companies:  Amplify Hope (help with rare diseases)

Drugs/Medicines:

WHO Model List of Essential Medicines      BLINK (lists medicines for a discount price). DrugBank  MERK Manual     Merk Veterinary Manual. PIMS Plus (searchable drug database, particularly potentially inappropriate drugs for older adults). FDA drug Index                    FDA labelling/product search. Medline Plus (drug/herb information)   Orange Book (Drug approvals)

CDC Drug Database (searchable database for FDA approved infectious disease drugs) FDA medication guide 

International Medical Communities:

Center for Disease Control (CDC).   International Society for Cell and Gene Therapy 

European Centre for Disease Prevention and Control (ECDC)

World Health Organization (WHO)

Rare Diseases

GARD (Genetic and Rare Diseases Center from NIH)

Save on Medical (a page where you can shop on medical procedures for the best price)

Disease Maps

Arbo Map (diseases like West nile, Dengue; CDC)

Genetic Diseases:

Hemoglobinopathies are among the most common inherited diseases around the world. They have become much more common recently in northern and central Europe, including Germany, due to immigration. The hemoglobinopathies encompass all genetic diseases of hemoglobin. They fall into two main groups: thalassemia syndromes and structural hemoglobin variants (abnormal hemoglobins). α- and β-thalassemia are the main types of thalassemia; the main structural hemoglobin variants are HbS, HbE and HbC. There are many subtypes and combined types in each group. The highly variable clinical manifestations of the hemoglobinopathies range from mild hypochromic anemia to moderate hematological disease to severe, lifelong, transfusion-dependent anemia with multiorgan involvement.

–Beta-hemoglobinopathies: affect the production of the beta-globin chain of the adult hemoglobin tetramer. This tetramer is composed of two alpha and two eta-like globin chains. When the levels of beta-globin or an altered beta-globin are reduced, as seen in beta-hemoglobinopathies, the function of red blood cells is affected, leading to anemia and multi-organ doamage. (Barker, “Advancing gene therapies for beta-hemoglobinopathies with novel gehome and epigenome editing toos” Cell & Gene Therapy Insights 2024: 10(9), 1163-1171)

—-Therapies:

——Transcriptional Gene regulation:

During fetal life, the body produces fetal hemoglobin, including the gamma-globin chain, but it is usually silenced shortly after birth. Rsearch has shown that patients who continue to express fetal hemoglobin into adulthood tend to ahve ameliorated clinical phenotypes. In some cases, people with persistent fetal hemoglobin expression, even those with mutations cuasing sickle cell diease, may not have symptoms and are hardly considered patietns. (Barker, “Advancing gene therapies for beta-hemoglobinopathies with novel gehome and epigenome editing toos” Cell & Gene Therapy Insights 2024: 10(9), 1163-1171)

Barker, (“Advancing gene therapies for beta-hemoglobinopathies with novel gehome and epigenome editing toos” Cell & Gene Therapy Insights 2024: 10(9), 1163-1171) is currentl performing research on modulating gene expression as a potential therapy for beta-hemoglobinopathies. While an ideal strategy for genetic diseases would be to directly correct the disease cuasing mutation, this is not always an easy approach. For example, beta-thalassemia is caused by over 400 different muations, meaning one would need to develop a seaprate therapy for eahc one. Fortunately, in the base of beta-hemoglobinopathies, their approach does not require a specific modificaiton of genes but rather focuses on turning them on or of to potentailly cure teh diase. Since beta-thalassemia is characterized by a dificiency in beta-globin expresion, they want to activate the gama-globin genes, which encode for teh fetal gama-globin genes that are the beta-like fetal blogin chain. This activaiton of fetal gamma-globin genes compensates for beta-globin deficiency. This approach involves inactivating a gene called BCL11A, which encodes for a potent transcriptional repression of fetal gama-globin expression. Normally in adulsts, BCL11A factor binds to the fetal gama-globin promoters and represses fetal hemoglobin production. By knocking out BC11Am tge gama globin gene can be reactivated, stopping the repression of fetal hemoglobin. This approach relies on the CRISPR-Cas9 system, a nuclease based system that genrates double stran breaks in the DNA, acting as a molecular siccsors. In the alternative, just one base can be changed using a base editor to create a new binding site for a transcriptional activtor. For example, by chaing adenine into guanine, a binding site for a potent transcriptional activator called KLF1 that binds to the gama-globin promoter and activates gene expression can be accomplished. Other approaches include epigenome editors based on CRISPR-Cas9. Histone modifications on teh gama-globin promoter are introduced that are typically associated with activate transcription of fetal gama-globin genes. To activate gama-globin genes, one would also need to remove DNA methylation, as this typically switches off genes. 

Rare Genetic Diseases:

80% of rare diseases are enetic. As a result, cell and gene therapy hold great promise for their treatment, especially those resulting from single gene defects (monogenic). Advances in gene-editing technologies, such as those based on clustered reularly interspaced palindromic repeats (CRISPR) and assocaited rptoein 9 (Cas9), enable precise correction of disease causing mutations in patient ceels, offering potential cures for previously untreatable conditions. 

One of the major hurdles in Orphan-drug development is the small size of patient populations affected by rare diseases. Limited patient numbers make it hard to recruit participants for clinical trials, leading to slower trial enrollment. 

Aromatic L-amino acid decarboxylase (AADC) (PTC Therapeutics) is a rare disesase in pediatric patients aged 18 months and up. AADC deviciency is a genetic disordr casued by a mutaiton in teh DDC gene, which leads to insufficient levels of the AADC prtoein. In turn, AADC deviciency is characterized by compromised production of dopamine, serotonin and other neurotransmitters, resulting in its key symptoms of developmental delays, muscle stiffness, movement problems and lethargy. Most patients with AADC deficiency need lifelong case, adn the disease can be fatal. Upstaza targets the underslying casue of AADC deficiency by delivering a functional copy of the DDC gene. The gene therapy is delivered right into the brain through a minimally invasive procedure and is meant to be a one-time treatment. In July 2022, the European Commisison granted the gene therapy, allowing its use in all 27 European Union member states. In March 2023, England’s National Instittue for Health and Care Excellence recommended the use of Upstaza for the treatment of AADC deficiency. (BioSpace, “FDA Action alert: Journey, Merus, PTC and Autolus” November 4, 2024). 

Arrhythmogenic cariomyopath (ACM): is caused by a genetic defect on the surface of heart muscle cells where the interlinking chains between cardiac cells are comprosimed. Over time, such problems lead to structural deffects in the heart. People often discover that they have the disease during strenuous exercise in their 20-30s. A person can wake up in the hosptial with an implanted defibrillator after haivng gone through an arrhymia sotrm that has cuased cardiac arrest. The defibrillator can save the person from acute trauma of cardiac arrest but does not protect them from arrhythmia burden. 

Regenerative Medicine is investigating a investigational new drug (IND), PjB-0402, as a candidate gene therapy designed to treat desmoplakin gene variant arrhythmogenic cardiomyopathy (DSP-ACM). The drug uses a known cariometabolic associated protein called FGF21 to treat patients. The drug is delivered to the liver, which then creates FGF21 and secretes it into the bloodstream. The investigation was supported by a grant of 4 million by the California Institute for Regnerative Medicine. 

DFNB9: is a form of autosomal recessive deafness cuased by mutations in OTOF, the otoferlin gene. There are more than 150 genes that are known to cuase deafness when mutated. However many of these are rare; there are about 6 or 7 genes that are the most common. Many groups are targeting one gene OTOF. But OTOF mutations are not the most common in hereditary deafness, accounting for 1-8% of genetic hearing loss. The most common type is DFNB1, casued by mutations int he GJB2 gene, which encodes connexin 26. But targeting OTOF has some advantages; first, many AAV vectors can target the inner hair cells but not the otuer hair cells. If a disease affects both types of hair cells, the delivery vector only targets one type and does not work. However, OTOF is expressed only in the inner hair cells, making the gene an attractive target. Second, hair cells (and other tissues) degeenrate if they are not functioning properly. Becasue the ear develops in utero, it is fully mature by the time the baby is born, so that cells may have already started to degeenrate and the window for intervention may have been missed. But with OTOF mutations, the hair cells do not degnerate. So, treating eyars latter can resore function. Akouos (a wholly owned subsidiary of Eli Lilly) accouned positive intial clinical resutls in AK-OTOF-101 gene therapy study. 

Monogenetic Disease epidermolysis Bullosa (EB): is a rare, monogentic skin dsiease characterised by the formation of extensive blisters and wounds on the skin and mucous membranes upon minimal mechnical trama. EB is characterised by the formation of extended blisters and lesions on teh patient’s skin upon minimal mechanical stresses. Causal for this severe condition are genetic mutations in genes, leading to teh functional impairment, reduction, or absence of teh encoded protein within the skin’s basement membrane zone connecting the epidermis to the underlying dermis. EB causing mutations can be present in at least 16 different genes encoding structural proteins within the skin essential for dermal-epidermal connectivity.  

Disease Treatment Strategies:

Cell-Based therapeutics: which involves the adminsitraiton of cells as living agents to fight diase has recently epxerienced explosive growth. Although cell based therapeis have many of the same translational barreirs as gene therapies, ncluding safety concerns over the potential tumorigenicity and high manufacturing costs that challenge product reimbusement, they have unique intrinsic features that offer the potentail for enhanced efficacy against disease. For example, cells can naturally migrate, localize and even undergo proliferation in specific tissues or compartments. Cell based modalities that harness these properties thus hold potential for biodistribution and targeted delivery advantages not only over biologics, which are subject to limitations imposed by they PK/PD profies, but also voer gene therapies, for which tropism specificity remian challenging to engineer. Furthemore, cells can actively sense a wide variety of extrnsic imputs form small molecuels, cell surface marker proteins and even physical forces. (Bashor, “Engineering the next generation of cell-based therpaeutics” Nature Reviews Drug Discovery)

–CART-T therapy: Progress in the commercializaiton of cell based therpaties has dramatically accelared within the past decade following FDA approval of CAR-T therapy. CAR-T products for refractory multiple myeloma as well as ALL and LBCI have reached the market, and there is potential for approval of therapies using donor derived natural kilelr (NK) cells.. Currently, numerous clinical trails have been completed for solid and liquid tumour indications, suing various effector cells types. However, despite this ongoing diversificaiton, most adoptive cancer cell based therapy trails continue to use patient deived T cells that, alhtough successful with haematological malignancies, present a persistent set of challenges for treating other cancer. These challenges include afety issues posed by cytokine release syndrome which reults from excessive activaiton of uncontrolled expansion of adminstiered cells. Addkitonally, a need exits for refined tumour antigen targeting to prevent antigen escape or off target cytotoxicity, both key hindrances to the applicaiton of CAR-T therpaies to solid tumors. (Bashor, “Engineering the next generation of cell-based therpaeutics” Nature Reviews Drug Discovery)

Recent advances in cell based therpaeutics have been driven by the development of CRISPR and CRISPR accocaited (Cas) prtoeins as programmable tools to engineer the human genome and epigenome in living cells. CRISPR-Cas systems can be targeted to specific genomic loci simply by altering the protospacer sequences of an associated guid RNA (gRNA), which provides an advantage over other genome editing tools, such as zinc finger nuclease (ZFN) and transcription activator-like effector nuclears (TALEN) prtoeins, that require protein engineering to target new sequences. Multiplexed CRISP-Cas9 based genome editing using Cas9 mRNA dn gRNAs that target T cell receptor (TCR), beta2-microglobulin and PD! genes simulanetously has been used in combination with a lentivirally delivered CAR, to generate allogeneic CAR-T cells deficient in TCR, HLA class I molecule and PD1 and has opened the door to universal CAR-T cells. These types of cominatorial starties could solve some o the grand challenges tht face cell therpaies, particulalry by decreasing the immunogenic profiels of autologus cell sources and enhancing the vibility of engineered cells. Bashor, “Engineering the next generation of cell-based therpaeutics” Nature Reviews Drug Discovery)

Patient Variability; Personalized Medicine:

Introduction: Existing tools often fail to understand differences between patients with the same disease. For physicians, diagnostic limitations present great challenges in delivering the best possible treatment to their patients. For ptients, the lack of effective tools means a potential waste of time exactly when time is of the essence. Payors also find themselves covering costs for expensive treatments that may or may not offer benefits to the treated pateints. 

Biomarkers for Patient Variability: designing a biomarker(s) that enable identificaiton of patient differentiators, one can optimize how clinicians choose therapies and select patients for clinical trials. Both of these factors can improve success rates for late stage clinical trials. 

Noncoding RNAs; RNA modificaitons: In one study, a novel noncoding gene was overexpressed in patients who eventually relapsed, but not in other patients. With respect to influenza, two long intergenic noncoding RNAs were assocaited with immune response. The noncoding RNAs became highly methylated after exposure to influenza. Shorter noncoding RNAs were also altered after infection. (see Snell, “direct RNA sequencing supports novel discoveries in RNA biology” in Genetic Engineering & Biotechnology News, November 2024)