What do analysts think will be the top 10 drugs in the year 2031 (as searched in GlobalData)?
Top 10 in the US in 2031 (USD Millions)
In the US analyst forecasts for 2031, obesity dominates (with immunology, derm and infection for other TAs). Along with the obesity peptides are 2 small molecules and 2 MAbs. The sales are in the tens of billions.
Top 10 in Europe (USD Millions)
In Europe, along with the obesity drugs and dupixent in derm, we see the oncology ADC Enhertu, the ang2 ophthalmology drug Vabysmo, a CNS CD20, and a GI integrin in the top 10. Sales are in the single digit billions.
Top 10 in Japan (USD Millions)
In Japan, obesity is not visible in the top 10. An anti-infective tops the list, followed by CNS, oncology, GI and including heme disorders. There are companies not in the top 20 for global sales. Most of the top 10 have sales below $1B.
Top 10 in China (USD Millions)
For China, obesity is back in the top 10, but Gardasil, an oncology HPV vaccine tops the list. Local company “fast followers” are apparent and most of the top forecasted drugs are not yet launched (presumably a reflection of the rapidly evolving pharmaceutical environment). To get into the top 10, sales are above $500M.
Conclusion: The marketplace for drugs shows considerable variation in different regions around the world.
Just over a week ago, AbbVie paid $2.1 billion for Capstan Therapeutics’ in vivo anti-CD19 chimeric antigen receptor (CAR)-T cell therapy (CPTX2309) for B cell-mediated autoimmune disorders, which is currently in phase 1 testing. In the past few days, EsoBiotec (acquired by AstraZeneca earlier in the year) also published its first clinical data on a lentiviral-delivered anti-B-cell maturation antigen (BCMA) CAR-T approach (ESO-T01) for multiple myeloma, detailing responses in four patients, two of whom showed complete remission. With a host of other companies working on in vivo delivery into endogenous T cells—including Interius BioTherapeutics, Umoja Biopharma, and Orna Therapeutics, the field of in vivo delivered CAR-T cells appears poised at a tipping point.
Ex vivo generation of CAR-T cells (left) is a complex and lengthy procedure, entailing isolation of T cells from patient blood (1), followed by activation, transduction, and ex vivo expansion for several weeks. After undergoing conditioning treatment (2), patients are infused with a bolus of expanded CAR-T cells (3). In the in vivo approach (right), delivery vector (targeted LNPs or lentiviruses, depicted as red dots) are infused directly into the patient, where they encounter T cells and selectively deliver genetic material encoding the CAR (red). Source:Â Molecular Therapy.
Since transforming the face of cancer treatment in 2017, autologous CAR-T cell therapy has been dogged by logistical issues that have limited commercial rollout and increased costs—the need for leukapheresis, laborious cell harvesting, heterogeneous cell expansion, lengthy turnaround times, and inconsistency of batches—with access limited to just a few clinical centers. Extensive waiting lists can mean many patients die before even being treated, which has driven the search for ex vivo approaches that shorten manufacturing times using fully closed systems and/or miniaturization. Given these challenges, delivery of a CAR-encoding mRNA to a T cell in vivo could be a game-changing technology: No need for viral vectors; no leukapheresis/chemo; no ex vivo manipulation, no requirement for multiple patient hospital visits; no convoluted training of personnel; and no risk of second primary T-cell cancers due to insertional mutagenesis. This last issue has loomed over the field, with all CAR-T therapies carrying black box warnings, although at the end of June the FDA removed all requirements for Risk Evaluation and Mitigation Strategies (REMS).
​Writing in Science, the founding team of Capstan Therapeutics, headed by Carl June and Bruce Levine at the University of Pennsylvania and Haig Aghajanian of Capstan, report proof of concept data that functional CAR T cells with antitumor activity can be produced in animal models without any ex vivo manipulation. A key breakthrough in their effort was the development of lipid nanoparticles (LNPs) specifically designed to target T cells and to overcome the propensity of LNPs to accumulate in the liver. To avoid this problem, the authors screened a set of ionizable lipids to identify L829, a lipid that incorporates a tertiary amine headgroup that reduces non-specific interactions with the hepatic system due to its pH-dependent protonation and neutral charge. Ester cleavage sites in the lipid also promote rapid breakdown in, and clearance from, hepatocytes. A final step was to decorate L829 LNPs with a mAb targeting CD5, a T-cell specific marker. The resulting LNP showed limited liver uptake in rodents and non-human primates compared with control LNPs.
To test the potential of L829-containing LNPs to generate functional CAR-T cells, the team engineered them to incorporate 1) mRNA encoding a CAR that binds CD19 on B cells and 2) an antibody targeting CD8+Â T cells. These CD8-L829-CD19 targeted (t)LNPs successfully delivered the mRNA in vitro to CD8+Â T cells from healthy subjects and from people with B cell-mediated autoimmune diseases. In vivo, these CAR T cells had anti-tumor activity in a humanized mouse model of B cell acute lymphoblastic leukemia.
The Capstan approach to CAR-T cell therapy: An IV bag, a targeted LNP, and an mRNA encoding the CAR of interest. Source:Â Science.
In cynomolgus monkeys that received repeated doses of CD8-L829 tLNPs containing anti-CD20 CAR mRNA (instead of anti-CD19, which is not cross-reactive between human and monkey), sustained B-cell depletion was observed that lasted for one month. Importantly, reconstituted B cells were predominantly naïve, implying an immune reset — a key therapeutic goal in autoimmunity.
The Capstan in vivo mRNA-encoded CAR T platform eliminates the need for ex vivo manipulation and lymphodepleting conditioning. It avoids the risks often associated with the use of viral vectors that integrate into the genome. It also is transient, allowing dosages to be optimized and quickly stopped if patients suffer adverse events associated with neurotoxicity or cytokine-release syndrome. It will be interesting to see whether the approach is scalable and whether it can open up conditions where long-term CAR-T cell persistence might not be necessary, such as autoimmune disease.
Going forward, an important question will be to determine the potential immunogenicity of the tLNP formulation (especially as the mRNA treatment may be given multiple times), and whether tLNPs cause elevations of human liver enzymes like alanine transaminase or aspartate aminotransferase. Liver toxicity of a novel liposome formulation already caused a clinical hold for Verve Therapeutics’ base editing therapy last year. Future work will also need to define optimal dosing, durability, and long-term safety of this approach. But the work of June, Aghajanian and their colleagues is a compelling advance promising a new era of widely available adoptive T-cell therapies for B-cell driven hematological cancers and autoimmune conditions. A single dose of any of the seven currently approved commercial ex vivo CAR-T therapies costs ~$500,000. A vial of an in vivo treatment is likely to cost an order of magnitude less.
MindLab took the top spot in June’s Innovator’s Pitch Challenge (IPC) at RESI Boston, standing out among dozens of early-stage life science companies who pitched to panels of active investor judges. In this brief interview, we speak with the MindLab team about their fundraising goals, experience participating in RESI, and what’s next for the company.
Watch the interview:
Interested in pitching your company at RESI?
Applications are now open for the Innovator’s Pitch Challenge at RESI Boston, September 17, 2025. Selected companies receive full access to the conference, partnering meetings with investors, and exhibit space in the RESI Exhibition Hall. New! The September 2025 IPC Pitch Package now includes an optional second RESI pass at no additional cost, allowing an additional team member to attend and participate in partnering. Apply now!
Acceleration of laboratory-based technical and computational cross-fertilization, and ethical and cost pressures on regulatory bodies and therapeutic innovators is driving advancements in preclinical human-based technologies.
Organ (Lab)-on-chip (OoC/LoC)is one of the most striking examples of new translational research technology expansion with ~35% CAGR expected over the next decade (below).
Collaborations between academia and CRO’s are driving improvements in organoid technology for the field of oncology broadly and are expected to improve OoC adoption. Academic innovation using commercial OoC technology is also advancing applications in specific indications in oncology. CRO’s continue to build off established uses in ADME and toxicology to explore R&D applications in oncology space and have even combined organ systems to support elaboration of multiple drug parameters in a single assay.
DEALS
The Tara Biosystems – Valo Health deal is a nice example of how an organ-on-a-chip technology approach has driven collaborations, acquisitions and deals:
Tara Biosystems and GSK collaborate on CV drug profiling (2019)
Valo Health acquires Tara Biosystems for CV OoC platform (2022, ~$75M upfront)
Valo and Novo Nordisk sign CV drug discovery deal (2023, $60M upfront, $2.7B total)
Emulate, TissUse and Mimetas have also been backed by strong big pharma collaborations (AstraZeneca, Bayer, Roche) and funding rounds.
​Drug development efforts targeting the constitutive 26S proteosome have led to the development of several important multiple myeloma (MM) and mantle cell lymphoma treatments, including the first landmark FDA approval of Millennium Pharmaceuticals’ (now Takeda) dipeptide boric acid Velcade (bortezomib) in 2003 and second-generation molecules, such as Amgen/Ono Pharmaceutical’s irreversible inhibitor Kyprolis (carfilzomib) and Takeda’s orally available inhibitor Ninlaro (ixazomib). Second-generation versions of these ‘pan-proteosome’ drugs have longer duration of effect, reduced peripheral neuropathy and increased safety in renally impaired patients, but may cause gastrointestinal and cardiac toxicity. This toxicological profile has shifted attention to developing inhibitors selective for an alternative form of the core 20S proteosome—the immunoproteasome, which processes peptides for presentation to CD8+ T cells in the MHC-I complex and is constitutively expressed only in hematopoietic cells, induced in immune cells stimulated in the presence of IFN-γ, and upregulated in certain cancers like MM.
The β1 subunit (particle components beta subunit 6; PSMB6), β2 subunit (PSMB7), and β5 subunit (PSMB5) found in the constitutive 26S proteasome (left) are replaced in the immunoproteasome (right) by the β1i subunit (low molecular mass polypeptide 2 (LMP2)/PSMB9), β2i subunit (multicatalytic endopeptidase complex-like 1 (MECL-1)/PSMB10), and β5i subunit (LMP7/ PSMB8), respectively. Existing inhibitors and their sites of action are indicated. Adapted from https://bit.ly/4kgmQj9​
Currently, Kezar Life Sciences’ is furthest along in development; in April, it completed a phase 2a trial in autoimmune hepatitis of zetomipzomib (KZ-616), a small-molecule that inhibits both the immunoproteasome core particle component beta subunit 8 (PSMB8; LMP7/β5i) and PSMB9 (LMP2/β1i). Merck kGaA (Darmstadt, Germany) is also pushing forward with a phase 1 clinical program of M3258, a small-molecule inhibitor specific for PSMB8 and intended for use in MM (Principia Biopharma’s selective PSMB8 inhibitor was swallowed up by Sanofi in 2020 when the pharma acquired the San Francisco-based biotech’s Bruton’s tyrosine kinase inhibitor program). Elsewhere, Leiden University startup iProtics recently received a €200K grant from the Dutch Biotech Booster to develop selective immunoproteosome inhibitors, while Auburn University spinout Inhiprot (West Lebanon, NH) received SBIR funding to develop a dual PSMB6/PSMB9 inhibitor for MM. Now, a new study reveals immunoproteosome targeting may also have benefits in neuroinflammatory diseases like multiple sclerosis.
The work, published in Cell and led by Catherine Meyer-Schwesinger and Manuel Friese, from University Medical Center Hamburg-Eppendorf, identifies a neuron-intrinsic mechanism of neurodegeneration in multiple sclerosis (MS) driven by the immunoproteasome.
Under healthy conditions, neurons utilize the constitutive proteasome subunit PSMB5 to regulate proteostasis and degrade 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a potent stimulator of glycolysis. This degradation is key because neurons rely more on the pentose phosphate pathway than on glycolysis to produce antioxidants like NADPH and glutathione for protection against oxidative stress.
However, Meyer-Schwesinger, Friese and their colleagues show that, during neuroinflammation, chronic exposure to interferon-γ leads to the induction of the immunoproteasome in neurons, triggering the replacement of constitutive proteosome PSMB5 (β5c) with PSMB8 (β5i). This subunit swap in neurons reduces proteasomal activity, resulting in accumulation of PFKFB3, which in turn enhances glycolysis, diminishes the activity of the pentose phosphate pathway, and impairs redox homeostasis — conditions that sensitize neurons to oxidative injury and ferroptosis.
Interferon-induced immunoproteasome markedly decreases proteasomal activity in neurons, leading to a switch in neuronal metabolism from oxidative phosphorylation (left) to glycolysis accompanied by oxidative injury and ferroptosis (right). Source:Â Cell
The team showed that this mechanism was operational in both experimental autoimmune encephalomyelitis (EAE; a mouse model of MS) and brain tissue from MS patients. Moreover, neuron-specific knock-out of Psmb8 or pharmacological inhibition using the small-molecule PSMB8 inhibitor ONX-0914 (originally developed at Onyx Pharmaceuticals/Proteolix) protected neurons in vivo from inflammation-induced damage. Similarly, blocking PFKFB3 with the small-molecule inhibitor PFK-158 or through conditional knockout in neurons reduced disease severity in EAE, prevented neuronal and synaptic loss, and reduced markers of oxidative stress and lipid peroxidation.
It is important to highlight that, unlike cancer or immune cells, neurons do not upregulate PSMB8 in response to a series of MS-related cytokines. So, the neuron-specific effect reported in this study might only become active upon chronic neuroinflammation (i.e. chronic exposure to interferon-γ). Understanding this mechanism might reveal new targets related to the immunoproteosome in the treatment of MS.
This brings us to challenges for translational efforts seeking to develop immunoproteosome inhibitors against MS. Several important neuronal processes, such as synaptic transmission and calcium signaling, are tightly linked to proteasome function; thus, pan-proteosome inhibitors like Velcade could be detrimental to the CNS. The saving grace of approved proteosome inhibitors is that current chemotypes (boronate-based peptides or epoxyketone-based binders) do not cross the blood brain barrier, at least in healthy individuals. Thus, any MS program might need to use intrathecal injection for compounds derived from existing chemical series or engage a medicinal-chemistry effort to design molecules that can breach the BBB and retain potency.
The gambit for immunoproteosome-selective drugs is that they avoid inhibiting constitutive 26S proteosome activity in most tissues (and non-inflammed CNS), which is what makes Velcade and its derivatives so difficult for patients to tolerate; an immunoproteosome inhibitor should therefore have a more favorable safety profile. But so far, immunoproteosome-targeting drugs have had their own share of toxicity problems in the clinic.
Last October, Kezar abandoned its program for zetomipzomib in lupus nephritis after the FDA placed a clinical hold on the trial after 4 patient deaths. The agency placed a second partial hold on the company’s autoimmune hepatitis trial in 24 patients last November due to concerns about steroid control and injection site reactions in 4 patients who were waiting to roll over into the open-label extension arm. Concerns about compromised immune surveillance of acute or latent viral infections due to hobbled antigen processing and presentation would also need to be explored.
In sum, the new work provides strong evidence that the immunoproteosome plays a key role not only in inflammation or infiltration of immune cells, but also in a metabolic switch in neurons which is a key driver of vulnerability in MS. It will be interesting to see whether either targeting immunoproteosome component PSMB8 or taking a completely different tack, blocking PFKFB3, will prove more practical as a neuroprotective strategy in MS.
Around 1 in 5000 people live with a maternally inherited mitochondrial disease like MELAS, Leber’s Hereditary Optical Neuropathy (LHON) or MIDD, for which there are limited or no treatment options. Gene- and base-editing therapies for mitochondrial DNA (mtDNA) have lagged behind CRISPR–Cas9-based approaches targeting nuclear genes. Whereas there is already a CRISPR–Cas9-based product on the market and >150 different active trials of investigational therapies, the company closest to the clinic with an I-CreI (mitoARCUS) meganuclease targeting a mtDNA point mutation in MELAS/mitochondrial myopathy (Precision Biosciences) announced last month that it was pausing development for commercial reasons.
Despite this disparity, there is reason for optimism as a flurry of different types of optimized cytidine and adenine base editors for mtDNA are now available, with base conversion efficiencies of 50% now achievable, and some newer formats reaching efficiencies as high as 82%.
The major types of mitochondrial base editors (above) and a selection of common mitochondrial diseases with their associated mutations (below). Source: Adapted from Hong, S. et al Cells 12, 2494 (2023).
The development of mtDNA editors is not without challenges. First, editors must dispense with the targeting guide RNA, as mitochondria possess a double membrane that lacks any RNA transport system, effectively thwarting CRISPR-based gene or base editors (instead, a mitochondrial targeting sequence is used to ferry-in editor proteins). Second, unlike nuclear DNA with two copies of a gene, every human cell contains thousands of mitochondria — oocytes contain a whopping 193,000 mitochondria on average — and each organelle contains an average 10 mitochondrial genomes. Those ~10,000 genomes per cell may not all have the same sequence, with mutations existing in a state known as heteroplasmy, in which both mutant and wild-type genomes co-exist in the same organelle. Disease only occurs when the percentage of mutant mtDNA exceeds a particular threshold, typically between 70% and 95%.
Heteroplasmic mitochondrial diseases, like MELAS and MIDD, could be treated using I-Crel/FokI meganucleases or restriction enzymes linked to either transcription activator-like effector (TALE) domains or zinc fingers (which introduce double-strand DNA breaks into target sequences, leading to elimination of mutant mtDNA and repopulation of wild-type mtDNA); other conditions like LHON are predominantly mutant homoplasmic, which means they can only be treated using base editors or supplemental gene therapy.
One key concern with base-editing technology has been its propensity for off-target and bystander changes. This has led to various strategies to increase specificity, such as engineering the deaminases to narrow the editing window or use of nuclear exclusion sequences to stop nuclear sequence editing. Now, two papers in Nature Biotechnology represent important advances that could speed up translational studies of mitochondrial diseases.
Liang Chen, Dali Li and their colleagues of ShanghaiTech University, China report the engineering of highly efficient mitochondrial adenine base editors (eTd-mtABEs) by introducing mutations into the TALE TadA-8e deaminase for greater activity and specificity. These editors achieved up to 87% editing efficiency in human cells and over 50% in vivo, with reduced off-target effects compared to earlier tools.
In the first study, the researchers used eTd-mtABEs to introduce mutations in the human ND6 gene, encoding a subunit of the oxidative phosphorylation (OXPHOS) system linked to LHON and Leigh syndrome. They found reduced levels of ATP and more reactive oxygen species in the edited cells compared with controls, consistent with disease phenotypes. Next, the team used this adenine TALE base editor to introduce two pathogenic T-to-C mutations in the mitochondrial TRNS1 gene of rat zygotes, a gene linked to childhood-onset sensorineural hearing loss. The resulting offspring showed sensorineural hearing loss, which was transmitted to the F1 generation, providing proof of concept that eTd-mtABEs can be used to create animal models of disease.
Adenine base editors delivered into rat zygotes inserted a mutation in mtDNAÂ TRNS1Â that results in sensorineural hearing loss that is stably inherited from one generation to the next (left). Mitochondrial adenine base editors injected into rat zygotes inserted a disease mutation in mtDNAÂ ND6Â that leads to loss of vision (right); when zygotes from these animals were injected with mitochondrial cytosine base editors, they gave rise to animals free from disease symptoms. Source:Â Nature Biotechnology.
In the companion paper, Chen, Li and their colleagues used the adenine TALE base editor to model Leigh disease in rats using a similar strategy. The resulting rats showed reduced motor coordination and muscle strength, defects that were obtained with editing efficiencies of only 54% on average. To test if the abnormalities could be reversed, the authors then used a cytosine TALE base editor in zygotes from the mutant rats. On average, the editing efficiency was only 53%, but this was enough to rescue the disease phenotypes.
This is the first report of direct correction of mtDNA mutations via a TALE base editor in an animal model. The next step will be to show feasibility in a model after disease onset (only the UK and Australia allow maternal spindle transfer therapy for mitochondrial diseases; no country has permitted mitochondrial base editing in human zygotes).
Achieving effective therapeutic mitochondrial base editing in affected target tissues will thus require efficient AAV delivery. For LHON, an already approved FDA AAV-2 product transduces the optic nerve and retinal ganglion cells, providing a translational path; ​GenSight Biologics also recently published 5-year outcome data for its AAV-2 therapy Lumevoq (lenadogene nolparvec) in LHON. But AAV delivery in other mitochondrial conditions will not be as simple: MELAS patients, for example, require efficient transduction of the CNS, kidney, skeletal muscle and cardiac muscle; MIDD patients need AAV delivery to the pancreas, inner ear, retina and kidney. Although a commercial AAV vector (AAVrh74) is available for muscle (Sarepta’s Elvidys), vectors that reach many of these other tissues have yet to be commercialized and may require next-generation AAV capsids and/or refinement of machine-guided design of cell type-specific synthetic promoters to reach target organs.
It is encouraging that the roughly 50% base conversion rate achieved in these new studies exceeded the heteroplasmy threshold required for disease manifestation and therapeutic rescue. At the same time, despite this remarkable success, concerns remain about off-target effects — both in mitochondrial and nuclear genomes — and narrow therapeutic windows. And with base editing approaches so far behind conventional gene therapies like Lumevoq in development, compelling commercial and clinical advantages benchmarked against best-in-class gene therapy will be needed to convince investors to back these approaches.
One parting thought: the past year has seen a noticeable uptick in publications on mitochondrial base editing technology from labs outside of the US. TALEN specialist Cellectis, headquartered in Paris, France, acquired 19% of equity in the mitochondrial base editing company Primera Therapeutics in 2022, ostensibly for its rapid TALE assembly platform (FusX System), which streamlines TALE repeat construction. In South Korea, Jin-Soo Kim at the Korea Advanced Institute of Science and Technology (KAIST) recently co-founded startup Edgene with Myriad Partners to develop mitochondrial base editors based on his seminal work on TALE-linked deaminases (TALEDs) enabling A to G conversion, which he has continued to optimize. According to Biocentury, 8 out of 13 base editing studies published in 27 translational journals over the past year came from labs in China. Wensheng Wei’s group at Peking University, a founder of Edigene in Beijing, continues to work on mitobase editors, with two recent patents on strand-selective mitochondrial editing. And Jia Chen of ShanghaiTech University, China, and his collaborators Li Yang and Bei Yang, are scientific advisors to Correctseq in Shanghai, which is developing transformer base editors for ex vivo and in vivo applications. It seems that mitochondrial base editing may be another area where US biotech may soon be finding itself chasing the dragon. David Liu and Beam Therapeutics may have something to say about that.
Ex vivo HSC lentiviral gene therapies have been on the market for nearly a decade, with six products approved and at least 55 now in clinical testing for rare inherited diseases, HIV infection or cancer. And yet, their commercial success remains in question. Bluebird Bio—which was valued at $10 billion only a few years ago and successfully shepherded to market Zynteglo against transfusion-dependent β-thalassemia, Skysona for early cerebral adrenoleukodystrophy, and Lyfgenia for sickle-cell disease (SCD)—was sold earlier this year to private-equity firms Carlyle and SK Capital for a measly $29 million. Last November, the company had treated only 57 patients (35 for Zynteglo; 17 for Lyfgenia and 5 for Skysona), with just 28 of 70 medical centers across the US ready to treat patients due to delays in accreditation and training of personnel. In Europe, Orchard Therapeutics halted marketing and production of a treatment for severe combined immunodeficiency caused by adenosine deaminase mutations (Strimvelis) after six years, forcing Fondazione Telethon to take over production. Even market uptake of Vertex’s much-heralded CRISPR/Cas9 BCL11a SCD therapy Casgevy has been sluggish.
These subpar commercial launches relate to the complexity of ex vivo lentiviral gene therapy: patient identification and qualification is lengthy; HSC mobilization and sourcing efficiencies vary due to patient heterogeneity; and manufacture and distribution processes remain lengthy and convoluted (sometimes requiring repetition if a poor quality product batch is generated). From first evaluation, patients are required to make several hospital visits over a period (of up to a year) and must undergo punishing conditioning regimes with lymphodepletive bisulfan before infusion, which itself carries infertility and cancer risks. All of these challenges have added impetus to the search for alternative and more efficient approaches for carrying out HSC gene therapy.
The potentially year-long patient journey for an ex vivo lentiviral HSC therapy (Source: Vertex)
​A group led by Alessio Cantore and Luigi Naldini, from the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, report in Nature that it may be possible to obviate these challenges by delivering recombinant lentiviral vectors in vivo soon after birth, when HSCs continue to circulate in the bloodstream in large numbers and are beginning their transition from the liver (where they are located in the fetus) to bone marrow (where they remain through adulthood).
Cantore, Naldini and their colleagues started by measuring the number of circulating HSCs in neonatal, 1-, 2- and 8-week-old mice, looking at the peripheral blood, spleen, liver and bone marrow. They found that HSCs were present in the circulation right after birth and that their number immediately declined. These cells could be transduced with lentiviruses, successfully engrafted, and persisted in the mice for several months.
Outlines of the experiments testing in vivo lentiviral therapy using a green fluorescent protein marker (top) or adenosine deaminase (ADA) gene construct in ADA-SCID mice (bottom). Source: Nature​
To show that these HSCs could be harnessed to treat genetic disorders, the team tried to correct three mouse models of disease — adenosine deaminase deficiency, autosomal recessive osteopetrosis and Fanconi anemia. Although the therapeutic effect of the cells varied depending on the disease, the results provided compelling evidence for the potential for in vivo gene transfer to HSCs.
The authors reported that human neonates also have circulating HSCs in high numbers. And although the therapeutic window in the mouse only existed during the neonatal period, it was possible to lengthen it by mobilizing the HSCs from their niche in two-week-old animals using protocols in clinical use (granulocyte-colony stimulating factor/CXCR4 antagonist Plerixafor) These observations raise the possibility of therapeutically targeting HSCs in newborns, potentially opening the gates to treatment of a variety of inherited conditions.
Compared with the headaches of ex vivo manipulation, the authors’ concept of simply injecting a lentiviral gene therapy into a newborn to bring about a genetic cure is certainly alluring. But reducing this to clinical practice will require optimization of many different factors. How to account for the heterogeneity and fragility of patient HSCs in a particular disease? How to measure the cellular activation/metabolic state of HSCs in newborns and assess the affect on amenability to lentiviral transduction in the hostile milieu of blood? What effect would shear stress in circulation have on lentiviral transduction efficiencies in situ? What would be the selective engraftment advantage provided to HSCs after engraftment of a particular gene? And what would be the potential safety implications of off-target transduction events in cells other than HSCs, given instances of dysplastic syndromes have been reported with ex vivo lentivectors?
Current ex vivo lentiviral gene therapy like Lyfgenia and Zynteglo infuse between 3–5×106 gene-modified CD34+ HSCs/kg in a patient. The challenge for in vivo lentiviral gene therapy will be to achieve transduction efficiencies that transduce as many cells and obtain similar engraftment rates in the rapidly turning over HSC population. Beyond these issues, there are additional practical challenges: can genetic testing of an infant happen fast enough to take advantage of the short therapeutic window for which an in vivo lentiviral HSC therapy could work?
Clearly, the new work raises many intriguing questions for the lentiviral gene therapy space. And for newborns with genetic diseases, such as severe immunodeficiencies or Fanconi anemia, in vivo HSC gene therapy may open up new treatment options.
The firm is focused on therapeutics companies and does not invest in medical devices, diagnostics, or digital health. The firm is open to considering assets of very early stages, even those as early as lead optimization phase. The firm considers various modalities, including antibodies, small molecules, and cell therapy. Currently, the firm is not interested in gene therapy. Indication-wise, the firm is most interested in oncology and autoimmune diseases but has recently looked at fibrotic diseases and certain rare diseases as well.
The firm is opportunistic across all subsectors of healthcare. Within MedTech, the firm is most interested in medical devices, artificial intelligence, robotics, and mobile health. The firm is seeking post-prototype innovations that are FDA cleared or are close to receiving clearance. Within therapeutics, the firm is interested in therapeutics for large disease markets such as oncology, neurology, and metabolic diseases. The firm is open to all modalities with a special interest in immunotherapy and cell therapy.
A strategic investment firm of a large global pharmaceutical makes investments ranging from $5 million to $30 million, acting either as a sole investor or within a syndicate. The firm is open to considering therapeutic opportunities globally, but only if the company is pursuing a market opportunity in the USA and is in dialogue with the US FDA.
The firm is currently looking for new investment opportunities in enterprise software, medical devices, and the healthcare IT space. The firm will invest in 510k devices and healthcare IT companies, and it is very opportunistic in terms of indications. In the past, the firm was active in medical device companies developing dental devices, endovascular innovation devices, and women’s health devices.
A venture capital firm founded in 2005 has multiple offices throughout Asia, New York, and San Diego. The firm has closed its fifth fund in 2017 and is currently raising a sixth fund, which the firm is targeting to be the largest fund to date. The firm continues to actively seek investment opportunities across a […]
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