Tag Archives: science

The Needle Issue #8

24 Jun
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

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 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.

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.

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The Needle Issue #7

10 Jun
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

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.

​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.

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.

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The Needle Issue #5

28 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

Last week’s ASGCT 2025 provided a stark contrast between excitement around DNA- and RNA-editing platforms and commercial interest in traditional gene replacement and cell therapy. Over the past few months, Pfizer decided to stop the commercialization of its hemophilia B gene therapy Beqvez, lentiviral gene therapy flagship Bluebird Bio agreed to acquisition by private-equity firms Carlyle and SK Capital Partners, and earlier this month, Vertex announced its was discontinuing its gene-therapy programs.The remarkable clinical progress achieved with base editing modalities over the past year was highlighted in an ASGCT keynote by Kiran Musunuru of the University of Pennsylvania on the ultra-rare condition carbamoyl-phosphate synthetase 1 (CPS1) deficiency. The fact that the UPenn group were able to design, preclinically validate and bring the treatment to a child in just 7 months is staggering:

Source: New England Journal of Medicine

Writing in the New England Journal of Medicine, the team led by Musunuru and Rebecca Ahrens-Nicklas describe the development of a personalized base-editing therapy with guide RNAs designed to remove the UGA stop codon in a neonate diagnosed with a Q335X variant of CPS1. Using an adenine base-editor, the team designed a bespoke, corrective therapy delivered in vivo using lipid nanoparticles (LNPs) comprising an ionizable amino lipid (ALC-0307), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and a PEG lipid (ALC-0159).

After preclinical validation in cell lines, mice and non-human primates, the authors administered two intravenous doses of the base editor, dubbed ‘k-abe’ — 0.1 mg/kg at seven months of age and 0.3 mg/kg one month later. Following treatment, the patient tolerated increased dietary protein and showed a reduced need for ammonia-scavenging medication, with no serious adverse events. Long-term clinical outcomes and safety remain under evaluation.

One of the most striking features of the study is the speed of therapy development—from diagnosis to treatment in a mere seven months, during which the team had to create cell and mouse models of the disease, screen various base editors with guide RNAs covering the site of the mutation to identify the most efficient approach, carry out toxicological assays in non-human primates, and obtain FDA regulatory approval to treat the child. The workflow reported represents a blueprint for rapid development of customized gene-editing therapies for patients with ultra-rare variants and provides one of the first glimpses of a coming era in advanced therapeutics.

The FDA has taken a very progressive attitude regarding N-of-1 therapies that involve platform technologies such as base editing. An accompanying Editorial in the NEJM, authored by Peter Marks, former Director of the FDA’s Center for Biologics Evaluation and Research, elaborates on the need for a regulatory approach that takes advantage of the data from the elements that remain consistent from one therapeutic product to the next, while allowing the customization required for individual patients — in the case of base editors, a short sequence of guide RNA.

Of course, despite the openness of regulatory authorities, several hurdles remain before bespoke DNA and RNA editing therapies becomes a reality. Among them, manufacturing, scalability and distribution are particularly problematic, and represent the biggest challenges for big pharma to address before widespread adoption of such approaches. Also, existing lipid nanoparticles preferentially travel to the liver. Targeting other organs remains a huge challenge for the field so ultrarare liver disease will remain the option in reach for base editing in the near term. But despite these concerns, we think that the report by Musunuru and his colleagues is a milestone in the development of genetic medicines and underscores the potential of gene-editing approaches to deliver bespoke cures for ultra-rare diseases.

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The Needle Issue #4

20 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

Lipid nanoparticles (LNPs), like those used in the FDA-approved siRNA drug Onpattro, remain the delivery vehicle of choice for mRNAs, gene-editing and base-editing therapies. One drawback of intravenously administered LNPs is adsorption of apolipoprotein E triggers rapid liver uptake via low-density lipoprotein (LDL) and other receptors on hepatocytes. This results in a relatively short half-life and limit application of LNPs in other organs. Peter Cullis, from the University of British Columbia, and his team report in Nature Communications a new LNP design that promises to enhance their lifetime in the blood.

In previous work, the team had established that LNPs consisting of an oil droplet of ionizable lipid like MC3, surrounded by a monolayer of bilayer-forming lipids like egg sphingomyelin and cholesterol, further surrounded by a proper lipid bilayer lasted longer in the circulation. In their new study, they systematically modified the ratio of bilayer lipid to ionizable lipid (RB/I) and found that LNPs with RB/I=4 showed liposomal morphology, high mRNA encapsulation efficiency, and excellent transfection properties in vitro and in vivo. Moreover, these LNPs with high proportions of bilayer forming lipids lasted longer in the circulation and showed higher transfection efficacy in lymph nodes and pancreas than Onpattro-like LNPs.

Cullis and his colleagues propose that the prolonged blood circulation lifetime is attributed to reduced plasma protein adsorption. The transfection competency of liposomal LNP systems is attributed to export of the solid core containing mRNA from the LNP as the endosomal pH is lowered. Their transfection potency, in turn, appears to depend on the cytoplasmic release of complexes that include mRNA and ionizable lipid, complexes that are generated as the endosome matures and its pH decreases. This work represents a promising strategy to increase the therapeutic index of drugs delivered by LNPs.

The new LNPs are being developed by Nanovation Therapeutics, a preclinical startup co-founded by Cullis in 2021. In September, Nanovation clinched a $600 million deal with Novo Nordisk to license worldwide rights to its long-circulating LNPs for extra hepatic delivery of two base-editing therapies for rare genetic diseases, and up to five additional targets in cardiometabolic and rare diseases. Cullis is a serial entrepreneur who has founded several companies around lipid-based delivery systems for nucleic acid-based drugs, including Inex Therapeutics/Protiva Biotherapeutics/Tekmira/Arbutus Pharma and subsequently Acuitas Therapeutics, which developed the MC3 LNP for Onpattro in collaboration with Alnylam Pharmaceuticals. The group also collaborated with Drew Weissman of the University of Pennsylvania on LNPs for mRNA vaccines, which lead to their use in mRNA COVID-19 vaccines.

To be a broad platform for the liver and beyond, LNPs must compete with several other delivery modalities, such as viral vectors and conjugates. In liver delivery, triantennary GalNAc-conjugated siRNAs, which target asialoglycoprotein receptors on hepatocytes, are now the delivery vehicle of choice for liver-targeted siRNAs. Apart from circulation lifetime, another issue that LNPs must contend with is organ accessibility due to fenestrations in blood vessels. In the case of the liver, pancreas, and bone marrow, pores are greater than 60 nm, allowing LNPs access to tissue. For mRNA vaccines, blood filtering lymph nodes also represent an excellent LNP target. However, tissues, such as brain (with its accompanying blood brain barrier), muscle and kidney have much tighter fenestrations (<15 nm), presenting an uphill delivery challenge for intravenous LNPs.

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The Needle Issue #3

13 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

A growing stable of biopharma companies are developing biparatopic antibodies, which hit the same target via two non-overlapping epitopes. Compared with monospecific mAbs, such antibodies display enhanced binding through increased avidity, slower target dissociation, improved internalization, and greater specificity against drug target families where members share significant structural similarity. Now in the Journal of Clinical Investigation, a group at the Broad led by William Sellers describes biparatopic mAbs that inhibit fibroblast growth factor receptor 2 fusions, which are found in a variety of cancers, including intrahepatic cholangiocarcinomas (ICCs).

Sellers and his team showed that their mAbs inhibit signaling through FGFR2 fusions and inhibit ICC proliferation. They generated a panel of 15 biparatopic antibodies from 6 parental human antibodies and systematically tested them for their anti-proliferative activity on cells expressing FGFR2 fusions. Two showed greater potency than the parental antibodies, both in vitro and in vivo. Moreover, these biparatopic antibodies potentiated the action of FGFR2 inhibitors on cancer cells, and their inhibitory effect persisted, even against FGFR2 fusions with mutations that drive drug resistance. Mechanistically, the biparatopic antibodies promoted internalization and lysosomal degradation of FGFR2 fusions.

Sellers is also a scientific founder of Cambridge, Mass-based RedRidge Bio, which was funded in March via an undisclosed Series A venture round. Another recent startup, Attovia, took its first VHH biparatopic nanobody program against IL-31 into the clinic earlier this year and is collaborating with SciNeuro Pharmaceuticals on a neurology target.

The FGFR2 fusion work follows in the footsteps of studies by Regeneron demonstrating that biparatopic antibodies are effective inhibitors of oncogenic fusions of other receptor tyrosine kinases (RTKs). In that work, Regeneron researchers targeted fusions of another FGFR family member, FGFR3. In theory, the approach should be generalizable to any cancer arising from RTK fusions.

Biparatopic antibodies can work either in cis (binding the same target twice) or trans (binding two different molecules of the same target; e.g., to facilitate receptor clustering). Although they have been in clinical testing since 2011, it took until 2022 for the first biparatopic product to reach the market. Nanjing, China-based Legend Biotech (now J&J) got FDA approval for a T-cell therapy against refractory multiple myeloma featuring a chimeric antigen receptor (CAR) based on two single-domain antibodies targeting two different epitopes on B-cell maturation antigen (BCMA). Last November, FDA also gave the green light to Jazz Pharmaceuticals and Zymeworks’s zanidatamab, a biparatopic mAb that binds HER2 in trans and is indicated for patients with HER2-positive biliary tract cancer.

Similar to the antibody drug conjugate (ADC) space, a commercial stampede is currently underway in China to develop biparatopic mAbs against HER2, with at least 4 companies (Xuanzhu Biopharm, Alphamab Oncology, Chia Tai Tianqing Pharmaceutical and Beijing Mabworks) with products in clinical development. Given that big pharma has yet to make major announcements around biparatopic mAbs—notwithstanding AstraZeneca’s/Medimmune’s discontinued effort to develop MEDI4276, an anti HER2 ADC based on a biparatopic scaffold— the recent co-development partnership deal between Pierre Fabre Laboratorie and RedRidge Bio likely augurs more deal activity around this antibody modality in the near future.

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The Quest for the Perfect Investor Fit: How Much Does Life Science Expertise Matter?

2 Oct

By Danielle Silva, Business Development, LSN

Here at LSN, I speak with many life science entrepreneurs about investor fit. Typically, life science executives believe that fit is a one-way street, meaning that they need to do all they can to prove they are a fit for a prospective investor. While it is certainly true that an integral part of the fundraising process is proving that your company is a fit for the firm’s investment thesis, this is not a one-sided negotiation. It is just as important for life science companies to make sure a potential investor is a fit for what the firm is looking to attain, and therefore, finding a potential investor needs to be both a strategic and tactical play.

What many life science CEOs struggle with is whether they should favor investors that have expertise in a particular area versus investors that are experienced in a certain phase of development. The answer, by and large, depends on what the life science company is looking to achieve in the long run, but there is of course no easy answer to this dilemma. Many entrepreneurs consider the problem a simple one – why would you want an investor that doesn’t understand your technology, or one who does not have expertise in your particular indication area?

While it is certainly important for investors to have a basic understanding of your disease area, this is only truly important if you are seeking scientific advisors for your firm. If this is the case, then finding a partner that has expertise in your disease area may be favorable to finding an investor that has knowledge of your stage of development. But what if, conversely, the executive is seeking a quick exit or a recapitalization? In this case, it may be more attractive to find an investor with a laser focus on your particular area. These investors already have a great knowledge of the space and thus probably already have a solid network that will be willing to acquire the company once the firm hits certain milestones.

Most life science executives I speak with, however, are not seeking scientific advisors, and instead are seeking investors with the business acumen to help take their product from discovery to distribution. These companies would benefit from a relationship with an investor that has knowledge of their particular phase of development, and who can thereby help to scale their business. It is also very beneficial for companies to be partnered with investors who have a deep knowledge of their phase of the clinical development cycle. These investors will have the expertise to help life science firms partner with appropriate firms in the R&D services space (such as CROs and other service providers).

Again, there is no clear solution to this problem. If your company is seeking an investor with a deep network in the space, then choosing an investor with sector expertise may be the answer. These investors, however, may not be able to help you scale your business to the point where your firm is an attractive investment or acquisition target for a larger investor within their network. Simply put, the answer is convoluted, no investor is the same, and everyone brings something different to the table. Life science executives should clearly define their goals in terms of growth and exit before deciding on an investor based on sector fit versus development phase fit.

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Creating a Dialogue with Life Science Investors

2 Oct

By Dennis Ford, CEO, LSN

I write about this subject often – I guess the main reason is that if I can get the message right, I can help educate life science fund-raisers that a current and accurate map does exist for raising capital. If you are in fundraising mode, please have an updated map. There, I said it!

The most interesting component of the fundraising dynamic is the concept of “introduction”. Scientist meets investor, buyer meets seller. One of the initial goals of any fundraising campaign is to get in front of potential investors, and this can be done in two general ways: the first being referral, and the second, fit. I will agree that a referral is often a good way to get a meeting, but many believe that it is the only way to get to a decent investor target.

Being a street-savy salesperson, I always get a bit riled when someone announces that referrals are the only way in. I mean, what if you get referred to an investor and he just simply doesn’t have a current mandate to invest, and if he did, it would be a medical device and you happen to be a therapeutic? My point here is that even though a referral may get you some preferential treatment in the form of a first meeting, there always needs to be a good fit. After all, it’s the final meeting that really counts. I am a big fan of the referral, but I am an even bigger fan of fit.

In my “sales guy mind,” the highest form of a qualified investor lead is a declared fit. A declared fit boils down to this: an investor actively declares a targeted and specific intent on investing in a certain part of the market. I think that is the highest form of investor target – self-declared mandate from the mouth of an potential investor. I mean, what else would a fundraiser want? OK, maybe I shouldn’t have asked that question… because I know the answer: a referred introduction, right?  No, wrong!

Of course, if you know someone who can provide an intro, that’s great. Sans that magical referral/intro, if you are a fit for the declared mandate, all you have to do is tell him via email or phone that you know what they are seeking and you are a fit. Honestly, that’s how it works. Spamming gets you a 1-2% hit rate, but reaching out based on fit gets you a 20-30% hit rate. Why? Because you match what the investor is looking for. Being armed with the knowledge of an investor’s current interest gives you the power to refer yourself.

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