There have been a number of recent developments in cell and gene therapy, as detailed in our bimonthly newsletter, Cell and Gene Therapy Business Outlook.

1. The US Patent and Trademark Office has ruled against a patent challenge by the University of California, Berkeley (UC Berkeley) over patents awarded to the Broad Institute of MIT and Harvard concerning the revolutionary genome editing technique adapted from CRISPR (clustered regularly interspaced short palindromic repeats) sequences found in bacterial genomes. Researchers Jennifer Doudna, PhD, of UC Berkeley, and Emmanuelle Charpentier, PhD, were awarded the Nobel Prize in Chemistry in 2020 for their pioneering work adapting and streamlining the system into a powerful, programable gene editing tool.  Doudna and Charpentier were the first to publish a paper on the CRISPR system in 2012, but key patent rights were awarded to researchers at the Broad Institute, who were the first to apply the system to edit the genomes of eukaryotic cells.  The UC Berkeley group appealed that decision and lost in 2017, then launched this new appeal in 2019.  The patents are potentially worth billions in licensing fees, and Berkeley group have said they intend to challenge the decision.
2. Bayer AG, based in Leverkusen, Germany, has announced plans to invest €1.4 billion ($1.55 billion) in new technologies and manufacturing sites in Bergkamen, Berlin, Leverkusen, Weimar, and Wuppertal over the next few years. The company plans to lay the groundwork for sustainable employment growth from 2025 onwards, with new R&D in growth areas such as cell and gene therapy and data science.
3. Celyad Oncology, based in Mont-Saint-Guibert, Belgium has announced that the U.S. FDA has placed a clinical hold on a Phase Ib trial evaluating its chimeric antigen receptor (CAR) T-cell therapy CYAD-101 given concurrently with FOLFOX and followed by pembrolizumab for the treatment of unresectable metastatic colorectal cancer (mCRC). A few days earlier, on Feb 28, the company had announced a voluntary pause following the deaths of two patients with similar pulmonary findings.  CYAD-101 is an allogeneic CAR T-cell product engineered to co-express a CAR based on NKG2D, which binds to stress-induced ligands expressed by a broad range of tumor cells, and an inhibitory peptide which reduces signaling of the TCR complex.
4. NeuroGenesis, a clinical-stage cell therapy company based in Rochester, NY, and Hadassah Medical Center in Jerusalem, Israel, have announced positive results from a placebo-controlled Phase II clinical trial evaluating NeuroGenesis’ NG-01 cells for treatment of multiple sclerosis (MS).  The trial was led by Dimitrios Karussis, PhD, and results were published in Stem Cells Translational Medicine.  NG-01 cells are an autologous proprietary subpopulation of bone marrow cells, which the company says has neuroprotective and neuro-regenerative properties, while reducing pro-inflammatory cytokine secretions.  Patients received either a placebo, intrathecal (IT) or intravenous (IV) injection of NG-01 cells.  At six months after treatment, the IT-injected group had significantly lower levels of neurofilament light chains (NF-L), an established biomarker for MS disease progression, in their cerebral spinal fluid compared to the pre-treatment baseline. IT-treated patients also experienced an improved disability score even at 12 months after treatment.  The company planning a larger, 60-patient Phase IIB clinical trial in the US and Israel which is expected to begin toward the end of this year, with centers at the University of Rochester Medical Center and the Hadassah Medical Center.
5. IDT Biologika, a Contract Development and Manufacturing Organization (CDMO) based in Dessau-Rosslau, Germany, and Exothera, a CDMO based in Charleroi, Belgium, have partnered to develop a large-scale manufacturing process for viral vector-based vaccines. Both companies specialize in gene therapy and viral vaccines, and collaboration will combine IDT’s upstream development pipeline with Exothera’s NevoLine platform for large-scale manufacturing, beginning with a feasibility study using IDT’s Modified Vaccinia Ankara (MVA) virus.
6. Ray Therapeutics, based in San Diego, CA, and Forge Biologics, based in Grove City, OH, have entered a manufacturing partnership to bring Ray-001, Ray Therapeutics’ lead optogenetics gene therapy program, into the clinic for the treatment of retinitis pigmentosa. Rather than attempting to repair the specific genetic defect responsible for RP, Ray-001 is a mutation-independent optogenetic therapy that bypasses the defective photoreceptors entirely by targeting other retinal cells along the vision circuit pathway.  The therapy is administered via intravitreal injection, where it diffuses from the vitreous into the retina to transduces the retinal ganglion cells (RGCs).  Over 100 mutations in more than 70 different genes can lead to RP, and no effective treatment is available. Forge will use its platform process, including its proprietary Ingition HEK 293 suspension cell line and its pEMBR adenovirus helper plasmid, to provide adeno-associated viral (AAV) process development, scale-up engineering, and cGMP manufacturing services.  Development and cGMP manufacturing will take place in Columbus, OH, at The Hearth, Forge’s 200,000-square-foot gene therapy cGMP production facility.
7. Janssen Pharmaceutical Companies of Johnson & Johnson, based in Titusville, New Jersey, has announced that the U.S. FDA has approved CARVYKTI (ciltacabtagene autoleucel) for the treatment of adults with relapsed or refractory multiple myeloma (R/R MM) after four or more prior lines of therapy. CARVYKTI is a chimeric antigen receptor T (CAR-T) cell-based therapy with two single-domain antibodies targeting B-cell maturation antigen (BCMA), a receptor preferentially expressed on mature B lymphocytes.  In a Phase Ib/II clinical study, the therapy achieved 98% overall response rate in patients with R/R MM, with 78% of those responding experiencing a stringent complete response (where a physician is unable to observe any signs or symptoms of disease via imaging or other tests). CARVYKTI is the second CAR-T cell therapy to be approved by the FDA for the treatment of R/R MM, joining Bristol-Myers Squibb’s Abecma (idecabtagene vicleucel), which was approved in March of last year.
8. Santhera Pharmaceuticals, based in Pratteln, Switzerland, has partnered with Seal Therapeutics, based in Basel Switzerland, to develop a gene therapy for the treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2 MD). LAMA2 MD is caused by mutations in the LAMA2 gene encoding the laminin-α2 chain, a subunit of the proteins laminin-211 and laminin-221 (also known as laminin-2 and laminin-4), which are major components of the extracellular matrix in healthy adult skeletal muscle.  The α2 chain components of these laminins are responsible for establishing linkages between the extracellular matrix and the muscle fibers, and provide mechanical support during muscle contraction.  Mutations in the LAMA2 gene result in missing or truncated α2 chain proteins which in turn build a weak extracellular matrix.  Seal Therapeutics’ SEAL technology (Simultaneous Expression of Artificial Linkers) platform expresses two engineered linker proteins to replace the function of the missing α2 chain. Seal Therapeutics is a spin-off of the Biozentrum of the University of Basel in Switzerland, and the technology is based on previous research there and at Rutgers University in New Jersey, partly funded by Santhera.
9. Cambridge, MA-based bluebird bio’s investigational therapy LentiGlobin (lovotibeglogene autotemcel, aka bb1111) is continuing to show promising results as a potential permanent cure for sickle cell disease (SCD). In a Feb 17 paper published in The New England Journal of Medicine, researchers led by Julie Kanter, MD, at the University of Alabama at Birmingham (UAB) report on an ongoing Phase I/II clinical trial of 35 patients who received one infusion of LentiGlobin.  The therapy consists of autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) transduced with the BB305 lentiviral vector encoding HbAT87Q, a modified β-globin gene which produces a form of hemoglobin less likely to cause sickling when it’s expressed alongside the mutated hemoglobin gene responsible for SCD (HbS). All patients had experienced a minimum of four severe vaso-occlusive events (the most common complication of SCD) in the two years before enrolling in the study. Of the 25 patients who could be evaluated, only three experienced moderate vaso-occlusive events, and none experienced any severe vaso-occlusive events. Total blood hemoglobin was also observed to increase.  Median of follow-up was 17.3 months, with some patients followed for up to 37.6 months.
10. Intellia Therapeutics (based in Cambridge, MA) and Regeneron Pharmaceuticals (based in New York) have announced updated data from their ongoing Phase I study evaluating NTLA-2001 as a single-dose treatment for transthyretin amyloidosis (ATTR). ATTR is a progressive disease resulting from the accumulation of amyloid fibrils of misfolded transthyretin (TTR) protein, particularly in nerve and heart tissue, causing amyloid polyneuropathy or cardiomyopathy.  NTLA-2001 is a CRISPR/Cas9 in vivo genome editing therapy designed to selectively cleave and silence the TTR The therapy was generally well-tolerated, and treatment resulted in a dose-dependent reduction in mean serum TTR levels which was sustained through the last measured timepoint (from 2 to 6 months for the high dose cohort, out to 12 months overall).  Mean TTR reductions of 52%, 87%, 86%, and 93% were observed in each of the four dose cohorts (0.1 mg/kg, 0.3 mg/kg, 0.7 mg/kg, and 1.0 mg/kg, respectively), and reductions were consistent all but the lowest dose cohort.  Intellia plans to begin a dose-expansion cohort in patients with ATTR polyneuropathy in the first quarter of 2022.  (See Cell and Gene Therapy Business Outlook vol. 1, issue 3, pg. 16 for a more information on Intellia Therapeutics’ NTLA-2001 therapy.)
11. PerkinElmer, based in Waltham, Massachusetts, has announced that its Germany-based subsidiary SIRION Biotech will collaborate with the Centre for Genomic Regulation (CRG) in Barcelona, Spain to develop adeno-associated virus (AAV) vectors for gene therapy treatments for type 1 and type 2 diabetes in the pancreas. The collaboration will leverage SIRION’s experience with capsid discovery and viral vector development with CRG’s understanding of genetic regulatory mechanisms to develop AAV vectors that can target specific cell types in the pancreas and express therapeutic genes in response to cell-specific regulatory elements.