细胞和基因治疗行业分析

收集资料：

1. gene therapy相关的近5年的review
2. 已有的研报
3. 微信公众号文章
4. YouTube的科普视频

先看review，了解专业术语，整个行业基本的逻辑框架。

了解一个技术最快的途径就是微信和YouTube上的科普视频和文章。

最后要看别人的研报，学习别人的分析逻辑和思路，同时给出自己的评价。

---

有点迷失在细节里了，跳出来思考一下大问题吧。

细胞和基因疗法不是万能的。

问题：是不是所有的疾病都可以用基因疗法来治疗？

答：回忆一个遗传学基本的框架，P = G + E + G·E，其中G和E有复杂的相互作用。如果是由E引起的疾病，那就不能用基因疗法，比如化学毒物、物理辐射等；基因疗法对遗传系统内生的疾病是有效的，其根源就在于基因突变（生殖过程或体细胞里）。

感悟一：所有生物医学衍生的疗法都是技术（细胞、基因治疗），本质还是离不开我们的基础研究的认知框架。这也就是为什么目前基因治疗只能用于单基因病，因为这个非常简单，把一个基因纠正即可；而对于复杂疾病则难以入手。PD-1需要基因疗法吗，显然不需要，PD-1基因并没有异常，它只是上游信号收敛到下游的一个显著特征。

感悟二：现在我们的基础研究已经处于非常严重的“眼高手低”的时代了，我们获取了太多的信息，我们的眼界可以看到火星，但我们的认知还被困在地球。可能我们真的需要一点耐心，才能彻底高清底层的运作架构，只有把这些彻底搞清楚了，下游的制药才能用最先进的技术来治疗疾病。

感悟三：或许继续搞计算生物学才是我触及梦想最快的途径，没事，先去产业界混混吧，说不定机会就在里面，我相信我一切的思考和努力都是有价值的。

随想：高通量基因编辑技术或许很有前景，我直接把GWAS得到的top100的位点全部矫正，那还有什么疾病存在？

---

FDA gene therapy: mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms

EMA gene therapy: biological medicinal product that contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to humans to regulate, repair, replace, add or delete genetic sequences and its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence

按遗传物质种类细分：

• DNA
• mRNA
• siRNA
• miRNA
• anti-sense oligonucleotides

按靶向细胞类型分类：

• germ-line【伦理问题】
• somatic cell 

按技术方式分类：

• viral vector-based
• gene editing-based

deliver therapeutic genetic materials：

• ex vivo - outside the living body，疾病：Hepatocytes肝细胞，retina photoreceptors视网膜光感受器，stem cells肝细胞，T lymphocytes T淋巴细胞；药物：Kymriah™，Zalmoxis™；优点：Less side effects，less renal clearance
• in situ - in position，疾病：cystic fibrosis囊胞性纤维症，muscular dystrophy肌肉萎缩症，cancer，药物：Neovasculgen®；优点：localized conditions，缺点：cannot be used for treating systemic disorders
• in vivo - in the living body

for in vivo：

A wide variety of physical and chemical methods including

• needles,
• gene guns,
• electroporation,
• sonoporation,
• photoporation,
• magnetofection,
• hydroporation,
• mechanical massage,
• lipid,
• calcium phosphate,
• silica
• gold nanoparticles
• viruses【最优，缺点：immunogenicity and carcinogenicity】

are being used to deliver genetic material to target cells. 

重点关注viral vectors

therapeutic DNA needs to escape the cellular endonucleases细胞内切酶 and renal clearance肾清除

An ideal vector should

• have enough space to transport large therapeutic genes,
• high transduction efficiency, and
• the ability to provide long-term and stable expression, as well as
• target specific cells,
• avoid random insertion of the therapeutic gene into the host genome, and
• infect mitotic as well as post-mitotic cells.
• possess the ability to be manufactured on a large scale

It should not be

• immunogenic or pathogenic
• cause inflammation 

病毒举例：

• One particularly popular use of viral vectors, such as
• adenovirus,
• Seneca Valley virus,
• poliovirus,
• vaccinia virus,
• herpes simplex virus,
• reovirus,
• Coxsackievirus,
• parvovirus,
• Newcastle disease virus,
• vesicular stomatitis virus, and
• measles virus, is in the form of oncolytic viruses (OV). 

undesired clinical outcomes due to

• off-target effects,
• cytotoxicity,
• viral transmissibility,
• impurity, and
• an immune response to the viral vector itself

基因疗法常识治愈的疾病：

Nonetheless, diseases for which a cure has been attempted include

• β-thalassemia,
• X-linked severe combined immunodeficiency (X-SCID),
• adenosine deaminase deficiency (ADA-SCID),
• cystic fibrosis,
• hemophilia,
• liver enzyme ornithine transcarbamylase (OTC) deficiency,
• head and neck cancer,
• metastatic melanoma,
• HIV,
• Leber's congenital amaurosis,
• Wiskott-Aldrich syndrome (WAS),
• metachromatic leukodystrophy (MLD), and
• severe lipoprotein lipase deficiency disorder (LPLD). 

some widely used viral vectors in gene therapy：

• Adenovirus (AV) 腺病毒
• Adeno-Associated Virus (AAV) 腺相关病毒
• Herpes Simplex Virus (HSV) 单纯疱疹病毒
• Retrovirus (RV) 逆转录病毒

该技术是何时引爆的？因为什么因素？

药物详情：

• Kymriah™, a groundbreaking prescription cancer treatment that uses the patient's own white blood cells or T cells for inserting the CD19 gene ex vivo
• Zalmoxis™ consists of donor lymphocytes transfected with Herpes simplex virus-1 thymidine kinase (HSV-TK) and truncated low affinity nerve growth factor receptor (ΔLNGF)
• Neovasculgen®, a plasmid vector carrying vascular endothelial growth factor (VEGF) gene, is directly injected into the target ischemic tissue to stimulate blood vessel growth
• Gendicine™, was developed by Shenzhen SiBiono GeneTech for the treatment of patients with tumors carrying a mutated p53 gene, a common cause for more than 50% of all types of human cancers.
• Oncorine™, another replication defective AV-based drug that carries p53 gene to cure head and neck cancer, made it to the Chinese pharmaceutical market in 2005.
• Rexin-G™, a chimeric retrovector loaded with a cytocidal dominant negative cyclin G1 gene to target and kill solid tumors, was approved by the Philippines FDA in 2005.
• Strimvelis™, was approved in Europe to treat an ultra-rare immunodeficiency syndrome, ADA-SCID, or Bubble Boy Syndrome, a fatal and life-threatening disease due to lymphopenia, and recurrent and opportunistic infections.
• Kymriah™, a lentivirus-based chimeric antigen receptor T cell (CAR-T) therapy for acute lymphoblastic leukemia
• Yescarta™ is another retrovirus-based CAR-T cell immunotherapy developed by Kite, a Gilead company, and approved by the FDA in 2017.
• Zalmoxis is another T-cell based medicine designated an orphan drug and approved by the EMA for treating certain leukaemias and lymphomas.
• Neovasculgen™, a non-viral first-in-class gene therapy drug developed by the Russian Human Stem Cells Institute, has been available since 2012 for the treatment of atherosclerotic peripheral arterial disease (PAD) including critical limb ischemia.
• Spinraza® has become the first approved treatment for the rare and often fatal disease spinal muscular atrophy (SMA).

top公司的top药物

contract development and manufacturing organization (CDMO) 合同开发和制造组织

Chimeric antigen receptor (CAR) T-cell therapy 嵌合抗原受体T细胞

四方格局

• 政策
• 资本
• 产业（企业+医院）
• 学研

待续~

参考：

• Genetic and Rare Diseases Information Center (GARD)  - NIH
• Global Genes® - rare disease
• National Center for Advancing Translational Sciences (NCATS) - NIH
• Drugwatch® - non-profit drug information network and organization
• ASGCT - American Society of Gene & Cell Therapy 
• National Gene Vector Laboratories (NGVL)