Research

Telling the Quacks from the Cures

Published on Mon, 05/15/2017

Many of you have seen posts on social media about treatments they have received in other countries or heard about through friends, that include everything from dietary aids to gene therapy, and want to know how you can assess the possible benefits and risks of these "treatments." In this complicated therapy environment, how can patients make decisions about whether an available treatment or therapy is safe and effective? How can you tell the quacks from the cures?

In Pursuit of a Cure

MDF is committed to the pursuit of improved Care and a Cure for people living with myotonic dystrophy (DM). We’re a non-profit advocacy organization and there is no other reason for our existence. In pursuit of a cure, we fund research, support infrastructure projects for therapy development, recruit investigators to work on DM, educate drug regulatory agencies, and work with companies to help them see the opportunities and potential for investments in a new therapy for myotonic dystrophy.

Patients and their families know well that the search for a cure, or even a treatment that can mitigate symptoms of DM, is a long and arduous process. We have recently seen the development of IONIS-DMPK-2.5Rx ended because the oligonucleotide drug did not reach its target tissue (skeletal muscle) in concentrations adequate to have a meaningful effect. Fortunately, Ionis has reported that it has alternative compounds that appear to have better tissue-targeting and we hope to see these move toward clinical trials.

Sometimes it’s Complicated

More broadly, we have seen significant recent controversy and lack of agreement regarding therapies developed for other rare diseases, with insurance companies refusing to reimburse for drugs they claim do not have enough scientific evidence to demonstrate a clinically-meaningful effect for patients. We also know that the ‘placebo effect’ where patients report significant therapy benefit when actually on a placebo (a non-active substance with no therapeutic effect), can also complicate the discussion, particularly when a given therapy has a relatively small demonstrable impact. 

Stick with What Works

Oligonucleotide drugs can succeed as therapeutics. Biogen and Ionis collaborated on the development of Spinraza for spinal muscular atrophy. The two companies exercised considerable care in development of these drugs and sought FDA approval only after obtaining results from two international, placebo-controlled clinical trials. The key here is that considerable drug effect was demonstrated in a large cohort of patients enrolled in the clinical trials. As a consequence, the drug is now marketed for all types of spinal muscular atrophy and, while the cost of the drug is very high, many families are getting insurance coverage for Spinraza. The evidence had to be there for both therapy approval and insurance company reimbursement.

Achieving a drug that is proven to have a considerable level of effect on measures that are clinically-meaningful to DM patients is a central requirement for both drug approval and reimbursement. 

The therapies that we hope to achieve for DM will come only from this evidence-based drug development and approval process. MDF regularly meets with biotechnology and pharmaceutical companies—including ten companies in the last two months—providing information and making the case that DM represents a good investment with a clear pathway to drug approval. Any legitimate clinical trial will be listed in ClinicalTrials.gov, and information about legitimate DM studies and trials will always be circulated by MDF.

Dangers lie in the pursuit of quack “therapies.” A brief Google search will reveal fabulous claims of cures for just about any disease, if the patient will only travel to a developing country, with less regulatory oversight, for the ‘breakthrough’ therapy. Most often, the claims of effectiveness lack substantiation. These “therapies” have certainly not gone through any drug regulatory agency for approval, and often supportive data has not even been published in a reputable scientific or medical journal. They are, to put it bluntly, quack “therapies” that are potentially harmful because safety data is often not there.

To the safety point, even in the U.S., unproven “therapies” that bypass FDA regulations have caused harm. Three women were recently blinded in Florida after receiving stem cell “therapy” injections for macular degeneration.

Do Your Homework

So, to steal from an old saying, ya can’t tell the quacks from the cures without a scorecard. If a DM therapy sounds too good to be true, the people behind it are probably just after your money. The reliable scorecard here is the physician who is knowledgeable of DM. If your doctor or any other reputable physician with an understanding of DM won’t prescribe the treatment, you probably should not be taking it. 

MDF is also happy to help you understand whether something is in a legitimate clinical trial, an approved therapy…or not. Browse the resources and tools available on the MDF website or call the MDF Warmline at 415-800-7777.

New and Important Review Articles on DM

Published on Thu, 05/04/2017

The June issue of Current Opinion in Genetics and Development is focused on the topic "Molecular and Genetic Bases of Disease." Four outstanding review articles in the issue have direct relevance to myotonic dystrophy (DM) and are currently available online.

The first article (by Drs. Nan Zhang and Tetsuo Ashizawa) reviews the formation of RNA foci in microsatellite expansion disorders, how RNA binding proteins participate in toxic RNA gain of function, and how transcriptional and RNA processing/transport may ensue.

The second article (by Drs. Kevin Yum, Eric Wang, and Auinash Kalsotra) discusses mechanisms underlying repeat expansion, diagnostic approaches to determining repeat length, and how DM repeat length relates to disease onset, progression and severity.

The third article (by Drs. John Cleary and Laura Ranum) reviews basic mechanisms of repeat-associated non-ATG (RAN) translation and how RAN proteins may enter into the pathogenesis of microsatellite expansion disorders, including DM.

The fourth article (by Drs. Charles Thornton, Eric Wang and Ellie Carrell) focuses on the latest molecular strategies being used in the development of candidate therapies for DM, reviewing approaches targeted at transcriptional silencing, post-transcriptional silencing, inhibition of interactions between MBNL and toxic RNA, and pathways downstream of RNA toxicity.

Taken together, this is a compelling series of review articles, of benefit to basic, translational, and clinical scientists of all levels working on DM.

References:

RNA Toxicity and Foci Formation in Microsatellite Expansion Diseases
Zhang N, Ashizawa T.
Curr Opin Genet Dev. 2017 Feb 13;44:17-29. doi: 10.1016/j.gde.2017.01.005. [Epub ahead of print]

Myotonic Dystrophy: Disease Repeat Range, Penetrance, Age of Onset, and Relationship between Repeat Size and Phenotypes
Yum K, Wang ET, Kalsotra A.
Curr Opin Genet Dev. 2017 Feb 14;44:30-37. doi: 10.1016/j.gde.2017.01.007. [Epub ahead of print]

New Developments in RAN Translation: Insights from Multiple Diseases
Cleary JD, Ranum LP.
Curr Opin Genet Dev. 2017 Mar 30;44:125-134. doi: 10.1016/j.gde.2017.03.006. [Epub ahead of print]

Myotonic Dystrophy: Approach to Therapy
Thornton CA, Wang E, Carrell EM.
Curr Opin Genet Dev. 2017 Apr 1;44:135-140. doi: 10.1016/j.gde.2017.03.007. [Epub ahead of print]

Patient-Reported Data to Guide Care and a Cure for DM

Published on Thu, 05/04/2017

MDF’s Patient-Focused Drug Development (PFDD) meeting, held in 2016 in conjunction with the U.S. Food and Drug Administration (FDA), highlighted the critical role of patients in developing clinically-meaningful outcome measures to facilitate drug development and approval. Identification of the symptoms regarded as most important to patients and caregivers, and the benefits they would most hope to derive from a therapy, provides critical guidance that must be included from the earliest stages of drug development.

Patient registries, like MDF’s Myotonic Dystrophy Family Registry, the National Registry for Myotonic Dystrophy & Facioscapulohumeral Dystrophy at the University of Rochester, the DM-Scope Registry in France, and the UK Myotonic Dystrophy Patient Registry, represent critically important data repositories to facilitate studies of the burden of disease for those living with myotonic dystrophy (DM).

The UK DM Patient Registry published a cross-sectional analysis of self-reported data from 556 myotonic dystrophy type 1 (DM1) patients with a confirmed diagnosis, representing approximately 8.5% of the estimated affected population in the United Kingdom (UK). Registered patients were also able to nominate healthcare specialists to enter their genetic and clinical data; these data augmented patient profiles and served to validate the patient-reported registry format.

Registrant gender was equally distributed (51% female) and a positive family history of DM was reported by 89% of registrants. Mean age of onset was 33 years. Fatigue/daytime sleepiness (79%) and myotonia (78%) were the most frequently reported symptoms—the occurrence of myotonia positively correlated with fatigue, dysphagia and ambulatory status. As in a prior report by the DM-Scope Registry, the UK cohort showed a higher frequency of severe myotonia in males, although fatigue did not show gender bias. Men also reported a higher frequency of cardiac abnormalities, non-invasive ventilation, and mobility impairments, while cataract surgery was more common in women. Most patients (65%) did not require assistive devices to walk. Severity of symptoms did not correlate with CTG repeat length obtained at the time of genetic testing.

While only one-third of patients reported having EKG, 48% of those were diagnosed with a cardiac conduction system abnormality and 36% had received an implanted cardiac device. Non-invasive ventilation was used regularly by 15% of patients. Of the patients with data available, 26% reported cataract surgery.

The UK group reported that the delays in receiving a genetic diagnosis of DM1 remain substantial and do not seem to have improved since the advent of genetic testing in 1996. They stress the importance of reducing the genetic diagnostic odyssey, not only to improve patient care and quality of life, but also to facilitate community readiness for interventional trials and approved therapies.

Taken together, knowledge of the symptoms that are most important to DM1 patients provides guidance not only for improved care, but also for the development of novel therapeutics. Studies such as that reported here, from the UK registry, provide an evidence-based underpinning that is essential for progress. An improved collaborative environment, whereby registry data is more readily shared, is a goal that will not only improve the science, but is in the best interests of those living with DM.

Reference:

The UK Myotonic Dystrophy Patient Registry: Facilitating and Accelerating Clinical Research
Wood L, Cordts I, Atalaia A, Marini-Bettolo C, Maddison P, Phillips M, Roberts M, Rogers M, Hammans S, Straub V, Petty R, Orrell R, Monckton DG, Nikolenko N, Jimenez-Moreno AC, Thompson R, Hilton-Jones D, Turner C, Lochmüller H.
J Neurol. 2017 Apr 10. doi: 10.1007/s00415-017-8483-2. [Epub ahead of print]

Reduced MBNL1 Precedes Structural and Functional Changes in the DM1 Mouse Brain

Published on Thu, 05/04/2017

The burden of disease for myotonic dystrophy (DM) is multi-systemic, including skeletal muscle weakness, fatigue, cardiac arrhythmias, respiratory insufficiency and intellectual disability. Modeling of this constellation of symptoms is important for mechanistic studies and preclinical therapy development. Yet, what is arguably the most widely available mouse model, the HSA-LR, is designed to model the skeletal muscle molecular, structural and functional deficits of skeletal muscle.

Dr. Guey-Shin Wang and colleagues at Academia Sinica (Taiwan) developed an EpA960/CaMKII-Cre mouse that carries an inducible human DMPK with 960 CTG repeats in the 3’ UTR. Cre expression occurs in the forebrain (cortex and hippocampus) after two weeks of age, preserving earlier neurodevelopmental events from toxic RNA exposure and MBNL depletion.

Atrophy of the cortex and corpus callosum, features of the myotonic dystrophy type 1 (DM1) patient central nervous system (CNS), were observed in the adult EpA960/CaMKII-Cre mice. The mice showed progressive neuropathological findings: reduced MBNL1 in dendrites of cortical layer V neurons at six months of age, brain atrophy (axon and dendrite pathology) by nine months, and loss of MBNL2 and MBNL-directed splicopathy were later events, at 12 months.

Functionally, EpA960/CaMKII-Cre mice were evaluated at six months for hippocampus-dependent spatial learning and memory using the Morris water maze—escape latencies were greater for mutants compared with controls, suggestive of slower learning. Evaluation of long-term potentiation (LTP) in hippocampal slices at six months of age also was consistent with synaptic dysfunction and the functional learning disabilities seen in these mice.

The EpA960/CaMKII-Cre mouse model recapitulates some features, including disease progression, seen in DM1 patient CNS. Moreover, the authors suggest that depletion of MBNL1 and MBNL2 in the CNS are distinct events with differing roles in disease progression. Early synaptic dysfunction may be triggered by MBNL1 depletion, and is a precursor to dendritic and axonal pathology. Since splicing changes were detected only later, commensurate with MBNL2 depletion, the early synaptic dysfunction likely is mediated by MBNL1-related, but alternative splicing-independent events.

Reference:

Reduced Cytoplasmic MBNL1 is an Early Event in a Brain-specific Mouse Model of Myotonic Dystrophy.
Wang PY, Lin YM, Wang LH, Kuo TY, Cheng SJ, Wang GS.
Hum Mol Genet. 2017 Mar 24. doi: 10.1093/hmg/ddx115.

Epigenetics Underlying the Parent of Origin Effect in CDM

Published on Fri, 03/31/2017

Inheritance of congenital myotonic dystrophy (CDM) is almost exclusively maternal and, while typically associated with large CTG expansions, is not always genetically differentiated from myotonic dystrophy type 1 (DM1) by repeat tract length. Correlations between CDM/DM1 genotype and phenotype can be improved through evaluation of somatic expansions. Yet it is clear that factors other than germ line repeat length underlie the bias toward maternal inheritance and the heterogeneity of CDM.

The laboratories of Drs. Karen Sermon (Vrije Universiteit Brussel) and Chris Pearson (Hospital for Sick Children) recently collaborated on an epigenetic analysis of the DM1 genetic locus in a cohort of DM1 and CDM patients. Prior reports showed that the DM1 locus resides in a 3.5 kB CpG island with putative CTCF sites, suggesting an epigenetic mechanism for DM1 regulation and disease phenotypes that diverge from CTG length assessments. Earlier reports also established variability in methylation status at that locus in both DM1 patients and DM1 transgenic mice. Drs. Sermon and Pearson hypothesized that CTG expansion might alter CpG methylation status and that a consequent regulatory dysfunction contributes to the severity of the CDM phenotype.

Drs. Sermon and Pearson and team evaluated multiple generations of several families, including 20 individuals with CDM. Results showed nearly an absolute correlation between the methylation status upstream of the expanded CTG repeat and the occurrence of CDM (19/20 cases). By contrast, this pattern of methylation was rarely found among DM1 patients (2/59 cases). The authors suggest that CpG site methylation is an important contributing factor, with the development of CDM not being determined by CTG repeat length alone.

Analysis of human embryonic stem cells (hESC) and chorionic villus samples from the study cohort identified upstream CpG site methylation only in maternally-derived samples; paternal samples never showed methylation upstream of expanded DMPK alleles.

Generational increases in both methylation and CTG expansion length were seen in each CDM family studied. Yet since CTG repeat lengths overlapped in DM1 and CDM, while upstream methylation was almost exclusive to CDM, the authors concluded that methylation status is a stronger indicator of CDM than absolute repeat length. Moreover, they speculate that the maternal inheritance bias of CDM may be a consequence of a failed survival of spermatogonia carrying the pathogenic methylation upstream of DMPK. Importantly, while their data suggests that it is rare, the authors do not exclude paternal inheritance for CDM.

Reference:

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE.
Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.

A Biomarker for Cardiac Dysfunction in DM1?

Published on Fri, 03/31/2017

Cardiac troponin-I, a sarcomeric regulatory protein integral to skeletal and cardiac muscle contraction, has long been utilized as a diagnostic and prognostic biomarker of heart disease. For muscular dystrophies, elevated serum creatine kinase and troponin are associated with myopathic changes in muscle. Understanding the sensitivity of the analytical tools, as well as the types of cardiac issues that may result in elevated cardiac markers in serum, is critical to use of these assays in monitoring myotonic dystrophy type 1 (DM1) patients.

The constellation of cardiac involvement in DM1 includes atrioventricular block, prolonged QT interval, prolonged QRS interval, increased ventricular premature contractions, atrial fibrillation/flutter, right/left bundle branch block, non-sustained ventricular tachycardia and left ventricular systolic dysfunction (Petri et al., Int. J. Cardiol. 160: 82-88, 2012). Prior reports identified a correlation between CTG repeat length and cardiac dysfunction and linked the degree of neuromuscular and cardiac involvement in patients.

A large multi-center study in Scotland recently reported out an analysis of serum levels of cardiac troponin-I (cTnI) in a cohort of 117 well-characterized DM1 patients recruited from outpatient clinics. Nine subjects had cTnI levels that exceeded the 99th percentile of the general population. One-third of subjects with elevated cTnI also had left ventricular systolic dysfunction. The authors noted that elevations in cTnI did not correlate with CTG length, were not predictive of severe conduction abnormalities and did not correlate with muscle strength (by MIRS score). There also was no association between cTnI level and the presence of an implanted cardiac device.

Overall, the authors suggest that cTnI levels represent a potential biomarker to assess risks in the management of DM1 patients and for stratification of subjects in clinical trials. Although the lack of correlation of cTnI levels and MIRS score suggests a cardiac origin for elevated serum cTnI, the underlying responsible pathology in the context of known cardiac phenotype of DM1 is currently unclear. Finally, the authors suggest that the overall sample of patients with elevated cTnI is small and propose these findings as exploratory, requiring follow-up of this and other putative cardiac biomarkers in larger cohorts.

Reference:

Elevated Plasma Levels of Cardiac Troponin-I Predict Left Ventricular Systolic Dysfunction in Patients with Myotonic Dystrophy Type 1: A Multicentre Cohort Follow-up Study.
Hamilton MJ, Robb Y, Cumming S, Gregory H, Duncan A, Rahman M, McKeown A, McWilliam C, Dean J, Wilcox A, Farrugia ME, Cooper A, McGhie J, Adam B, Petty R; Scottish Myotonic Dystrophy Consortium., Longman C, Findlay I, Japp A, Monckton DG, Denvir MA.
PLoS One. 2017 Mar 21;12(3):e0174166. doi: 10.1371/journal.pone.0174166.

Using Gene Editing to Correct DM

Published on Mon, 03/13/2017

A potentially revolutionary technology may allow development of a drug for DM that can correct a patient’s DNA by selectively removing the expanded CTG and CCTG repeats in DM1 and DM2, respectively.

This new gene editing technology has emerged from the discovery of how bacteria protect themselves from invading viruses. There very likely will be a Nobel Prize awarded to scientists who discovered how this bacterial defense mechanism could be used to edit human gene defects. There certainly has been a rather public fight over the patent rights that are potentially worth billions of dollars among the research groups at the University of California, Berkeley and the Eli and Edythe L. Broad Institute of MIT and Harvard.

CRISPR is an acronym for short, repetitive DNA sequences that function to immunize bacteria from viruses. CRISPR DNA works together with a family of proteins, known as Cas proteins, which cut and thereby inactivate the invading virus’ DNA. Working together, CRISPR and Cas can recognize viral DNA as foreign and then inactivate it via the DNA-cutting Cas protein.

Researchers Jennifer Doudna (U.C. Berkeley) and Feng Zhang (Broad) have shown that the CRISPR/Cas system can be adapted to cut human DNA at highly specified locations to either remove existing genes or to insert new genes. The potential value for DM is that known mutation-containing DNA sequences, specifically the expanded repeats in DMPK or CNBP, could be cut to remove the disease-causing expanded repeats. Doudna and Zhang are likely to share a Nobel Prize for this discovery, while it appears that Zhang and the Broad Institute have won the patent rights battle.

Is gene editing using the CRISPR/Cas system going to be available soon for DM? The direct answer is, no. Several issues need to be resolved before any clinical application of gene editing is realized. The specificity and efficiency of gene editing will need to improve. Delivery of the gene editing reagents also must be optimized—these are large molecules that will have to be delivered by intravenous injections and must then gain access to cells throughout the body of DM patients in order to correct the multiple symptoms of the disease. Lastly, there is the issue of safety—studies need to show not only that the CRISPR/Cas system is designed to edit the DMPK or CNBP genes, but that it does not cause harm by editing unintended genes. MDF is working with researchers and biotechnology companies to help advance CRISPR/Cas gene editing for DM.

Gene editing is entering clinical trials this year for some types of cancer. The strategy is to edit the patient’s immune cells, outside of their body (thereby circumventing some barriers to the technology), and the cells that are put back into the body have gene edits so they attack the tumor. This human study is an important proof of concept, and a step that will be critical as we move toward the application of gene editing for DM.

Adequate Rationale to Launch Clinical Trials

Published on Fri, 02/24/2017

Reports over the last decade have challenged the quality and strength of preclinical evidence, the scientific rationale that’s behind the launch of clinical trials. The U.S. National Institutes of Health (NIH) now requires applicants to address scientific rationale, rigor, biological variables, and the authenticity of biological and chemical reagents. Applying such considerations in developing the case for clinical testing of an experimental therapeutic can help ensure that trials do not fail for avoidable reasons.

The European Neuromuscular Consortium (ENMC) recently held a workshop entitled "Finalizing a Plan to Guarantee Quality in Translational Research for Neuromuscular Diseases." MDF staff participated in the workshop that emphasized “choke points” in ensuring rigorous research—the funders and publishers. The proceedings of the workshop are to be published in Neuromuscular Disorders.

All stakeholders are responsible for adequacy of the rationale for clinical trials. DM investigators are encouraged to observe established standards for preclinical efficacy studies, such as the National Institute of Neurological Disorders and Stroke (NINDS) rigor guidelines (pdf). The path to an approved therapy for DM is an arduous one and should not be complicated by clinical trials of candidate therapeutics that do not have a solid scientific basis.

Changes in NINDS Postdoctoral Training Initiatives

Published on Fri, 02/24/2017

The National Institute of Neurological Disorders and Stroke (NINDS) released two Funding Opportunity Announcements (FOA) over the past few months that re-work how the Institute funds postdoctoral fellowships. MDF encourages trainees to consider these options, as well as funding from other NIH Institutes, including the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

The F32

The first Funding Opportunity Announcement (FOA), the NINDS Ruth L. Kirschstein National Research Service Award (NRSA) for Training of Postdoctoral Fellows (F32; PAR-16-458), has been the standard funding mechanism for individual postdoctoral fellowship awards. The change in this FOA pertains to the timing of eligibility for an F32: “support by this program is limited to the first 3 years of a candidate's activity in a specific laboratory or research environment. For example, if an award is made 18 months after the start of the postdoctoral position in the fellowship laboratory or research environment, the award duration will be for a maximum of 18 months.”
 
Effectively, this FOA limits the timing of submission of an F32 application to the period from 12 months before to 12 months after the actual start date of fellowship training. The stated rationale is to encourage project design and F32 submissions at an early career stage and timely completion of mentored training. Applicant-generated preliminary data is discouraged in order to facilitate proposal of innovative projects with substantial impact. F32 award budgeting levels are set by the NIH annually.

The K01

NINDS recognized that additional training and research accomplishments for Ph.D.s (medical-degree holders have other K award options) may be necessary to facilitate the transition from an F32 to an independent faculty position. The second FOA in the series, NINDS Postdoctoral Mentored Career Development Award (K01; PAR-17-145), provides an important vehicle for the transition. This FOA allows for the timing of submissions at any time “between the second through fourth year of cumulative mentored postdoctoral research experience.” K01 funding also is restricted to the first six years of cumulative postdoctoral support. 

Overall Funding Strategy for Postdoctoral Fellowships

Collectively, NINDS’ F32 and K01 FOAs provide support for the postdoctoral training of Ph.D. recipients. They also represent mechanisms for increases in salary and research support when advancing from F32 to K01, as well as elevating the level of responsibility that the trainee would take in the research. The value of the K01 for later stage trainees lies in some differences from the F32, including: (a) recipients can carry their K01 to a faculty position, (b) salary paid by the award can be up to a maximum of $95,000, and (c) the K01 carries $30,000/year in research and career development funds.

The overall strategy here is to help candidates take on innovative, impactful projects while moving more quickly toward, and being more competitive for, independent faculty positions. As with any NIH application, an understanding of Institute-specific requirements and the review environment is critical to success. Thus applicants for these postdoctoral support mechanisms should seek advice from NINDS Program Staff very early in the process of preparing an application.

FDA: How to Talk with Us About INDs

Published on Fri, 02/24/2017

The U.S. Food and Drug Administration’s (FDA) Office of New Drugs has developed an online course entitled "Best Practices for Communication Between FDA and IND Sponsors During Drug Development." Their stated goal is to communicate “best practices and procedures for timely, transparent, and effective communications between investigational new drug application (IND) sponsors and FDA at critical junctures in drug development.” A more detailed draft guidance document (pdf) of the same name is also available.

While IND filings may be second nature to experienced drug developers, the guidance offered in this short course will benefit most investigators in better navigating the FDA’s IND process, and thereby lead to more rapid clinical testing of candidate therapeutics.