Pharmaceuticals & Vitamin D

Most Recent Inventions

Gene Correction of Pompe Disease and Other Autosomal Recessive Disorders via CRISPR and other RNA-Guided Nucleases

UW–Madison researchers have developed a complexed CRISPR-Cas system (S1mplex; P170309US01) for treating patients with inherited autosomal recessive conditions. The work focuses on Pompe disease. The inventors identified new guide RNA target sites and repair templates that could be used for gene therapy strategies and cell therapeutic strategies.

The inventors demonstrated successful editing of fibroblast and induced pluripotent stem cells from three Pompe patients at UW Hospital having heterozygous mutations (each allele containing a different mutation, both leading to loss of function of the enzyme). Using their complexed CRISPR-Cas technology markedly increased editing precision (18.4-fold) in two different cell lines (HEK and hPSC), easing concerns about off-target effects. Importantly, rapid glycogen processing improvements were observed after gene correction – 24 hours and 96 hours, respectively.

Oligolactic Acid-Paclitaxel and Oligolactic Acid-Docetaxel Prodrugs for Injection

UW–Madison researchers have developed oligolactic acid prodrugs based on PTX, DTX, rapamycin and selumetinib for PEG-PLA micelles for injection.
  • Oligolactic acid acts as a compatibilizer between anticancer drugs and PEG-PLA micelles, resulting in enhanced drug loading, physical stability and controlled release.
  • Oligolactic acid prodrugs are stable in PEG-PLA micelles and upon release convert back into parent drug by a combination of “backbiting” and esterase-based hydrolysis rather than by random hydrolysis.
  • Oligolactic acid-PTX prodrug injected in PEG-PLA micelles has higher plasma exposure than PTX injected in PEG-PLA micelles at an equivalent dose.
  • Oligolactic acid-PTX prodrug injected in PEG-PLA micelles has higher antitumor efficacy than PTX injected in PEG-PLA micelles at an equivalent dose.
  • Oligolactic acid-rapamycin prodrug injected in PEG-PLA micelles has higher antitumor efficacy than rapamycin injected in PEG-PLA micelles at an equivalent dose.

Bacterial Membrane Nanoparticles as an Immunotherapy System for Cancer Treatment

UW–Madison researchers have engineered a bacterial membrane-coated nanoparticle (BNP) capable of acting as a cancer treatment/vaccine. The BNP consists of a nanosized polyplex made up of a PC7A polymer, a CpG oligonucleotide inside the bacterial membrane and surface attached maleimide (Mal) groups. PC7A provides both a pH responsiveness, which allows for membrane interactions at neutral pH, and subsequent endosomal escape once internalized into the cell. CpG functions as an immunostimulatory molecule (as a toll-like receptor agonist). And Mal groups decorate the surface of the BNP to capture tumor remnants created by radiation treatment, accelerating cellular recognition of the tumor.

In combination with radiation therapy, the inventors show that BNP treatment led to significant tumor growth suppression and enhanced survival rate in a model of a B78 melanoma tumor, a hard cancer to treat. By enabling patients’ immune systems to recognize the unique antigens on their own tumors, this combination therapy may represent a universal approach to achieve personalized cancer immunotherapy using off-the-shelf agents.

New Hormone Analogs for Treating Hypoparathyroidism

UW–Madison researchers have developed backbone-modified analogs of PTH(1-34). The analogs exhibit advantageous properties; they are biased toward Gs activation/cAMP production relative to β arrestin recruitment.

The analogs were generated via an unconventional strategy in which the backbone of a natural PTHR-1 agonist was altered, rather than the side-chain complement. More specifically, selected α-amino acid residues were systemically replaced with either β-amino acid residues or with unnatural D-stereoisomer α-amino acid residues.

The researchers have shown that backbone-modification can rapidly identify potent agonists with divergent receptor-state selectivity patterns relative to a prototype peptide.

Compounds and Methods for Modulating Frataxin Expression in Friedreich’s Ataxia

UW–Madison researchers have generated new chimeric complexes that selectively increase FXN mRNA production to eliminate the physiological cause of Friedrich’s Ataxia. The synthetic transcription elongation factors (Syn-TEFs) of the present invention comprise a bromodomain inhibitor (such as Brd4), bound to a linker (such as PEG), which is further bound to a polyamide designed to target a gene sequence of interest near the repeats (see image below). Mechanistically, the complex binds selectively to the DNA near the triplet repeats in FRDA patients, and then the linked bromodomain inhibitor binds BRD4 and thereby recruits the elongation machinery to restart the paused transcription complex.

The inventors observed a 4.3-fold improvement at 500 nM after 1 day, which should be sufficient for real improvement, since FRDA carriers only have 40% of normal expression and show no symptoms. Increasing the dose to 1 μM increased FXN mRNA 8.5-fold after 1 day, with 3-fold improvement after only 6 hours.

Most Recent Patents

Treating Multiple Sclerosis with UV Light

UW–Madison researchers have developed a method for suppressing MS symptoms by irradiating a patient with a narrow band of ultraviolet (UV) light. The light has a wavelength between about 300-315 nm. Patients could be irradiated using commercially available lamps or blankets. A typical treatment regimen could be 10-30 minutes of exposure for several days.

Natural Antibiotic to Treat Clostridium Infection and More

UW–Madison researchers have identified a potential new antibiotic to treat infections caused by C. difficile, Staphylococcus and other drug-resistant strains. The compound is a natural product called ecteinamycin. It was discovered and isolated from a sea squirt bacterium (Actinomadura). Preliminary data suggests ecteinamycin is potent, selective and able to protect cells against bacterial toxins.

Effective and Robust Method of T Cell Expansion and Activation

UW–Madison researchers have shown for the first time that the addition of inhibitors which block the binding of BAFF to its receptor BAFF-R/BR3 activates both CD4+ and CD8+ cytolytic T cells such that the killing of target human tumor cell lines is significantly augmented.

Specifically, the researchers demonstrated in vitro that a neutralization antibody to the BAFF receptor, BR3, significantly increased CRTAM+ CD4+ and CD8+ T cell proliferation and their anti-tumor cytotoxic activity via increases in granzyme B. This was shown for even aggressive melanoma cell lines such as A375 whereby a four day co-culture with BR3 neutralized T cells almost completely eradicated the tumor cells from culture. This innovation removes a significant roadblock in the industrial production/manufacture of T cells ex vivo for T cell and chimeric antigen receptor (CAR) T cell immunotherapy, which is currently one of the most exciting new cancer therapies.