of the immune system to treat cancer either actively, passively, or by a combination of these approaches, which exploit the fact that cancer cells often have macromolecules on their surface that can be detected by the immune system (aka tumor-associated antigens, TAAs). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs, whereas passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines.

Numerous antibody therapies have been approved by the FDA and other regulatory authorities worldwide. In contrast, active immunotherapies, which usually involve the removal of immune cells from the blood or from a tumor for reintroduction to the patient, have lagged in such approvals. In fact, the only US-approved cell-based therapy is Dendreon’s Provenge®, for the treatment of prostate cancer. A recent series of NY Times articles highlights some powerful examples of cancer immunotherapy, especially from the perspective of interviews with patients and their physicians.

Taken from howitworksdaily.com

Taken from howitworksdaily.com

For the purpose of this blog, I’ll add that adoptive T-cell therapy is a form of passive immunization by the transfusion of T-cells, which are found in blood and tissue and usually activate when they find “foreign” pathogens. These pathogens can be either infected cells, or antigen presenting cells present in tumor tissue, where they are known as tumor infiltrating lymphocytes. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumor death.

As depicted below, T-cells specific to a tumor antigen can be removed from a tumor sample or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the resultant cells being reinfused. Importantly, activation can take place through genetic engineering, such as gene editing by CRISPR.

Cancer specific T-cells can be obtained by fragmentation and isolation of tumor infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer). Taken from Wikipedia.org

Cancer specific T-cells can be obtained by fragmentation and isolation of tumor infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer). Taken from Wikipedia.org

CRISPR Goes Clinical in China

As I write this post, Chinese scientists at Sichuan University’s West China Hospital in Chengdu will reportedly become the first in the world to inject people with cells modified using the CRISPR gene-editing method. This landmark trial will involve patients with metastatic non-small cell lung cancer who have not responded to chemotherapy, radiation therapy and/or other treatments.

The team will extract T cells from the blood of the trial participants and then use CRISPR to knock out a gene encoding a protein called PD-1 that normally regulates the T cell’s immune response to prevent it from attacking healthy cells. As depicted below, this so-called checkpoint has been targeted by small molecule inhibitors (anti PD-1), but with somewhat limited success so far—notably including failure of a would-be billion-dollar drug (Opdivo®) recently reported by Bristol-Myers Squibb. Nevertheless, the presently envisaged PD-1 gene-edited cells will be amplified in the lab and re-introduced into the patient’s bloodstream to circulate and, hopefully, attack the cancer.

Taken from smartpatients.com

Taken from smartpatients.com

Potential Concerns of CRISPR Clinical Trials

While the Chinese trial may be groundbreaking, it is not without risk. There is concern that the edited T-cells could attack normal tissue as it’s well documented that CRISPR can result in gene edits at the wrong place in the genome. To help mediate this risk, the T-cells will be validated by biotechnology company MedGenCell—a collaborator on the trial—to ensure that the correct gene is knocked out before the cells are re-introduced into patients.  Since the primary purpose of this phase one trial is to determine if the approach is safe, participants will be closely monitored for side effects, and researchers will pay close attention to biological markers in the blood.

Some may say that this type of trial in humans is premature, but China has always tried to be a leader in CRISPR research. Carl June, a clinical researcher in immunotherapy at the University of Pennsylvania in Philadelphia explains, ‘China places a high priority on biomedical research.’ And Tetsuya Ishii, a bioethicist in Japan, is quoted in Nature magazine as saying that ‘When it comes to gene editing, China goes first.”

Initial CRISPR Clinical Trial in USA Awaiting Review Board and FDA Approvals

While the Chinese team seems positioned to be the first to conduct a CRISPR clinical trial, the US isn’t far behind. As reported earlier this summer, the Recombinant DNA Research Advisory Committee (RAC) at the NIH has approved an analogous—but genetically more complex—proposal to use CRISPR-edited T cells for cancer immunotherapy. The RAC reviews all proposals for human trials involving modified DNA that are conducted in the United States, and the investigators now have to convince review boards at their own institutions, and the FDA, to allow the trial. This will hopefully be done by the end of 2016.

The proposed trial is a collaborative effort involving the University of Pennsylvania, M.D. Anderson Cancer Center in Texas, and the University of California, San Francisco. This trial will be funded by a $250-million immunotherapy foundation formed in April 2016 by former Facebook president Sean Parker. According to a news item in Nature, The University of Pennsylvania will produce the edited cells, and will recruit and treat patients alongside the collaborating medical centers in Texas and California.

In this study, researchers will perform three CRISPR edits with T cells from patients with several types of cancers: 1. a gene for a protein engineered to detect and target cancer cells will be inserted, 2. a natural T-cell protein that could interfere with this process will be removed and 3. the gene for a protein that identifies the T cells as immune cells and prevents the cancer cells from disabling them will be removed. The researchers will then infuse the edited cells back into the patient.

Both of the studies being performed by the Chinese and US teams are very exciting to me. I will be paying close attention to the progress of these studies over the next few months and hope to report back to you with some very interesting and ground breaking results.

Survey Indicates Public Concern in the US About Gene Editing in Babies

A Pew Research Center pole focusing on concerns about gene editing was recently reported in Nature. The poll surveyed more than 4,700 people in the United States and the results indicate that more people are concerned than enthusiastic about gene editing.

The quadrants below (from 0-100%) show responses to the question, “How worried or enthusiastic do you feel about gene editing to reduce disease risk in babies?”

Taken from nature.com

Taken from nature.com

While these findings speak for themselves, I hasten to add that this same pole also asked “Have you heard or read about this topic?” The following replies (in quadrants from 0-100%) indicate that a substantial percentage of respondents who have not at all read about gene editing nevertheless expressed either worry or enthusiasm for gene editing. Ditto for those who read a little about gene editing.

babies

It would seem, then, that we should take this poll with a grain (or two) of salt as it apparently includes a substantial amount of uninformed opinion. This is not too surprising given the complex nature of gene editing and it’s relatively new position in research. We can see from the results of this poll that a significant amount of education may be needed to garner increased public support for gene editing. Hopefully, the results of the studies highlighted above will begin to pave this road.

Hope for the Best but Expect Complications

This section heading, which summarizes my parting comments about the advent of CRISPR-enabled clinical trials, is based upon my having participated in several decades of research on nucleic acid-based concepts for radically different approaches to traditional small-molecule therapeutics. First was the idea of using chemically modified antisense oligonucleotides to block gene expression, which encountered non-specificity issues, low potency, delivery, and a host of other issues that took two decades to sort through. Then there was the idea of using chemically modified short-interfering RNA (siRNA) for modulating gene expression via RNA interference (RNAi). This, too, encountered similar problems in reaching the clinic. Ditto for anti-microRNAs (antagomirs).

I’m hoping that CRISPR-based therapies meet with success far faster—and prove to be affordable to society. I won’t, however, be surprised if progress is slow—and quite expensive.

Are you excited about potential CRISPR-based therapies? Do you have concerns about their safety and efficacy? Do you believe the general public is ready to accept gene editing therapies? Please share your thoughts as your comments are always welcome.

Anti-Antisense Makes Sense

  • Antisense Oligos Blocking Antisense RNAs Makes Proteins for Therapeutics
  • New Antisense Approach is Analogous to (-1) x (-1) = 1
  • Drug Company OPKO-CURNA is Taking This Approach to the Clinic

I apologize for the somewhat cryptic headline and mathematical byline for this blog, but they really do encapsulate the following: the underlying molecular biology involves a novel antisense oligo approach to “turn on” a protein, in contrast to all previous use of an antisense oligo to “turn off” a protein. I’ll rationalize the mathematical analogy later.

Taken from nature.com

Taken from nature.com

Recognizing the potential therapeutic value of this “turn-on” mechanism, a startup company with the quirky name cuRNA—a contraction for “cure” and “RNA”—was founded, and was acquired by OPKO—a health care conglomerate—and renamed OPKO-CURNA.

What follows is a condensed version of the full story of yet another example of how basic discoveries in nucleic acid research have “morphed” into new therapeutic strategies, which in turn lead to the genesis of small start-ups that oftentimes get acquired by bigger pharma companies. All of these kinds of stories include variations on a theme that are both informative and interesting—in my opinion.

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Point-of-Care PCR 2.0

  • Ubiquitome Quickens Pace of POC Apps for Its Freedom4
  • Cepheid Unveils its POC Diagnostics System
  • Hopkins Crew Brews “Coffee Mug-Sized” Gizmo for Fully Automated Chlamydia Testing
Kiwi Dr. Jo-Ann Stanton holding Ubiquitome’s Freedom4 at Tri-Con 2015

Kiwi Dr. Jo-Ann Stanton holding Ubiquitome’s Freedom4 at Tri-Con 2015

Regular readers of this blog will recall a recent byline exclaiming “Honey I Shrunk the qPCR Machine”, which spotlighted the unveiling of startup company Ubiquitome’s first point-of-care (POC) product—Freedom4—developed in New Zealand. Up until then, this far away—for me—exotic island country brought to mind folks fondly nicknamed Kiwi—after the native flightless bird, not Chinese fruit. Mightily impressed by this tiny but powerful qPCR device, I vowed to thereafter keep an eye on these Kiwis’ democratized POC apps enabled by its nifty handheld 4-sample high-performance qPCR device.

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Liquid Biopsies Are Viewed as “Liquid Gold” for Diagnostics

  • Invasive Needles and Scalpels Seen as Passé
  • Noninvasive Sampling Advocates Focusing on Circulating Tumor Cells (CTCs) 
  • New Companies are Pursuing the Liquid Biopsy “Gold Rush”

Biopsy Basics

Ultrasound is a real-time procedure that makes it possible to follow the motion of the biopsy needle as it moves through the breast tissue to the region of concern, as discussed elsewhere (taken from oncopathology.info via Bing Images).

Ultrasound is a real-time procedure that makes it possible to follow the motion of the biopsy needle as it moves through the breast tissue to the region of concern, as discussed elsewhere (taken from oncopathology.info via Bing Images).

As defined in Wikipedia, a biopsy is ‘a medical test commonly performed by a surgeon or an interventional radiologist involving sampling of cells or tissues for examination.’ Biopsies can be excisional (removal of a lump or area), incisional (removal of only a sample of tissue), or a needle aspiration (tissue or fluid removal). Despite the value of these traditional types of biopsies, they are more or less invasive, lack applicability in certain instances, and require accurately “going to the source” of concern, as pictured to the right, for ultrasound-guided breast cancer biopsy. Better methodology is highly desirable and is the topic of this post. By the way, if you want to peruse a lengthy list of scary risks associated with various type of common invasive biopsies, click here to see what I found in Google Scholar by searching “incidence of complications from biopsies.”

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Drug Developer’s Dream-Come-True May Be Patient’s Nightmare

  • HCV ‘Miracle’ Cure’s $84,000 Price Tag Causes Significant Controversy
  • 2014 Sales of the Drug Register Over $10 Billion
  • Competition is Rising, but Prices aren’t Getting Lower
  • Hepatitis C Vaccination Seems Elusive

Having been involved in drug discovery and development for many years, I can assure you Gilead’s new drug, Sovaldi™, is truly a drug developer’s dream come true. Solvaldi™ (sofosbuvir) is a drug used to protect against hepatitis C virus (HCV). Compared to other antiviral or anticancer agents, this nucleotide-analog prodrug, pictured below, produces an extraordinarily high cure rate of well over 90% in HCV-infected patients after only a 12-week (84-day) course of treatment that involves simply taking only one pill per day. That’s amazing!

Stereochemical structure of sofosbuvir (taken from positivelyaware.com via Bing Images).

Stereochemical structure of sofosbuvir (taken from positivelyaware.com via Bing Images).

This miracle-like drug, however, comes at a seemingly very high price: a single pill costs $1,000—adding up to a total treatment cost of $84,000 per patient. The estimated cost of manufacturing this pill is only $68-$136, so there’s been quite a bit of media coverage devoted to discussing why the cost to consumers is so high, how this effects drug payment systems, and strong concerns about the viability of treatment in underdeveloped countries where HCV infection is relatively high. This seeming price-gouging is also causing a budget dilemma for whether or not to treat U.S. prisoners who have rampant rates of HCV infection. Before getting to these prickly issues, let’s start at the beginning with the discovery of this “drug developer’s dream-come-true.”

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Top Picks from Tri-Con 2015

  • “Honey I Shrunk the qPCR Machine” Tops Presentations
  • High School Student Wins Popular Vote for Best Poster
  • BioFire Defense FilmArray is More Interesting Exhibitor
  • Extra Bonus: Swimming with the Sharks

The 22nd International Molecular Medicine Tri-Conference—better known as Tri-Con—took place on Feb 15-20 in San Francisco, where I and 3,000+ other attendees from over 40 countries took part in a jam-packed agenda. In this blog I’ll briefly share my top 3 picks—and an “extra bonus”—but first some insights into the challenges involved in navigating a large conference like this.

The first challenge was scoping out four simultaneously occurring “channels”—diagnostics, clinical, informatics, and cancer—to select as many interesting items as possible from all the presentations (500), panel discussions (30), posters (150), and free “lunch-nars.” The new Tri-Con’15 app with a word and name-searchable agenda (including abstracts) made this easier than previous years. I was even able to put selected items into a calendar/to-do list with 15-min reminder alarms—very slick and convenient. Every big conference should have an app like this!

The second challenge came once I was physically onsite. It took a bit of effort to navigate from one room to another in the huge, multi-room Moscone Center without GPS guidance. I was also struggling to make it to the talks and events on time without getting hijacked by bumping into friends—which happened a lot.

The third and final challenge had to do with posters. Given all of the other exciting options during the conference, I really had to focus to stay on-task and make sure I was present at my poster at the specified times, yet alone try to get around to the other posters of interest. This was definitely not easy, since my poster entitled Pushing the Limits of PCR, qPCR and RT-PCR Using CleanAmp™ Hot Start dNTPs attracted a steady stream of interested visitors. But that’s a great challenge to have, so I can’t complain too much.

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Broccoli May Reduce Symptoms of Autism

  • Study Reports Remarkable Response to Broccoli Extract
  • Autism Advocacy Group Offers Cautious Optimism
  • Father/Son Cozy Combo for Commercialization Pathway

I’m quite sure that most of you, like me, are very familiar with various ways to improve or preserve your well-being by doing such things as adopting a Mediterranean diet, eating less red meat and more chicken, fish and beans, drinking a glass of red wine, and so on. And like me, you might be somewhat skeptical of the actual benefits but, nevertheless, try to follow some of these recommendations—especially if you enjoy a nice merlot.

A small new study found that a chemical in broccoli sprouts may help alleviate the symptoms of autism. Credit: James Baigrie/Getty Images. Taken from ABC News.

A small new study found that a chemical in broccoli sprouts may help alleviate the symptoms of autism. Credit: James Baigrie/Getty Images. Taken from ABC News.

Having said that, I was tempted to ignore a very recent ABC News story with a headline that read “Broccoli Sprout Extract May Help Curb Autism Symptoms” were it not for two things: firstly, autism is a very common and challenging disorder, and secondly the story referred to a publication in the Proceedings of the National Academy of Sciences (PNAS), which is a very highly regarded scientific journal. So, let’s consider some facts about autism, and then delve into the publication.

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You and Your Microbiome – Part 2

  • Global Obesity Epidemic is Linked to Gut Microbiome
  • DNA Sequence-Based Microbiomes Accurately Associate with Obesity
  • Blue Agave Margaritas Contain Beneficial Gut Microbes
  • Investments in Microbiome-based Therapies on the Rise, but is there Hype?

Last August, my post entitled Meet Your Microbiome: The Other Part of You dealt with growing recognition that trillions of microbes—mostly bacteria but also fungus—reside in and on each of us, and influence our health status. Moreover, the compositions of these microbiomes change with our diet, what we drink or breath, and who we contact—family, pets, and close friends.

Since then, I’ve collected a string of microbiome articles delving into the implications of this dynamic, symbiotic relationship, and selected some topics that I thought were “blogworthy.” This Part 2, as it were, focuses on overweight/obesity, microbiome therapy, and burgeoning business opportunities.

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