我们的目标: Assaying Compounds in Clinical Development for Orphan and Emerging Microbial Diseases

As champions of children diagnosed with rare orphan diseases and other unmet third world medical needs, we recognize an important opportunity within the global drug development community. This opportunity is the challenge to systematically test not only all approved drugs but also those drugs in various stages of clinical development for potential utility in treating orphan childhood diseases and unmet medical needs common to the third world. It is our goal to obtain the set of 2000+ compounds currently in clinical development into a format compatible with high-throughput screening assays and to make this resource available to all non-profit and academic researchers investigating orphan diseases and emerging microbial diseases (e.g., viruses like SARS and bacteria like anthrax) that while most prevalent in the Third World can become global health emergencies.



Rare Diseases Share the Same Molecular Defects with More Prevalent Illnesses

The recent completion of the Human Genome Project has accelerated the identification of the genetic basis for many rare orphan childhood diseases as well as diseases specifically affecting third world populations. For many of these diseases, the newly identified causative gene can be firmly situated within biochemical, signaling or regulatory pathways common to diseases of greater general public health concern such as cancer, heart disease or diabetes. For example, the genes causing each of Neurofibromatosis Type-1, Cowden Disease and Retinoblastoma have all been subsequently shown to be highly relevant to many forms of cancer including breast cancer, glioblastoma multiforme and prostate cancer. Developing a drug useful in treating the symptoms of any one of these diseases may lead to the simultaneous development of drugs with the potential to treat many more commonly occurring cancers.


最近人类基因组计划的完成加速证明了基因是许多罕见的儿童疾病和特别地影响第三世界人民的疾病的成因。因为这些疾病,最近用生物化学,电信号或隧道方法证明大众关心的疾病譬如癌症,心脏病或糖尿病都是由基因导致的。例如,基因导致的I型Neurofibromatosis(纤维神经瘤),Cowden症和Retinoblastoma随后被证明与许多癌症包括乳腺癌,glioblastoma multiforme和前列腺癌密切相关的。在为治疗这些疾病的当中的任何一个的症状而开发的有用药物也许会导致药物同时向治疗许多共性癌症的方向发展。


Targeting a Rare Disease as the First-In-Man Indication
Significantly Reduces Development Time and Costs

Focusing a development program towards an orphan disease can also increase the overall efficiency of executing a specific developmental program. Many orphan diseases are championed by a national community-building non-profit organization (e.g., Tuberous Sclerosis Alliance, Crohn’s and Colitis Foundation of America, Cystic Fibrosis Foundation, Juvenile Diabetes Foundation). These organizations not only serve as a clearinghouse for access to both in vivo and in vitro models of the selected disease but many offer access to a ‘Clinical Alliance’, a coordinated group of medical specialists with strong clinical expertise in the orphan disease who can design clinical trials and then efficiently recruit target patients to execute these in a timely fashion. Most importantly, these organizations serve as the grassroots voice for patients affected with the condition and their families/caregivers. Novartis recognized this opportunity when developing imatinib (Gleevec®), a receptor tyrosine kinase inhibitor expected to be useful against many different types of cancer. Novartis selected Chronic Myelogenous Leukemia, a rare leukemia where over 80% of cases are associated with a specific genetic mutation called the Philadelphia Chromosome, as the first indication for imatinib. Leveraging all of the benefits listed above, imatinib completed all 3 phases of clinical development in 3½ years (compared to the industry standard of 6+). In addition, owing to the strong lobby of patient advocates, the drug was ushered through the FDA approval process in a matter of months and set a new standard for “Best Practices” in drug development.


集中于一种罕见疾病的研发项目能增加执行一个特效药研发项目的综合效率。许多罕见疾病由一个全国社团性、非盈利性组织(如,Tuberous Sclerosis(结节性硬化症)联盟,美国的Crohn和Colitis基金会,Cystic Fibrosis基金会,Juvenile Diabetes基金会)支持。这些组织不仅对于特定的疾病的体内和体外研究者提供一个交流场所而且对'临床联盟'--一个在罕见疾病方面有丰富临床经验,能设计临床试验并及时找到目标患者人完成临床测试医学专家协调小组的成立起了一定的促进作用。最重要地,这些组织对于患者病情和他们的家庭照料的影响起基础的作用。当Novartis开发imatinib(Gleevec®)对许多不同类型的癌症起抗性作用的tyrosine kinase抑制剂受体时认可了这个机会。Novartis选择了慢性骨髓性白血病,一个80%是因为一种叫Philadelphia染色体的基因突变有关的罕见白血病,作为imatinib的第一表征。支持所有好处上述列出了得, imatinib在3½年结束了3个阶段所有临床研发(业界标准的6+)。另外,由于议员耐心地提倡,药物数月内通过了FDA(粮食与药物管理局)审批流程,并规定了一个药物研发地"最佳的实践"新标准。

Old Dogs Can Learn New Tricks: New Indications to Treat Rare Diseases
Are Found For Currently Marketed Drugs

When looking for candidates to treat orphan diseases, the first and easiest place to look would be the set of drugs already on the market. These drugs already have proven safety in the general population and have met Regulatory guidelines with respect to manufacturing, distribution and dispensation. All that is needed is a clinical trial showing the drug’s usefulness to treat the orphan disease. In fact, this approach was recently applied by the research community for Tuberous Sclerosis, a genetic disorder that causes the development of benign growth, or hamartomas, in selected tissues. Rapamycin, also known as sirolimus, has become a standard immunosuppressive drug following kidney transplant. In the past 5 years, scientists have uncovered the mechanism of action for rapamycin, namely that it binds and turns off a protein called mTOR and subsequently shuts down cell growth and protein synthesis so target cells stop working properly. Last year, scientists working on Tuberous Sclerosis have shown that the two causative genes for TSC, tuberin and hamartin also serve to, directly or indirectly, keep mTOR activity in check. Consequently, in patients with Tuberous Sclerosis where either tuberin or hamartin is broken, mTOR activity is increased and cells grow in a somewhat unconstrained fashion with resulting hamartomas. One treatment goal for patients with Tuberous Sclerosis would be to regain control of cell growth and eliminate the hamartomas. Rapamycin, because it can control mTOR, may be a useful solution for Tuberous Sclerosis patients where mTOR is dysregulated. A clinical trial to test this hypothesis will be shortly underway and a successful outcome can, very expediously, make this drug available to all patients with Tuberous Sclerosis.


当寻找治疗罕见疾病地候选药物时,第一个和最容易看的会是已上市地药物。这些药物证明口服安全性,并已有关于制造,发行和销售地管理指南。所需的仅是一次临床试验证明药物对治疗罕见疾病有效。实际上,最近这种方法已由研究团体运用于Tuberous Sclerosis-导致良性肿瘤恶化的基因突变,还有在所选组织里的hamartomas。Rapamycin,亦称sirolimus,成了后来肾脏移植的标准排异抑制药物。在过去5 年,科学家揭示了rapamycin的机理,即它用mTO束缚和转动蛋白质R并随后停止细胞生长和蛋白质合成因此目标细胞异常。去年,从事Tuberous Sclerosis研究的科学家表明引起基因TSC的二个蛋白质为,tuberin和hamartin,并在检测中直接或间接的抑制mTOR活性。因此,Tuberous Sclerosis患者的tuberin或hamartin异常,mTOR活动会增加以致细胞生长失控最终导致hamartomas。一个治疗Tuberous Sclerosis患者的想法是恢复细胞生长控制并消除hamartomas。Rapamycin,因为它能控制mTOR,是Tuberous Sclerosis患者的一种mTOR调控方案。一个临床试验测试将会进行如果成功,将非常迅速,使这种药物用于大部分Tuberous Sclerosis患者。

Screening Marketed Compounds is Good; Screening Compounds Under
Development Will Leverage Up-To-Date Industry Know-How

Current reports from the Pharmaceutical Industry state that, on average, 15 years elapse from when a Discovery scientist selects a protein for a drug target until a drug product that modulates the target is approved by the FDA. This suggests that the subset of marketed drugs, including rapamycin and imatinib, represent, on average, the scientific innovation of 15-30 years ago. Most of the current ideas and ‘hot topics’, especially the recent boom in drug target identification and selection owing to the completion of the Human Genome, are not yet represented among the subset of marketed drugs. At best, these drugs are still in late-phase preclinical or clinical development. We believe that the sooner these drugs ‘under development’ are made available to the scientific community championing orphan childhood diseases and diseases common to the third world to test for clinical relevance to these medical conditions, the quicker patients in need can have access to useful and potentially life-saving medicines. Below, we propose a mechanism by which all investigational new drugs in clinical development can be made available to non-profit and academic groups wishing to assay these in validated in vitro or in vivo models of orphan diseases.

筛选销售复方药中有用的; 筛选研发中复方药将是最新的产业技术


A Third-Party Provider Will Collect and Distribute the Developmental Compounds

From an operational standpoint, the feasibility of this goal has already been proven using the set of marketed drugs. Microsource Discovery Systems, Inc. of Gaylordsville, CT, commercially offers The Spectrum Collection™, a high-throughput screening-ready array of 2,000 biologically active compounds including over 1,000 of the currently marketed drugs. The National Institute of Neurological Diseases and Stroke (NINDS) acquired this library for distribution to non-profit and academic groups investigating neurological disorders. Under this program, many scientists have had access to the compound set and useful compounds are being pursued. Results of this screen for Amyotrophic Lateral Sclerosis (ALS) can be found at www.alsa.org/news/news052201.cfm. Following this lead, our own research program at the Rothberg Institute for Childhood Diseases has screened this library in our in vitro cell growth assay for compounds selective in suppressing/killing Tuberous Sclerosis-derived cells while sparing comparable wild-type cells. Of the 2,000 compounds screened, 1 compound met our criteria for a hit and we are avidly performing follow-on experiments to validate its candidacy as a novel drug capable of managing symptoms associated with Tuberous Sclerosis.


从操作的立场而言,使用已销售药物的这个目标的可行性已经被证实。Gaylordsville, CT Microsource Discovery Systems公司。商业上提供光谱收集器,一种高吞吐量的有2,000种生物活性化合物包括1,000中已销售药物的筛选阵列。National Institute of Neurological Diseases and Stroke(NINDS)获取了这个库用于非盈利和学术小组的神经病学研究。这个节目中,许多科学家得以使用那样他们梦寐以求的有用的化合物。这个为Amyotrophic Lateral Sclerosis(ALS)筛选的结果在www.alsa.org/news/news052201.cfm。在这以后,我们在Rothberg儿童疾病研究院的自己的研究计划筛选了这个库,寻找我们用于体外细胞生长试验的化合物--可以有选择性地杀死Tuberous Sclerosis细胞而不会伤害原生细胞地化合物。筛选了2,000种化合物,1种化合物符合了我们的标准,我们热情地进行第二次产品实验以确认候选药物作为一种新药能治疗与Tuberous Sclerosis相关的病症。

Cross-Industry Collaboration To Accelerate Drug Development for Orphan
and Emerging Microbial Indications

Our challenge is put forth to all pharmaceutical and biotechnology companies that have small molecule compounds with active IND applications and whose manufacturing processes are sufficiently robust such that compound availability is not limiting to contribute a sample of each investigational compound to this project. With the help of a 3rd party distributor with a proven track record in this area, we will then coordinate an effort to distribute the library to interested investigators. We will measure success by the number of IND applications submitted from this set of compounds in support of orphan childhood diseases and emerging microbial diseases common to the Third World.





BERothberg MD

Bonnie E. Gould Rothberg, MD
Medical Director
The Rothberg Institute for Childhood Diseases

 Jonathan M. Rothberg PhD

Jonathan M. Rothberg, PhD
The Rothberg Institute for Childhood Diseases